2ll B6

PRINCIPTES
OF

votuME - ll

S. S. KADAM
M. Sc.,Ph.D.
PoonaCollegeof Pharmacy,
Principal,
P UNE -4 1 1 0 3 8 .

K. R. MAHADIK
M. Pharm.,Ph.D.
in Pharmaceutical
Professor Chemistry'
PoonaGollegeof PharmacY,
P UNE -4 1 1 0 3 8 .

K. G. BOTHARA
M. Pharm.,Ph.D.
in Pharmaceutical
Professor Chemistry'
Collegeof Pharmacy,
A.l.S.S.M.S.
KennedyRoad,NearR'T.O.'
P UNE -4 1 1 0 0 1 .

errrraiic.4

l nt275
 PRINCIPLES
OFMEDICINAL
CHEMISTRY:
Vo|umeII lsBNN0.978€1€5790i3+
$ghteenthEdition : September,2007
Reprint
Edition : January,2OO9
: Dr.K. G.Bothara
Price : Rs.350,US$ 35.00
Thetext of this publication,or any part thereof,shouldnot be reproduced or transmittedin anyform or storedin anycompc.-er=:rae
includingphotocopy,
systemor devicefor distribution recording,
tapingor informationretrieved
systemor reproduced on anydisc,uip€.ce--r-E.Ec
mediaor other information storagedeviceetc. withoutthe writtenpermission of Authorswith whornthe rightsare reserved.BreaJ.r :rs
condition
is liableforlegalaction.
Everyeffort has beenmadeto avoiderrorsor omissions in this publication.
In spiteof this, errorsmaycreepin. Anymistakes*J 7
discrepancy notedmaybe broughtto our noticewhichshallbe takencareof in the nextedition.lt is notifiedthat neitherthe publisher:T( :€
authorsor sellerwillbe responsible
for anydamageor lossof actionto anyone,of anykind,in anymanner,therefrom.
Published By : Deslgned
By PrintedBy :
NIRALI PRAKASHAN ABHA COMPUTECH ARIHANT PRINTERS
Abhyudaya Pragati,
1312ShivajiNagar, A-13,Swaranjali,
S.No.110/2 PlotNo.E-54.MarketYard,Guttekad,.
OffJ.M.Road, BehindMedinova
Center, Shivteerthnagar,
PaudRoad,Kothrud, PUNE- 411 037
PUNE - 411005 PUNE - 411038 Tel- (020) 24268680 / 4480
Tel- (020)25572336/37/39. Tel- (020)25450915
Fax- (020)255L!379
DFINNUil|IX
CHIITBS
NiraliPrakashan
119,Budhwar Peth,Jogeshwari
MandirLane 385,S.V.P.
Road,Rasdhara
Co-op.
Hsg.Society
Pune411002,Maharashtra tt4umbai
Girgaum, 400004,Maharashtra
Tel:(O2Ol24452044,66022708Fax:(O20)24451538 Tet: (O22)23856339,/ 23869976,Fax:(O22)23869976
OISIRIBUTI||II
BRAIIGIITS
NAGPUR JALGAON
Pratibha
BookDistributors NiraliPrakashan
AboveMaratha Mandir, ShopNo.3,FirstFloor, 34,V.V.GolaniMarket,NaviPeth,Jalgaon425001
RaniZanshi
Square, Niigpur
Sitabuldi, 440012, Maharashtra,Tel:(0257)2220395
fel i (O7L2)254 7129,Mob:98222OI952
Maharashtra, Mob:9423491860
NASIK KOLHAPUR
NiraliPrakashan NiraliPrakashan
741,Gaydhani Sankul,FirstFloor,Raviwar
Karanja GaneshKrupa,2430-^,GandhiMaidanRoad,
Naslk422001,Maharashtra BookDepto,ShivajiPeth,
NearGulnrohar
T e l:(0253)2506438,Mob: 9422253 5 3 8 41.6O72,Maharashtra.
Kohlapur Mob: 9860183678
HYDERABAD BANGALORE
NiraliBookHouse Pragati
BookHouse
22,Shyam Enclave,
4-5-947,
BadiChowdi HouseNo.l,Sanjeevappa Lane,AvenueRoadCross,
Hyderabad 500095,AndhraPradesh opp.RiceChurch,Bangalore- 560002.
Tel: (040)65545313,Mob: 944O030608 Tel: (080)64573344,64513355,
Email:niralibooks@yahoo.com Mob: 9880582331, 9845021552
Email:bharatsavla@yahoo.com

PragatiBooks
9,/1,MontiethRoad,BehindTaasMahal,Egmore, 600008TamilNadu
Chennai
Tel: (044)6518353s,Mob:94440 01782/ 9a45O2t552/ 9880582331
Email: bharatsavla@vahoo.com
RHlt]0uil,ffs
PragatiBookCentre PragatiBookCentre
157,Budhwar Peth,Opp.RatanTalkies 676/8,Budhwar Mandir
Peth,Opp.Jogeshwari
Pune411002,Maharashtra Pune411002,Maharashtra
Tel: (020)24/.5 8887/ 6602 2707, Fax: (020)2445 AA87 Tel: (020)66077784/ 66020855
PragatiBookCentre PragatiBook@nue
152,Budhwar Peth,Pune4I7OA2,
Maharashtra 9t7/22, SaiComplex, F.C.Road,Opp.HotelRoopali.
Tel : (020) 2MS 2254 / 6609 2463 Pune411004,Maharashtra
Shivajinagar,
Tel: (020)2566 3372/ 66022728
PragatlBookCentre
22/A,Budhwar
Peth,AmbarChamber,
AppaBalwant
Chowk
Pune: 411002.Maharashtra

PragatlBookCorner
IndiraNiwas,
111- A,Bhavani
ShankarRoad, (W)Mumbai400028,Maharashtra
Dadar
tet : (o22\24223526/ 6662 5254
pragationIine.com
v\..ww. pragatibooksieirs'il*rG

L
l-

PBEFACE TO EIGTITEENTTI EDITION

In the last two decades,the phasesof euer-growinguolumeand euer-changingnatureof

the drug information are witnessed. This is mainlg due to an increasein the rate of

introductionof new drugs and an increasein the number and depth of pubtished.work on

both, new as weII as existing drugs. Aboue facts necessitatedaddition of aII recent

informationwhereverit deserves,
while presentingthe eighteentheditionof this book.

The book uas apPreciatedin all cornersof the profession.It has now attained the
reputation as a class-roomtext book for undergraduateand post-graduatestudentsof
pharmacg.Hou)euer,our aim remains.The sameas to presenta reuiew of basic principlesof

medicinal chemistrgand to explain the effectsof structuratmodifi.eations

of the lead nucleus
on the selectiuitgof action,d.urationof action andon the intensitg and frequencgof adoerse-

effects.

Thisedition followsthe generalarrangementand classificationof drugs as it was in the

preuiousedition. Each chapter is reuisedthoroughlg to meet the needsof future factsand

fantacies.Since this book is written basicallyfor degreestudents,a backboneund.erstand.ing

in basic disciplinesis assumed.

We wish to place on recordour sincerethanks to our publisherMr. D. K. Furiafor his

kind cooperation.We are greatlg indebtedto our eolleaguesfor their generoushelp and.

criticism. We also wish to acknowledgeindebtednessfo all who haue assistedfor the

completionof the book.

Suggestions
from ail cornersof the professionare welcome.We are responstble
fonang
deficiencies
or errorsthat might haue remainedand would be gratefulif readerswould call

them to our attention.

Pune
IWarch,2008 Authors
 t . GeneralPrinciples ': f " " " " "" I

hysico-Chemical
Parameters
and DrugAction 1I

rug Metabolism
r9 42

Receptor
43 56

ProteinBinding
5 7 -U

Cholinergic
Drugs

AdrenergicDrugs _ r?o
9

8. CentralNervou$SystemDepressants ..............r..t...... 121 .. t57

(a) Volatileanaesthetics

(b) Sedatives- hypnotics

(c) Anticonvulsants

9. LocalAnaesthetics r...........r....t.....r. r59 r66

10. PsychotropicDrugs
167 - 198
(a) Neuroleptics

(b) Antidepressants

(c) Anxiolytics

1 1 . OpioidAnalgetics 199 221

12. CentralNervousSystemStimulants
 13- fuiti-Histaminic Agents ""':'* '#"*+"
.;;

14. Anti-lnflammatoryAnalgesicAgents

15. DrugsActing on Cardio-Vascular

System

(a) Cardiotonicdrugs

(b) Antiarrhythmicdrugs

(c) Antianginaldrugs

(4) Antwn(tensive
drw

,1.6. I$euromuscula
r Elockers 325

SteFoids 339

(a) Adrenocorticoids

(b) Sex-hormones

(c) Oral contraceptiveagents

18. Prostaglandins .. 383 392

19. Drqg Design 420

421 - 447

SampleQuesfions 448 457

Indac 459 472

ooo
 \

I.1 INTRODUCTION
INTRODUCTION The deslrecl pharmacologicalresponse of a
clrug can only be achievedif it is present at the
12 Pf,OCESSESOFDRUGABSORPTION siies of action in an appropriateconcentrationficr
sufficientlylong time. This appropriateconcen-
tration is generallygoverned by many factors.The
13 DISTRIBUTION
OF DRUGS important'amongst them are :
0 Amount ancl frequencyof clrug admini-
STORAGEDEPOTS sterecl.
(iD Routeof administration.
(iii) Factorsaffecting drug absorption, distri-
METABOLISM
ANDEXCRETION bution anclelimination.
(A) Factorc affectlng accesslblllty of drugs to
the actlve sltes :
Once the drug is administereclin the body, it
unclergoesa chainof complexeventstill it reaches
to its site of action,which is representecl in Figure
1.3.The processby which a clrugis releasedin the
bocly from its dosage Formis known as absorption.
Sincethe cluration.andthe intensigrof drug action
is a functionof rate at which the clrugis absorbecl,
an unclerstancling of the factorswhich can affect
the rate of absorption of a clrug is necessary.
Thesefactorsinclude.
(i) concentrationof the clrug aclministeredor
dose.
(iD rout/of administration.
(iii) ctrugsolubility.
(iv) in case of solid dosage forms, the rate
dissolution may govern the rate
absorption.
(1)
 \

Princlplesof lledlclnal Chemlstry(Vol.ll) 3 H

\f,ecr
Communication betweenthe insideand outsideof
PolarsrouosIi
a cell includesthe exchangeof metabolitesand
electricalsignals,the flow of heat and changesin
shape.Theseprocessesdepend on the clifferences Lipoid
in temperature, pressure and electrochemical
potential on both sicles of the membrane.
Temperaturedifferencescauseheat flow, pressure Protein
differences cause changes in shape ancl Water
electrochemical potential differences cause flg. l.l : Gencrd pattcm of a blologlcel mcEbi.E
moleculartransportand electricalsignals.Usually, Although blological membranesare known to be
membranes consist an assortment of lipid complex and hlghly varlableboth in structureand in
molecules with diverse chemical structures, functlon,it seems probablethat there ls a common
structuralbasls to all of them. Under the electron
together with protelns and sometimes mlcroscope,all the natural membranesthus far
polysaccharldes. The lipids are typically fatty acid examlnedare ln the order of tOOA" in thlcknessand
estersthat dlffierln the length of fatty acid chain, are generallyconsideredto conslstof a llpld bilayerof
the Gorter - Grendeltype wlth adsorbedproteln or
the degreeof unsaturatlon,the changeor polaritlr non-llpid layers.
of the esterlfoinggroup and the numberof fatty r.2 PROCESSES Of DRUGABSORPTION :
aciclsesterlfiedper molecule. The maln processesby whlch a drug molecule
Proteinsmay constitute upto 8O%of the cell crossesthe naturalbarriersare :
(a) Slmple diffi.rslon (b) Diftusionof lons
membrane(e.g., red cell membrane)or as little as (c) Facilitatecldlffusion acrossthe membrane
18%.(e.9.,nervemyelin).Variations areevenwider (e) Poretransport (d) Actlve transport
In bacteria.The lipid contents also vary widely G) Phagocytoslsand (f) Flltration
plnoqytosis.
from membraneto membrane,constitutlngupto (a) Slmple dlffuslon : The drugs are absorbed
80% of myelin, but only 15% of skeletalmuscle from gastrolntestlnaltract, cross the Intestlnal
membrane.Not only the total lipid content varies, endotheliumby simple dlffi.rsion.This processcan be
deffnedas, the flow of drug acrossa cell membrane
but also the chemical nature of the lipids. The from a solution of higher concentratlon(Ce) to the
hydrocarbonchalnsvaqr wldely in the natureof solutlon of lower concentration(Cs) wlthout ener$/
polar groups, length and saturationextent. utilisatlon.
Sterol Fattyacids Triglyceride
Part Portion

o ./\ \.,
-cH, co NH (-O NH CH CO NH
NHt
Water
Il8 1.2: Ccntrd fcaturesof the Devsonend Denlcltl'smodcl of blologlcel menbrerc
/

Hof klcind ll)

Chemlstry(Vol. 4 Cflieral Ptitrclplos

'the importantfieaturesof simple diffi.rslonare : absorption, hence drugs that inhibit gastric
(i) lt depends and proceeds along a concen- (e.9. atropine,amphetamine,morphine
emptylng
tratlon gradient.
(ii) lt does not involve enersf expenditure. etc.) may decreasethe rate of absorption.
(iil) Partitioncoefficlentplaysa governing role in D
lf we replace by another term, P (i.e.
the transport of llpophllic clrugs by this clx
process. diffi.:sionconstant),equation t.l can be rewritten
(iv) The transport of ionic or polar drugs by thls
processis influencedby the differencein pH as,
on both the sldesof the membrane. T = -!'A.dc ...(1.2)
(v) The process termlnates as. soon as the Fickin 1885,derivedthis equationand now it
concentrationof free drug ls sameon both the ls knownas Fick'slaw of dlffi.tsion. The minussign
sldesof the membrane(i.e.,at equlllbrlum). indlcatesthe passageof a drug from the area of
Simple dlfrrsion can be expressedmathematlcally
law, is follow : higher concentration to the area of lower concen-
using Fick's whlch as
tratlon. The continuous removal of the drug
dm dc
... ( l .t) moleculesfrom the serosalside of the intestinal
dt dx
dc wall by blood circulation tends to keep the
- -DA dx concentrationon the other side alwaysnegligible.
where, This serves as an additional driving force for the
clm transportof drug molecules.
Rateof drug diffrislon
dt The rate of diffi.rslonof a drug ls a functionof
A Surfaceareaof the absorbingmembrane an areaof absorbingsurface.It is much greaterin
dc Difference In solute concentratlonon refolcling
both sldesof the membrane the small lntestinedue to its folding and
dx Membrane thlckness Into valves of Kerckring and villl. lt, thus provides
dc = an absorbingareaof some4500 m2.
(1.e. concentratlongradlent)
dx The pH differenceacrossthe cell membrane
D = Proportionallty constant. Here lt ls and the dissoclationconstant(plk or pKb) of drug
distributloncoefflclent.lt lncludes all alsogovemthe rateof drug absorptlon.Slncemost
other factorsthat may affect drug, nature of the drugs are elther weak acldsor weak bases,
and condltlon of the absorbing
membrane thelr acidityvalue (ratioof ionisedand unlonised
forms)ls dependentupon pH and pKa.Hencethe
Movement of GIT membranefacilltatesthe
dissociationconstantplays a vital role in deter-
contact of drug moleculeswlth the absorbing
mlnlngthe abilltyof drug to crosscell membrane
surface.This leads to an Increasedabsorptionof
e.g. barblturates.
drug. Food ln the stomachInterferesln the drug

Tissue
Depots

Gastrointestinal
Tract PLASIv{A

FreeDrug Metabolism

Parenteral
route Excretion

Ilg' 1.3
Principlesol MedicinalChemistry(Vol.ll) 5 GeneralPdncipbs

(b) Dlffuslon of lons across the membrane : Limitations of this processinciucle

Sometimes,a potentialclifferenceclevelopswhich (a) Its saturablenatureclueto linrited number
leacls.topolarisation of biologicalmembrane.One
side of the membranebec.on'les positivelycharged of carriermacromolecules ancl
and other sicle gets a negative charge. When a (b) Competitiveinhibitionof transportof one
positively chargecl ion (i.e. cation) comes in clrug by the presenceof another clrug bearing
contact with the positivelychargeclface of the similarstructuralfeatures.
membrane, it will be kickecl away from the
'membrane.Similarly,anionswill be drivenaway by (d) Actlve transport Some substances
negativelychargeclface of the membranein the cliffuseacross the biologicalmembraneat much
opposite clirection.This process worl<son the more faster rate that cannot be accountecion the
forces of repulsion and naturallycloes depend basisof their lipiclsolubilityor moleculesize.This
upon the electrochemical concentrationgradient transport which proceeds against the concen-
i.e. on Lrioelectricalpropertiesof the membrane trationgradientand utilisesa seriesof specialised
generateclclueto polarisationof the membrane. carriermoietiesis termeclas active transportof
(c) facllltated dlffuslon i As the name clrug.
indicates,it is an acceleratednrovement or This carrieraiclecltransportsystem is chara-
cliffusionof moleculesthat can not be justifieclby
cterizecl by,
their lipophilicityor molecularsize.This cliffusion
proceeclsgenerally along the concentration (i) utilizationof energysuppliedby metabolic
graclients.Such cliffusionis termeclas downhill activity of membrane,
diffusion(i.e. from higher concentrationto lower (ii) proceeds against the c o n c e n t r a t i o n
concentration).Downhill clifF.rsion requiresno net graclient,
expenditureof energl. A seriesof acceptor-donor
macromoleculescarry out this cliffusion.But (iii)absorption rate is inclepencleni of
sometimes,facilitatecldiffusionalso trains away concentration.
moleculesagainstconcentrationgradient.This is The mechanismsthat bring these and similar
known as uphill diffusion where energy is movementsare often terrnedas pumpse.g.,Ca++
expendecl.Uphill cliftision is also termed as Active
transport. ATPase pump, Na+, K+-ATPase pump etc. Uncler
The acceleratecl
cliffilsionof clrugmoleculesis the conditionsof nonavailabilityof energy, the
brought out by carrier macromolecules which materialthus transportecl, clriftsback againuntil
oscillatebackanclforth acrossthe cell-membrane. equilibriumon both siclesof the barrieris reached.
The loose complex is formed betweencarrierand Active transport,is identicalin most of the
drug molecule. Arriving at another sicle, loose aspects with facilitatecl transport. The only
complex clissociatesto relieve the molecule and clifferenceexists between facilitatedtransportand
carrierreturnsback to lift again a new passenger. active transportis, that the formercloesnot utilize
The processto certain degree, exhibits substrate energy(i.e. proceedsalong concentrationgraclient)
specificity. Facilitateclcliffusion can be well i.e. clownhill cliftrsion whereasthe latter process
illustratedwith the exampleof transportof anti- proceedsagainstthe concentrationgradient i.e.
bioricslike, valinomycinor gramiciclinA. The eight uphill cliffusionand needsenerg/ consumption.In
carbonyloxygens of the four valine residuesin the case of ionic molecules,transportmay occur
valinomycinskeleton,faceinward,forminga cage againstan electrochemicalpotentialgraclient.The
*ithin which, potassiumions can easilybe helclby exact mechanismof active transportis still not
coordinatebonds. Thus potassiumions can get clear but it woulcl appear that, on the mucosal
errrry through the hydrophobic interior of the surfacesicle of GlT, carrier proteins form a loose
:nembranewhen it is in 'sound-sleep"within a complexwith the drug molecule.This compex
of hydrophobicside chainof the antibiotic. trainsaway the clrug moleculeto the serosals de
"rosaic
C-ramicidin acts as transport antibiotic by where the complex dissociatesto relie',e
furning cirannelsthat transversethe membrane. passenger.The carner may then rerL:T'r:a
7

ffiof liledicinalChemistry(Vol.
ll) 6 GrdFri#

K@ Na @
Outside
thecell
=

Loosc'complex Cellmemt'rarc

Insidethecell

KO Na@
Energyconsuming
conversion
Flg. t.4 : Worklng of Na+-K+- ATPasepump
mucosalsurfaceempty handed or may pick up absorption processesacross placenta and blood
another molecule.during its journey back to braln barrier.The processis of great importance
mucosalside.Beforepickingup anothermolecule, and enablesthe cell to accumulatemetabolites
it is involved in an energy consumingchemical from an external environment where the
reactionthat convertsthe carrierprotein (Ca)into a concentrationof the substancemay be relatively
new form (Cs). The new form Cs, releasesthat very low, to excrete unwanted substance,to
molecule to mucosal sicle and unclergoesa develop membrane potentials and probably to
spontaneouschangeto its originalform, C1. maintaina normalcellvolume.
Llmltatlons : The active transport of glucose across
(a) Active transportis site specificas well as a blologicalmembranels aided by sodiumions.The
substratespecificprocess.lt means that special glucosemoleculeand sodium ion both, bind to a
carrierchannelsare appointedto carry particular specificcarrierprotein.Thiscomplexwhen enters
glpes of chemical structures.Similarly these the cell,the sodiumion is effluxeclout throughthe
substrates are usually absorbed from their operatlon of Nat K+ ATPasepump. Suchaided
correspondingspecificsites lscateclin a limited type of transportmechanlsmis termed as co-
segmentof the smallintestine.Forexample,ileum transport.
is a site of diffilsionfor bile acids.
(b) Sincecarrlerchannelswith a specificcarrier
moleculesare allotted to transport drugs from
particular chernlcal structural class, the carrier
system becomessaturated,
(i) if the drug is presentat higher concen-
tration orland
(ii) if another substrate of close structural
similarityis simultaneously adminlstered.
Pump
(c) Substrates that interfere with cell
metabolismor in energl generation,may cause
non-competitiveinhibition of active transport tlg. 1.5 r Co-transporrtof Glucosc
syscem, Nat K+-ATPase pump is widely dlstributedin
Actlve transportplays an important role in the cell-membranesand especiallypresentin hlgh
renaltubule reabsorption,secretlonof H+ into the number in different secretorycells along with
stomach,accumulationof lodlde ions in the excitabletlssuesuchas nerveand musclecell. It is
thyroid gland,absorptionof glucose,aminoacids, malnlyconcemedwlth the transportof aminoacld
some vltamins and metabolitesIn Intestine. and glucose
during nerve excltability and
 ffol. ll)
of MedicinalChemistry
Principles 7 Principles
General

++
Na-K-ATPase
Na*- K*- Arpaseenzyme
ATP A DP +Pi+ H-
fug* Phosphorylated
enzyme

Pi + HrO Na*- t<*- ATpase+ pi

Dephosphorylation
Phosphorylated enzyme
enzyme Ilg. 1.6
maintenanceof cell-volume.The enryme,Nat K+- The hydrostatlcforce arlsesdue to the pressureof
ATPasewas discovered in t957 by JensSkou in a drug solution (solvent drag) at one slde of the
the cell-membrane.lt hydrolysesATPmoleculeto membranewhich lmposeslts pressureat the site of
releaseenerg/ necessaryfor functioning of this absorptlon.These pores may have electrlcal charges
pump.Theenrymeand the pump,botharetightly that may influencethe diftrslonof chargedbodies,like
bound-withthe plasmamembrane. The hydrolysis catlonsor anions.
of ATPmoleculeneedsthe presenceof Na+,K+ and In summary, there are three possible routes
Mg++ lons. through whlch a polar substancecan be passively
The phosphorylationreactionis catalysedby transportedacrossa membrane.Theseare :
Na+ and Mg++ ions whereas the dephospho- (i) Diffusion down a concentrationgradient
rylationneedsthe presenceof K+ ions. (polar transport).
The Nat K+ -ATPaseenryme is the pharma- (ii) Diffuslondown a gradientof electrlcpotential
cologicalreceptorfor digitalis.Digltalislike drugs (ion transport).
bind to the extemalsurfaceof the enzyme.Cardiac
glycosides Induce conformation (lll) Filtratlon.
inhibit dephosphorylation reactiol ln thls caseof diffi.rslonrestrlctedby a llpid barrier,
ATPaseenryme. the penetratingmoleculecan enter the cell provlded lt
(d) Porc transport : The aqueousfillecl pores has the approprlate solubillty characteristlcsto
or channelsare presentacrossthe cell-membrane. dlssolvefirst ln the liplclof the membraneand then ln
The dlffuslon of small slzed polar moleculesis the aqueousphaseon the other slde. This mechanism
mainly govemed by these channels.The dlameter does not requlreaqueouspores ln the membrane.lt
of theseporeswas estimatedto be nearabout4oA has been supported experlmentallyby the correlation
which seryesas a major limltation to the transport of llpld-water partltlon coefflclentswlth membrane
process.'lt is an example of passivediffnsion penetratlonratesIn the caseof many non-electrolytes.
where the rate of transport depenclsupon the (g) Phagocytoslsand Plnocytosls : Droplets of
concentrationof drug and does not utillze ener$/. extracellularfluld along wlth solute moleculesare
Variouselectrolytes,urea, low molecularweight carrledlnto the cell through the ficrmatlonof vacuoles.
sugars,etc. are transportedby this mechanlsm. Phagocytosisls described as cell eatlng process
(c) tlltratlon : The naturalmembraneconslsts
whereaspinocytoslsls referred to as cell drlnklng
of numerouspores of diffierentslzesembeddedIn process. Both these processes are examples of
it, whlch generallycontrol the diffitsionof small engulflng of extracellular fluld
and substances
slzed moleculesof water-solubleor llpld-insoluble dissolvedIn lt. Phagoqytosis
can carry macromolecules
substance.lf a mechanlcalpressure(hydrostatlc (suchas protelns)Into the whereaspinocytosls
cell,
pressure)is lmposedon the blologicalmembrane, has
llmltatlon of carrylnglarge molecules.
the drug moleculeswill oozeout to the other side.
Prlnclple behlnd these processes has been
Suchtransportmechanismis termedas filtration.lt
exploited to develop new drug dellvery system.
means, Recently, techniques have been developed to
envelopedrug moleculesby 'llposomes'whlchcan be
Filtration= Simpledlffi,rsion+ Hydrostatlcpressure. engulfedby the cells by plnoqrtosls.
/
=rnmr= :c Medrcinal (Vol.ll)
Chemistry 8 Principles
I.3 DISTRIBUTIONOf DR.IIGS
lf a drug is administereclinto the bocty,blood
irculation servesas a transportsystem for it, to
reach at its site of action. The most prominent
organsllke heart,kidney, liver and brainsharemajor
portion of the drug, thus characterising the first or
initial phaseof clistribution.The entry of drugs into
the cells depenclsupon many mechanisms.Very
small water-solublemoleculesancl ions (".9., K*,
Cf-) eviclentlycliffilsethrough aqueous channels.
Lipicl-solublemoleculesof any size diffirse freely
through the cell-membranes. Water-solublemole-
culesand ions of moderatesize incluclingthe ionic
forms of most drugs, can not enter cells readily
except L'ryspecialtransportmechanisms.Drug that
is too large to passthrough any pores and is also
practicaliyinsolublein the membrane,can form a
lipict-soh.rble complex at the membrane surface.
The complex then moves by cliffiusionwithin the
membrane. In a complex biological system like
hurnanbody, along its way to the site of action,a
drug may meet with a number of outward
instanceswhich control the clistributionof the
drug. These instances,however, are dependent
upon the physico-chemicalproperties of a drug
and may be one of the followinggpes :
(l) A corrsiderable amount of drug admini-
stered rnay be retained by reversible
storage clepots.
(2) The drug may undergo cei-tainmetabolic
alteration by biological enzyme systems
before it reaches to its site of action,
which may result into more or less active
form.
(3) Beforea drug gets a chanceto act on its
normalsite, it may be excretedunchanged
or in its metabolicform.
I.4 STORAGEDEPOTS
Plasmaproteins, certaln tissues, neutral fat,
bone ancl transcellularfluids (gastrointestinal
tract), are founclto act as clrug reservoirsor storage
sitesfor drug.
The drug storecl in these clepots is in
equilibriumwith that in plasmaancl is releasedas
the plasma concentrationof the drug falls below
its therapeuticconcentration.Thus, the plasma
concentration of the clrug is maintained which
sustainsancl prolongs the duration of action of
the clrug.
PlasmaProtelns : Approximately6.50loof the
bloocl constitute the proteins, of which 5Oo/ois
albumin.Most clrugsbound to plasmaproteinsin
the albumin fraction; binding to other plasma
proteins, generally occur to a much less extent.
Albumin has a net negativecharge but can interact
with anionsas well. The bindinggenerallyinvolves
ion-ion interactionwhich is further strengthened
General
by the presence of secondary binding like
hydrogen boncling(non-ionicpolar portions),
hydrophobicanclvan der Waal'sforces(non-polar
portions)of the molecule.Ionizationis thus not a
the specifici$t ancl intensi$r of
The protein binclingis found to be
a reversibleprocess.
Proteinbinding reducesdiffusionof the drug
to the sites of action, metabolismancl excretion.
The size of clrug-proteincomplex is largeanclhence
cannot pass through glomerular filtration which
prolongs its duration of action. Protein bincling
alsodelaysthe metabolismof the clrug.
Sinceprotein binclingis rathera non-selective
process,other drugs with similar physicochemical
characteristics,may exert an inclirect biological
effect by clisplacing active substances from
protein binding which may result into (a) dange-
rous adverse effects and (b) misinterpretation
about the actionsand dose of the drug.
Tlssue Reservolrs : Depending upon its
physico-chemicalcharacteristics,a drug may be
storeclin various tissues,like liver (antimalarial
ctrugs),thyroid (locline),lung, spleenand muscle.
Tissue bincling of drugs usually occurs with
proteins, phospholipidsor nucleoproteinsancl is
generallya reversibleprocess.
Neutral Fat : Sincefat constitutesarouncll(Pb
(starvation)to 500/oof the total bocty weight, It
servesas a main storage site for clrugshaving a
high partitioncoefficient(lipict/watersystem)or a
high lipid solubility(thiobarbiturates).
Other drugs which get reaclilydepositeclinto
the fat, are adrenergicblocking agents (ctiben-
amine), neuromuscularblocking agents (hexa-
fluorenium)etc.
Bone : Heavy metals (like lead or radium),
clivalentmetal ion chelatingagentsand antibiotic
(tetracyclinegroup) are the examples of the
compoundswhich, in considerable concentration,
are retaineclby bone.
I.5 METABOTISMAND EXCRETION
The terminationof clrug effect is causeclby
biotransformation (alterationin the structureof a
clrugdue to the actionof enrymesor due to other
biochemicalprocesses)and excretion.
The effects of clrugs are terminated byt
redistribution between the compartments,
storage,excretionof the unchangeddrug and its
metabolites.Compounds having a molecular
weight lessthan about 4OOare excreteclin urine;
larger moleculesare clearedby the liver. Bile is
excreteclinto duodenum,where a proportionof
drugs (e.9., antibiotics,carcliacglycosides,
vitamins)is reabsorbedby the enterohepaticcycle.
oao
 2.I INTRODUCTION
21 INTRODUCTION Drug design is an integrated cleveloping
clisciplinewhich portenclsan era of 'tailorecldrug',
22 FERGUSON
PRINCIPLE a clrug sans sicle-effects.It seel<sto explain
effects of biological compounds on the basis of
23 IONIZATION molecular structures or its physico-chem ical
properties involvecl. lt studies the processes by
which the clrugs procluce their effects; how they
24 COMPLEXATION
react with the protoplasm to elicit a particular
pharmacologicaleffect or response,how they are
Z5 SURFACE-ACTIVITY modified or detoxifiecl,metabolisedor eliminated
by organism. These concepts are the building
HYDROGEN
BONDING stones upon which the edifice of drug design is
built.
z7 OXIDATION.REDUCTION
POTENTIAL In an effort to interpret the SARof a clrug,two
main approacheshave emergeclviz. (1) The group
anclmoie! approachancl (2) Integralapproach.
28 BIO-|SOSTERISM
The former placesemphasison the significance
of certainchemicalgroups in the drug moleculeas a
whole ancl particularly concerneclwith overall
physico-chemicalproperties. Moclulating the
structureof a clrug implies introcluction,elimination
or substitutionof certaingroups in the clrug.This
may leaclto the developmentof a parallelclrugwith
the characteristicssimijar to the leacl compouncl,
like vitamin analoguesand hormone analogues.
Hence, the activity is maintainecl,although
structureis changed.This can be expresseclby an
idea of 'bio-isostericgroups'which generallyhave
similar biologicalactivit5r.The spectrumof action
of the existing compounclmay be changedor side-
effects can be changeclto main effects.

(e)
 Frinciplesof MedicinalChemlstry(Vol.ll) 10
E. J. Ariens mentioned the following physico-
chemicalparametersaffectingdrug-activity.
' 'The chemical properties of a drug are deter-
rninant for its biological action and activity. The
varioirs physico-chemical properties of bioactive
compounds in general, are parameters related to
the interactionof the drug with its environment."
The physico-chemical parameters can be
divided into three main categories.
ll) Parameterswhlch are an exprcsslon of
the hydrophoblc aggregatlon forces at slte of
actlon l
These include partition coefficient" surface
activi!, Rf value, and the partial vapour pressure
of a solution.
Hydrophobicgroups and hydrophobicaggre-
gation forcesrepresentedby these parameters give
relatively large contribution to binding energy.
They allow, by variation in size of the groups, a
lradual change in the lipid water balancewhich
rules distribution by passive transport.
(2) Parameters whlch are an expresslon of
the charge dlstrlbutlon In the molecule and
thus of the electrostatlc force at slte of actlon :
le redox potential, the baseor acid
tstants,the electronicpolarization, some of the fundamentalcellular processese.g.
, dipole moments, the ipductive field effect and the general
resonance effect, especially in conjugated
sletems, the capaci$l of chelate formation, and H-
bond formation and finally the characteristicsin lR
and NMR spectra. Electrostaticforces represented the chemical structuree.g. qyclopropane,diethyl
eters give a relatively low contri-
rg ener$/. TheYcontribute more to
the selectivityin drug'receptor interactionanclare
essentially involved in substrate activation in
enzymes and conformational skeletons important
for the induction of a stimulus in the macro-
molecularreceptormolecules.
(3) Parameters whlch are an expresslon of
spatlal anangement of the molecule :
Theseparameters. representspatial arrange-
ment of variousgroupsin the moleculeand play a
role in the possible steric hindranceon the
intramolecularlevel.Thelocation,size,volumeand
chargeof particulargroupsplaya role here.
Physic+CherticalParameters
& DrugAction
The intensigl of the pharmacologicalresponse
elicited by many drugs is probably directly related
to the concentration or activigr of a drug in the
immediate vicinig of the receptor site in the body.
Since it is not possible to measure this concen-
tration directly, the study of physico-chemical
parameterspresentsa picture of indirect measure-
ment of the concentration of a drug at receptor
site. It follows, therefore, that drug molecules
exert their effect by influencing receptor sites in
living systems through their physico-chemical
properties.
2.2 fERGUSONPR,INCIPTE
Pharmacologicallyactive compounds can be
divided into two major groups :
(a) the structurdlly specific and
(b) structurally non-specific.
The structurally specific drugs bring about
their effects by combining with a specific receptor.
The SAR of such groups can only be varied within
relativelynarrow limits.
The structurallynon-specificdrugs do not act
on specific receptor. lnstead, they penetrate into
the cell or accumulatein cellurlarmembranes,where
they interfure by chemical or physical means,with
anaesthetics, hypnotics, volatile insecti-
cides and certain bactericidalagents.The biological
effiectof such drugs is more closely correlatedwith
the physicalpropertiesof the molecule than with
ether and chloroform, though having different
structures,are good general anaesthetics.
H2 cHz
Cyclopropane
(Hydrocarbon)
crFFO-CzFb ct-tctr
Etylether (Ether) Chlorcfirrm
ttg. 2.1
Pdnclpbsof lledlclnal Chemlstryflol. ll) 11 Physlco€hemlcalParamslers& DrugAc.tion

Fergusonsuggestedin 1939,that the potenqy ol gasee

Table2.1: Concenlrations andvapoursproducing
the
of structurallynon-speciffcdrugs wals determlned samedegreeol anaesthesla
Inmlceat37'C
by their thermodynamicactivlty. This quantltyls a Anaesthetic
agent Saturatlon Activity
pressure
at37'C (pdps)
measureof the proportion of the moleculeswhich (ps)(mmHg)
are free to react wlth enzyme systems, nerve
Nitrous
oxide 59,300 0.01
membranes and slmllarbiologlcally
importantsites.
Acetylene 51,700 0.01
Themoleculeswhichare not freeto act In thls way,
Methylether 6,100 0.02
are reactlngwlth one another,wlth the molecules
Ehyleneoxirle 5,900 0.01
of the solventor wlth moleculesof other solutes.
Ethyl
chloride 1,790 0.02
It follows, therefore, that the thermodynamic
Diethyl
ether 830 0.03
actlvit5lof a drug in solutlon is not determlned
Methylal 630 0.03
entlrelyby lts concentratlon.In the caseof volatile
Ethylbromide 725 0.02
anaestheticsadmlnisteredwlth alr or o4ygen, the
thermodynamlc activlty ls proportional'to the
Dimethylacetal 288 0.0s
Diethyliormal 110 0.07
relative-,saturatlonof a drug (a). The relative
Pj Dichlorethylene 450 0.02
saturationof a drug is defined as for volatile Carbondisulphide 560 0.02
Po
Chloroform 324 0.01
drugsand gases.
Table
2.2:Bacteilcidal
concentralions
of mlscellaneous
Pt
Relativesaturation(a) . . . (2 . 1 ) organlc
compoundstowardSalmonella
typhosa
Po
Relative
where, Gompound BactericidalSolublli$ Satura-
Pg= partlalpressureof the drug tn solutlonor ln Concentratlon(So) tion
the gaseousmixtureand
(sr) (S/so)
Po = vaPourpressureof the pure drug at the Thymol 0.0022 0.0057 0.38
Propaldehyde 1.08 2.88 0.37
sametemperature.
Methylethyl 1.25 3.13 0.40
For non-volatiledrugs of llmited solubilitythe ketone
relativesaturatlon(a), is given by Acetone 3.89 9.7 0.40
S1 Aniline 0.17 0.40 0.44
Relativesaturation(a) =
so ...(z.zl Cyclohexanol 0.18 0.38 0.47
where, Butyraldehyde 0.39 0.51 0.76
St = molar concentratlonrequiredto produce 2.3 TON|ZAT|ON
the blologicaleffiectand lonized form lmpartsgood water solubilityto
the drug which is essentlal for good binding
So= molarsolubltltyof the drug. Interactionsof drug with lts receptor. While non-
Ferguson'stheory predlcts that the anaes- ionized form helps the drug to cross cell
membranes.Hencea good balanceof lonlzed: non
thetic agents wlll show the same degree of ionized forms ls essentlalfor better pharmaco-
biological actlvlt5l if thelr concentratlonsare klnetic and pharmacodynamlcfeatures.Most of
adjustedso that their thermodynamicactlvltlesare the effectfuedrugsare amineshavinga plG valuein
equal (or relatlve saturatlonvalue (a) are equal). the range6 - 8. Hencethey are partlallylonizedat
lhls theory ls also applicableto substancesother blood pH to createbalancedratlo of lonlzed: non
han anaesthetlcs and it was orlginallyapplledto ionlzedbrms..
The rate of absorptlonof a drug whlch is
tsectlcldesand antlbacterlalsubstances. capableof exlstlngboth In lonlsedand unlonised
 of MedicinalChemistry(Vol.ll)
Principles 12 Physico-Chemical
Parameters& DrugAction

forms, is clepenclenton the concentrationof its Forweak basesor acicls,the pKa value together
unionisedform. rather than on its total concen-
with the pH of the medium determine which
tration. The unioniseclform is a function of both,
the clissociation constant (pKa or negative fraction of the drug molecules is undissociatedand
logarithm of acidic dissociationconstant)and the thus availablefor penetration through the various
pH of the environmentwhich is representecl by lipicl barriers. The rate of penetration thus is
Henderson-Hasselbach equation. strongly depenclenton the lipophilicityof the drug
ForAcicl,pKa- pH = log (Cu/Ci) . . . (2 . 3 ) moleculein its unioniseclform.
ForBase,pKa - pH = log (CilCu) . . . (2 . 4 )
The lipophilic-hyclrophilicbalanceplays a role
where, Ci ancl Cu are the concentrationsof the
ionisedanclunioniseclclrugsrespectively.lt can be not only in passive transport but also in active
seen that a solution of weak acicl,aspirin (pKa = transportancldrug metabolism.
3.5) in the stomach,(pH = 1.O)will be more than
Table2.4
990lounioniseclancl since unionised form is lipicl
soluble, it will get more easily absorbed in the CHCI3/H2Opartition
coefficient
of unionised
stomach. Quinine, a weak base (PKa : 8.5) in barbiturates
and% absorption
fromratcolon
stornach(pH = 1.0) woulcl have only one out of
1O,0OO,O0O molecules in unioniseclstate, hence Barbiturates Partition % Absorption
would be most unabsorbablein stomach.In spite Coeflicient
of the fact that certain drugs exist in unionisecl Barbital 0.7
state, they are poorly absorbecldue to their low
Amobarbital 4.9 17
lipid solubilify.The clistributionor partitioncoeffi-
cient of drug 'n unioniseclstate between fat-like Phenobarbita 4.8 20
solvents (such as chloroform) and water or an Cyclobarbital 13.9 24
aqueousbuffer r,rixturenearly at the pH of the site en
Pentobarbita 28.0
of absorptiongi' es an idea of the lipicl solubilityof
the clrug. Secobarbital 50.7 40
Table2.3
pKaVal'res
of acidsandbases Table2.5
Acids pKa Bases produced
Anaesthesia byprimary
alcohols
in tadpoles
Scale (Overton
andMeyer)
acids 1 Antipyrin
StrongSulphonic Weak
Benzyl Anaesthetic Partition
Penicillin Alcohol concentration
in coeff icient
acid
Salicylic aqueous (cottonseed
Aspirin .1 medium oil/water)
Benzoicacid 4 cH3oH 0.57 0,00966
Phenvlbutazone
4
c2HsoH 0.29 0.0357
Amidopyrin
c
Sulohadiazine Reserpine caHToH 0.11 0.156
Barbital I Morphine iso-CaHeOH 0.045 0.588
Sulphapyridine Quinine As the length of the hydrophobic chain
Weak Diphenyl- I Procaine Strong increases.both the partition coefficient and the
hydantoin Ephedrine anaestheticpotency increasewhile the aqueous
Principles
ot Medicinal
Chemistry
ryoL[)
concentrationdecreases.For weak acids and bases
the ionised and non-ionised forms have
completely different lipid/water partition
coemcients.The ionised groups (usually COO- or
-N+HR2)interactstrongly with water dipoles and
consequentlypenetrate only poorly or not at all
into the lipoidal cell-membranes.Thus drugs that
are partially ionised at body pH enter cells at rates
that are strongly pH dependent.
Phenobarbital,a weak acid, caused a drop in
the plasma drug level, when the plasma pH was
lowered by CO2inhalationin clog. lt is becausethe
greater fraction of the total phenobarbitalin the
blood assumed the non-ionised acid form. The
plasma concentrationof undissociateddiffusible
phenobarbital was thus increased and a large
amount of the drug moved across the cell-
membranesand into cells where the pH remains
relatively stable. Plasma alkalosis produced
opposite effect. Hence to promote just such a
shift of the drug out of the tissues, alkalosis is
induced therapeutically in the treatment of
barbituratepoisoning.
The co-ordinated effect of pKa and lipid
solubiligl of a drug on its absorption led to the
developmentof eryrthromycin propionate.The pKa
value of erythromycinis 8.6 while that of ester is (4) Calcium is an important constituent of the
6.9. Sincethe partition coefficientof ester form is
about 180 times larger'thanthat of eqlthromycin,
the ester yields 2 to 4 times higher blood levels
than does erylthromycin.These observationsare in
accordance with the Handerson-Hasselbach
equatron.
2.4 COMPLEXATION
Since complexesof drug moleculescannot
crossthe naturalmembranousbarriers,they render
the drug biologically ineffective. The rate of
absorption is therefore, proportional to the
concentrationof the free drug moleculesi.e., the
diffirsibledrug.
Due to the reversibilityof the complexation, claims both in favour of enhancement and
there ahvaysexistsan equilibriumbetweenthe free
drug and the drug complex. Such equilibriumis
representedbelow :
Drug + C-ornple<ingAgent Drug Complex
Complexationreduces the rate of absorption
-
of the drug but does not affect the total
13 Parameters
Physico-Chemical & DrugAction
availabiligof it, becausethe erbscrptionof the free
drug moleculesshiftsthe equilibriumto the right,
causingthe free drug moleculesto be releaseclfrom
the drug- complex.
Membrane
Freedrug
x
Macromolecular
q
ho complexing
agent
Removalof freedrugcauses of it
release
fromthedrugcomplex
Elg.2.2
Examples of Drug-complexes :
( 1) Phenobar b i t a l f o r m s a n o n - a b s o r b a b l e
complex with polyethylene glycol-4OoO.The
dissolution rate of phenobarbital tablets
containingPEG'4OOO, is only one-third of that
of control tablets.
(2) Amphetaminecarboxymethylcellulose is yet
anotherexampleof non-absorbable complex
(3) Tetracyclines have been known to foitn
complexeswith divalent ancltrivalent cations,
which are much lesseffectivelyabsorbed.
mucousmembraneof GIT.The complexation
of this calcium with EDTA, increasesthe
permeabili! of the membrane,probablydue to
the widening of spacebetween epithelialcells
due to removalotcalcium. Therefore,presence
of EDTA,increasesthe absorptionof mannitol,
quat er nar y a m m o n i u m c o m p o u n d s o f
sulphanilicacid ancl heparin,which are very
poorly absorbedin ordinarycondition.
2.5 SURFACE-ACTIVITY
As regards to the effect of surfactants or
surfaceactive agents on clrug absorptionthrough
biologicalmembrane,there have been opposing
retardationof clrug absorption.The main contro-
lling factorsin this regard are - the chemicalnarure
of the surfactant,its concentration. its effecr on
biologicalmembranesanclthe micelleformadon'.
It is evident that while in lower concen[adons
the surfactant enhanced the rate. the sarn€ il::
Principles
of Medicinal (Vol.ll)
Chemistry 14 Physico-Chemical
Parameters
& DrugAction

higher concentrationsreduced the absorptionrate.
In lower concentration,the amphiphilesreducethe
surfacetension ancl bring about better absorption
through better contact of the molecules with the
absorbingmembrane. But when the concentration
crossesthe criticalmicelle concentration(C.M.C.),
the surfactantmoleculesin the bulk of the solu-
tion form colloiclalaggregatescomprising nearly a
Fewhundredsof themselves,and these molecular
aggregatesare called micelles,which entrap the
clrug moleculesin their hyclrophobiccore, resulting
in the retarclationof the rate of absorption.
The resulting large attractive force between
moleculeslowers the solubili\r, especiallyin the
non-polar solvents which are not capable of
breal<ing the H-bonds.
On the other hancl,antipyrine cannot form H-
bonclsancl has only comparativelyweak attractive
forcesbetween its moleculesand hence if is freely
soluble in non-polarsolventsancl has the proper
partition characteristics
to penetratethe CNS

I
C :C
/\

Dftlo.' M icellc H ,C , H
- flg. 2.3
I - Phenyl-2.,
3-dimethyl-5
Bile salt solutions of approximately physio- pyrazolone(Antipyrine)
logical concentrationgreatly enhancethe clissolu- (2) Salicylicacicl(o-hydroxy benzoicacicl)has
tion rate of poorly water-solubledrugs like griseo- quite an appreciableantibacterialactiviry, but the
fulvin ancl hexestrolby virtue of micellar solubi- para isomer (p-hyclroxybenzoic acicl)is inactive,
Iization effect.
becausesalicylicacicl is the ortho isomer that can
2.6 HYDROGENBONDING
form intramolecular H-bonds.
Atoms which are capableof forming H-bonds
are electronegativeatoms: these inclucleF, Cl, N, O "\H
and S.
Though H-bonclsare relatively weak boncls 20
their presencemay have a profouncleffect on the (-

biologicalaction of a clrug. I
for Example : o-H
(1) 1-phenyl -3-methyl -5-pyrazoloneshows Saliqylicacicl
no analgesicproperties while I -phenyl-2, 3- The m - anclthe p-isomerscan form only inter-
climethyl-S-pyrazolone (antipyrine)is a well known molecularH-bonds.
analgesic agent. This effect appears to be best
explaineclby the fact that the first compound
through intermolecularH-bonclingforms a linear o---H o
polymer.
Ilto-" \o t/to-"
p-Hydrorybenzoic acid (climer)
Salicylicacidis lesssolublein waterthanthe p-
isomer but its partition coefficient(benzenewater)
is approximately300 times greater, while p-
hydrory benzoicacid has low partition coefficient
C:C C:C
/\ /\ t \ ancl hence low anti-bacterialaction. In salicylic
HrC H H.rC H H3C H acid, intramolecularH-bond has the phenolic
hyclroxylgroup masked but the carboxylicacicl
Intermolecularhydrogenbonding group is free and can function as an anti-bacterial
I -Phenyl-3-methyl-5-pyrazolone agentsimilarto benzoicacicl.
mmrryfr of le<licinalChemistryflol. ll) 15 Physico-Chemical & DrugAction
Parameters

3) The nucleic acids, fundamental repro- the dihydro form. This reaction has a potential of
ductive units of cells, provide an important Eo = - 0.185 volt. By retainingmost of the
example of molecules held together by specific structuralfeaturesanclaltering its redox potential,
hydrogen bonds. The genetic code of the cell, one may develop compoutrds antagonisticto
w,hich constitutes the instruction for the riboflavin.Kuhn prepared the analogue,in which
synthesisof the cell proteins,is presentin the cell the two methyl groups oFriboflavin were replacecl
nucleus.in the form of DNA. The code consistsof by chlorinesand havinga potentialof Eo = - O.O95'
sequences of 4 purine and pyrimidine bases- volt. lts antagonistic properties.are due to the
pyrimidine pairs are held together by specific dichloro-dihydro form being a weaker reducing
hydrogen bonds. agent than the dihydro form of riboflavin.It may
be absorbedat specific receptor sites but not have
CHr a negative enough potential to carry out the
"-*.H------q
N biologicalreductionof riboflavin.
N----H -
H{/
N
\ \R
H.rc
I
R
Hrc N
Adenine Thymine ICH,'(CHOH)3CH20H
lH
-N
o-__------H
N
H {/
N
\ I
I R
R I
H RiboflavinanalogueEo = - 0.095 V
Cytcine (3) The optimum anthelmintic activitv in a
Thus H-bonds pla/ a key role in maintaining series of substituted phenothiazinesis associatecl
the structuralintegrig of the basepairs of DNA. with the E- potenti,alof 0.583 volt (acetic acicl -
2.7 OXIDATION- R,EDUCTIONPOIENTIATS water) which coulcl lead to maximal formation of
The tendency of a compound to give or to semiquinone ion (a radical ion) at physiologic pH.
receive electrons,is measuredquantitatively by its (against mixed infestation of Syphacia obvelata
oxidation-reductionpotential or redox potential. and Aspirculurus tetraptera in mice). The
Sincethe oxidation-reductionpotentialapplies semiquinone facilitates an essential biological
to a single reversibleionic equilibriumwhich does electron transfer reaction, producing a toxic or
paralysing effect.
not exist in a living organism, the correlations
The necessityof a free 3 or 7 position in the
betweenredox potential and biologicalactivi! can- phenothiazinenucleusfor significantanthelmintic
only be drawn for the compoundsof very similar activity and the inactivigl of phenothiazine
structureand physicalproperties. Followingare the tranquillisingclrugs (2-substituted1O-dimethyl-
examples: aminopropylphenothiazines)is only due to the
(1) The optimum bacteriostaticactivity in clifficulty of correlating redox potential and
quinones is associatedwith the redox potential at activitSr.
+ O.O3volt, when tested against Staphylococcus 2.8 BIO-|SOSTERISM
aureus.
(2) The biologicalactivityof riboflavinis due In SARstudiesand drug design, it is always
to its ability to acceptelectronsand is reducedto necessaryto compare the formal and three
Principlesof MedicinalChemistryflol. ll)
climensional structure with the substituent and
functional groups of compounds that show a
similar spectrurn of biological activities. In most
instances,one may find similaritiesin molecular
shapeand overall chemical functionsand will base
one'sexplanationof biologicalsimilaritieson these
resemblances. This total complex of analogiesthat
comprisessteric, electronicand molecularorbital
comparisonis calledbio-isosterism.
Bio-isostericreplacementis the principalguide
followed by medicinal chemists in developing
analoguesof the 'lead' compound, whether as
agonistsor antagonistsof biological effects.The
parametersbeing changeclare molecularsize,steric
shape, bond angles, hybriclisation,electron
lipiclsolubiligr,water solubiligr,p Ka,
clistribution,
the chemical reactivig to cell components and
metabolisingen4ymesanclthe capacitSl to undergo
H-boncling(receptorinteractions).
In order to developa new drug the structureof
the drug is consideredto consist of two parts,
(l ) Crltlcal or essentlal.
(2) Non-crltlcal or non-essentlal : The non-
critical part allows sufficient changes without a
considerablechange in the biological activigl. The
variousmolecularmodificationscloneon this non-
critical part are c.lassifiedas follows.
(a) Selectophores Those modifications
which confirm selectivitSl action of the drug by
regulatingdrug clistribution.
(b) Contactophores : The modifications
which by increasingpenetration,help the drug to
reachthe receptorsite.
(c) Carrler moletles or conductlng moletles
: Thesemoietiesincreaseaffinity of a drug.
Thusnon-criticalpart of a drug moleculeis not
involved in drug receptor interactionsbut is
involved in passivetransportof the clrug.
16 Physico4hemicalParameters
& DrugActlon
While any change or modification of critical
part of the drug molecule will result in the change
of its biological activig, ohly those groups having
similar steric, electronic and solubility chara-
cteristicscan be interchanged.The study of such
groups (bio-isosters)and their application in
medicinalchemistryis known as Bio-isosterism.
More recently Burger classifiedand subdivided
bio-isostersas :
(l) Classlcalblo-lsosters:
(a) Monovalentatoms and groups,
e.g.CH2,NHz,OH andSH.
(b) Divalent atoms ancl groups,
e.g. R-G-R, R-NH-R, R-CH2-Rand R-Si-R
(c) Trivalentatoms and groups,
e.g.R-N = R, and R-CH = R
(cl) Tetrasubstituteclatom.
e.S.,= C =, = NO =, and= lS=
(e) Ring equiValents
e. g. - CH= C H - , - S - , - O-, -NHand -C}lz-
(2) Non-classlcal blo-lsostens :
Thesenon-classicalbio-isostersdo not rigidly
fit the steric and electronic rules of the classicbio-
isosters. These are further subdivided into.
(a) Exchangeablegroups (b) Rings versus non-
cyclic structures.
BIO-ISOSTEN.IC
APPTICATTONS
(l ) An importantcompounclof catecholamine
seriesis phenylephrine.
OH
I
CH-cHz-NHCH1
Phenylephrine
"-)
nntnctcs ot lledicinalChemistry(Vol.ll)
An alkylsulphonamiclo group may be substi-
ruted for the phenolic hyclroxyl group. Some of
the resulting compouncls have agonist activig
whereasothers are antagonist.
OH
I ,H -
CH- CH. - NH,
RO,SNH
Alkylsulphonamidophenylethanolamine
While a classicexampleof rings versusnon-
qyclic structuresis diethylstilbestrolancl estracliol.
Diethyl stilbestrol
OH
HO
Estradiol
Diethylstilbestrolhas about the same potenq/
as the naturally occurring estradiol. The central
double bond of diethyl stilbestrol is highly
important for the correct orientation of the
phenolic and ethyl groups (tians) at the receptor
site. Table 2.6 contains a variety of bio-isosters.
including classicaland non-classicalexamples,
incorporatingmarketed drugs as well as interesting
.experimentalcompounds.
OH
I I
CH- cHz- NHCH1
o N
\H
Roz
Receotor
17 Physico-Chemical
Parameters
& DrugAction
Applicationof bio'isosterismwere also found
in the designing of histamine - l - receptor
antagonistsand anticholinergics(antispasmodics)
by replacingbenzeneby thiophene,
/N-,
-CH2 by O or S andsoon.
The first applicationof classicalisosterismmay
be founclin ring equivalents.Examplesinclucle
pyridineand thiazole,benzeneand thiophene.
The sulphur atom of the phenothiazinering
system of neuroleptic agents was replaced by
-CH = CH - or -CH2CH2- leadingto the azepinering
analogues that openecl up the held of tricyclic
antidepressants.In imipramine by isosteric
exchangeof -N - with -c =, amitriptylinewas
obtainecl.
The .purpose of molecular moclificationis
usuallyto seek subtle change in the compound
that shoulclnot alter some propertiesbut change
others in orcler to improve potency, selectivi\r,
clurationof action and reduce toxicig. Bioiso-
sterism makes it possibleto limit some of these
changes. All aspects considered, retention of
overallmolecularshapeis the overriclingcondition
for analogyof action.
In the clesignof bio-isostersan appreciationof
the biochemical mocle of action may play an
importantrole e.g., aspirinace$rlatesprostaglanclin
synthetaseancl thereby deactivatesthis enzyme
which orclinarilycatalysesthe biosynthesisof
nociceptive prostaglandins.lsostersof aspirin in
which the phenolic oxygen atom (X) has been
replacedby 'classical'isostericgroups or atoms are
inactive becausethey cannot releasethe acetyl
group at all (X = CH2)or at an adequaterate (when
x =s,NH).
OH
CH-cHz-NHCH3
Receotor
7

3.1 NTnODUCTTON
31 INTRODUCTION
Drug undergoes metabolism which leaclsto
lossof its physiologicalactivig and an increasein
BIOTRANSFORMATION
METABOLIC
the polari! and water solubilityof the drug which
resultsin more rapideliminationof the metabolite.
3it REACTIONS
CONJUGATION
The metabolism of any clrug is generally
characterisedby two phasesof reaction, namely
3.4 OXIDASEENZYMES
CYTOCHROME
metabolic transformation(biotransformation)and
conjugation.
FACTORSINFLUENCING
METABOLIC
PATHWAYS
Metabolic transformations or biotrans-
OF DRUG
formations are enzyme reactions in which ctrug
may undergo a wide variety of oxiclation,
&6 INDUCERS
OF DRUGMETABOLISM
reductionand hydrolysis,resulting in the intro-
duction or unrnaskingof functionalgroups which
3.7 INHIBITORS
OF DRUGMETABOLISM increasethe polarily ancl hydrosolubilityof the
molecule and serve as the centresfor the second
phaseof metabolicreactioni.e., conjugation.
Conjugation reactions are biosynthesisby
which the drug or its metabolites are combined
with endogenousmoleculesor groups, such as
glucuronic acid, sulphate, amino acids, acetyl
group or methylgroup, makingthe moleculemore
polar, less lipicl solubleanclthereforeit is readily
excreted.
Most drugsare metabolised,at leastto some
extent, by both phasesof metabolisme.g., acegl
saliqylicacid undergoeshydrolysisto saliqylicacid

(te )
 niupts of MedicinatChemistry(Vot.ll) A DrugMetabolism

The latter is rapidly oxidised to acetic acid by (s)

acetaldehyde oxiclase and other enzymes. This
reaction is irreversibleand proceeds faster than the
former. Acetic acid, then may enter the N
tricarbo>qrlicacid qycle ancl reaches to final stage H3CO CH,
of oxidation to CO2. N
CH3CH'OH= CH3CHO -----+ CH3COOH H3CO NHz
J TCn qycle
Trimethoprim

-(2) Chloral hydrate is transformed to

trichloro-aceticacicl by alclehydedehydrogenase. N
CI OH CI HsCO CH
tl I _COOH I
cl -c--cH oH CI - C OH N
I I HsCO NHt
CI CI
(6)
Chloralhydrate Trichloroaceticacicl
(3 )

so,NH - coNH - CHz- CH2_ CH3

cHr cHr
Chlorpropamide

NH

so2NH
COOH COOH
OH
Met'enamic
acid Hydroxymethyl
derivative
Ketone oxldatlon : e.g.
(7) o
CH cooH il
CzHs

Acidderivative
(4)

Methadone

CH., /\
CH,OH
\/
)Ft

cooH COOH

Clonixin 4-dimethylamino
- 2, 2-cliphenylpentanoicacid
 \

Principleeof MedicinalChemistrypot. tt) 2 DrugMetabollsm

(8) ococH3 (e)

..C = Q|l
+ (CHJ:-N= O
Trimethylamine tnmetnytamlneoxide
o (10) Sulphoxlclatlon
tl
HrC-c-o
Ethynodiol
diacerate
N CI
IcH2cH2CH2N(CH3)2
OH
Chlorpromazine (o)
o
tl

CI
Norethisterone
cH2CH2CH2N(CH3)2
Chlorpromazine
sulphoxicle

CzHs
HN
cH(cH3)cH2cH2CH3 HN
o (o)
N
N
H
H
Thiopental
Pentobarbital

O,,N O- P= S
| (o) ozN O-P=O
oc2Hs
oc2H5 oc2Hs I
Parathion
oc2H5
Low anticlrloine-estrase
activitv Paraxon
High anticholine-estrase
activitv

Microsomal
oenydrogenase
-

Medazepam 2-hydroxymedazepam
Diazepam
tlg. 3.3
 ffol. ll)
nnciltcs of MedicinalChemistry B DrugMctabollsm

(11) carbonyl compounds generates alcohol deri-

vatives, while nitro and azo reduction leads to
amino derivative. Since the hyclroxyl and amino
HN groups are much more susceptibleto conjugation
than the functional groups of the parent
compounds, reductive processes facilitate the
H drug elimination.
Pentobarbital
(o) Examples:
(t )
czHs OH
HN I_ - H,O
chc- C OH -.+ CIIC_ CH'OH
-c H r I
H
H OH
Chloral hyclrate Trichloroethanol
Pentobarbitalalcohol
Other oxldatlve reactlons : These include (zl
sulphur atom replacement reaction and ring NH'
formation. Former is an important and significant
metabolic reaction for thiobarbiturates and for +H
phos phoroth io n a t e in s e c t icid e s. P a ra t h io n Nitroreductase
through the latter reaction, is transformed to a
very toxic compound, paraxon (an active HOCH o HOCH
UHO
cholinesteraseinhibitor in mammals) by the liver I ll ltl
CH-NH-C-CI{CI,
microsomesas shown in Fig.3.3. I
cH2oH CH-'OH
IBI Reductlon:
Chloramphenicol Arylamine
Theseprocessesplay an important role in the
metabolism of many compounds containing
carbonyl, nitro and azo groups. Biorecluctionof
(3) NH.

H,N N= N so.,NH" *H
, ?
Azoreductase
NH"
Prontosil sozNH' NH"
ulphanilamide

( l ) Bis-N-de-methvlation
o
+(2) tl
Oxidative
deamination CHCH,C- H
(4)

Chlorpheniramine cHcHrcH,OH Reduction

 A DrugMetabollsm
Principlesof MedicinalChemistryffol' ll)

(s)
o
tl OH
I
OH OH
cHC6Hs + [H]
cHc6H5

R (+) Wartarin

(6)

C H r - C H - CHr
[+ H] I
a T\TIJ
r\rlt o OH

AmDhetamine Phenvlacetone l-Phenyl-2propanol

(7)

O rN HzN

Clonazepam

tcl Hydrolytlc Reactlons: generally are polar and functionally mcre

Themetabolismof esterand amide linkagesin
many clrugs is catalyseclby hyclrolyticenzymes
presentin liver, kidney, intestine,bloocland other
tissues.The metabolic products formed, namely
carboxylicacids, alcohols,phenols and amines
susceptibleto conjugationand excretionthan.the
parentesterand amides.
Amide hydrolysis,qlpearsto be mediatedby
liver microsomal amidases, esterases and
deacylases.
hinciplec ol MedicinalGhemlgtry(Vol.ll) 6 DrugMetabolism

cooH cooH
(l)
ococH3 ol{ o
tl
+ HO-C-CHr

Aspirin acid
Salicyclic Aceticacid
(2)
ls€Cl o - c -cooH
I
cHr cHr
Clof,rbrate P-chlorophenoxyi
sobutyricacid

(3)

I
Metabolite
Carbamazepine COOH
CH.COOH cHlo CH"COOH
_f

N CHr N CH.t
I-o I
c H

lndomethacin

(5 )
NH, + HOOC

cHl cHi
Lidocaine

(6)
+ HO - CH2CH2N(C'H5)2

coocH2cH2N(c2H5)2 cooH
Procaine Para-amino
benzoicacid Diethvlaminoethanol
/

of Medicinal
Principles ffd. ll)
Chemistry 26 DrugMetabolism

IDI Other lmportant Reactlons;

(l) N-clealkylaflon :

CHI

Aminopyrine antlPYnne
O-dealkylatlon:
NHCOCH3 NHCOCH3

HsC2O HO
Acetophenetidine p-Hydroxyacetanilide

H3CO
Codeine Morphine

Aromattzatlon:

COOH COOH

Cyclohexane
carboxylic
acid Benzoicacid

3.3 CONIUGAnONnEACT|ONSOR PHASEIr for example, decreasethe polari$l of clrug

R.EACTIONS
Metabolic transformationsor phase - |
reactions,clo not always produce hydrophllic
(more polarand water soluble)or pharmacologlcally
inactlve metabolites.Drugs exhibiting increased
activi$l or activi$l different from the parent drug,
generally undergo further metabollsm through
conjugation or phase ll reactions, resultlng ln
deactivationand excretionof the inactlve,hlghly
polar conjugates.All the phase ll reactlonsdo not
increasethe polarity. Methylation and ace$llatlon,
metabollte.
Phasell reactionsare classlffedmalnlyinto :
(a) Methylation and ace$llationwhich do
not generallyincreasewater solubilltybut serve
mainlyto termlnatethe pharmacological activlty'
(b) Attachmentof small,polar and ionisable
endogenousmoleculessuch as glucuronicacid,
sulphate,glyclne and glutamlneto the phase I
metabollte.
(c) Of mlnor importance,are the other
conjugattue pathways e.g. coniugation with
Principles
of Medicinal (Vol.ll)
Chemistry 27 DruqMetabolism

Table 3.1 : Phasell or coniugatlonreactlons

Conlugatlon Slte Conlugating agent functlonal grouPs

Glucuroniclation Microsomes UDPGA - oH,- cooH,- NHz,- SH
Sulphatation Cytosol PAPS - oH, - NHz
Acetvlation Cytosol Acetyl-CoA - cooH
Glutathion Cytosol Clutathion Epoxides,arene oxides
Methylation Cytosol SAM -oH, -NHz
Amino acid Cytosol Glycine - cooH
UDPGA: urlcllne dlphosphoglucuronlcaclcl, PAPS: 3'-phosphoadenoslne-5'-phosphosulphate
SAM : S-aclenosylmethlonlne

glycosicles,phosphate, other amino acids and (2) Subsequenttransfer of the glucuronic

conversion of cyanicleto thiocyanate. group from UDPGAto an appropriatesubstrate.
-Thusphase Il reactionsinclucle
(l) Glucuronicaciclconjugation. Uridine-5'-diphospho-c-D-glucuronic
Acicl
(ll) Sulphateconjugation. (UDPGA)
(tlt) Coniugationwith glycine,glutamineand
other hmino acicls. UDP- glucuronyl Substrateclrug
(lV ) Clu t a t h i o n e o r m e r c a p tu r i c a c i d transferase
conJuganon.
(v) Acegrlation. p-glucuronicleof the substrate
(Vl) Methylation. The transfer step is catalyseclby microsomal
(VIl) Nucleosicle and nucleoticleformation. e n z y m e s called UDP -glucuronylt ransf erases
presentmostly in the liver but also occur in many
(l) Conlugatlonwlxh Glucuronlcaclcl :
other tissueslil<ekiclney,intestine,skin, lung and
The reaction involves the conclensationof Dr a ln .
the clrug or its metabolitewith the activatedform Types of compouncls formlng glucuronlcles
of a readilyavailableglucuronicacicl,[i.e. uridine
( I ) Alcohols ancl phenols form ether type
cliphosphateglucuronic acid {UDPGA)1,which
glucuronides.
is synthesisecl from glucose-I ,phosphate.
(2) Aromatic and some aliphatic carboxylic
Gluctrronic acicl conjugation proceeds in two
steps. acids form ester type glucuronicles.
(3) Aromaticaminesform N-glucuronicles and
('l) Formation of the activateclform from
(4) Sulphhydrylcompounclsform
glucose I- phosphate.
S-glucuronicles.
Phenols,alcohols,aminesand amiclesall form
Phosphorylase O- or N- glucuronicles. Many enclogenous
Glucose-
| -Phosphate
substances,like steroicls,are also excreted in this
Uricline-5'-cliphospho-
o-D-glucose(UDPG) way. Glucuronicles are nor.mallynon-toxic, highly
water solubleanclexcretedin the urine or bile.
Uricline-5'-cliphospho- Glucuroniclation of one functionalgroup is
cr-D-glucuronic acid usually sufficient to effect excretion, diglucuro-
(UDPGA) rogenase
nide coniugatesusuallyclo not occur.
7

Principles
ol Medicinal
Chemistryflol. ll) a DrugMetabollsrn

Compounds contalnlng hydroxyl group :

- CH. o
il
NHC- c H l
OH o
I _CH il
ozN CH - NH C_ CHCI,
| .--...

rH o) OH
I

Morphine Acetaminophen Chloramphenicol

(ll) Compounds contalnlng carboxyl group :

CH COOHi CH COOH)

oc6H5
Salicvlic
acid Naproxen Fenoprof'en

(lll) Aromatlc amlnes :

c-cH-1 ;NCH'CH.,
f-
c6H5cH2
CHrCH.,CHrrNHlCH3

Desipramine
o
Meprobamate Tripelennamine

0v) Sulphhydryl compounds : ( v )c - Glucuronlde :

tn-*

nC,Hj OH Siteof glucuronide

I o tbrmation
cHr
Methimazole Propylthiouracil Phenylbutazone
Prlnciplesol MedicinalChemistry(Vol.ll) E DrugMetabolism

o o
ll tl
HO - S -o-P-o-cH2
il I
o oH
OH
o.
I ll
HO
(ll) Sulphate conlugatlon :
Sutphate. con\ugate,s are tormed by \he
reactions of phenolic and aliphatic hydro4yl group
and of certainamino groups with an activatedform
of sulphatethrough an ether linkage. Hence they
are also termed as "etheral sulphates".Sulphate
conjugationgenerally results into highly polar
compoundsthat are readily excreteclin the urine.
The soluble fraction of liver contains the enzvmes
that catalyse the sulphur activation and transfer
of sulphate to the substrate.
The sulphate moiety is present in activatecl
state in 3' - phosphoadenosine - 5' - phospho-
sulphate (PAPS).The sulphotransferase enzyme
then catalysesthe transfer of sulphate group to
the phenolic acceptor. The sulphotransferase
en4ymesare structurespecific.Hencefor clifferent
substrates, specific sulphotransferaseenzymes
catalysethe reactions.
(lll) Con;,tt",lon wlth glyclne, glutamlne and
other arnlno aclds :
The amino acids, glycine ancl glutamine are
utillsecl by mammalian systems to con.iugate
carboxvlic acicls. ln contrast to lucuronicacicl.
o OH
tl
c-cH2cH2cHr-N
Adenine
o
P -oH o-s-oH
tl tl
o o
SultateconJugate
glycine and glutamine are not converted to
activated torm. lnstead the carboxvlic acid
substrate is activated with ATP to acetyl CoA
complex. This complex then reacts with glycine
and glutamineto form conjugateancl free-acetyl
Co-en4ymegroup.
(lV) Glutathlone or Mercapturlc acld conlugates
The glutathioneconjugationis important in
the eliminationof polycyclicphenolsanclhalicles.
The metabolicallygeneratedreactiveelectrophilic
species manifest their toxicity (e.9., tissue
necrosis,carcinogenicity,mutagenicity, terato-
genicity) by combining covalently with nucleo-
philic groups presentin vital cellularproteinsand
nucleicacids.The tripeptide,glutathione(cysteine
glycine-glutamate)may be couplecl via its
sulfhyctryl group to various compounds
possessingan electrophiliccentre.
group (-SH), of glutathione
The sulfhyclryrl
reactswith these electrophilicspeciesto form S-
substituted glutathione aclclucts ancl thus
protectsthe vital cellularconstituentsby effective
disposalof electrophiles(i.e., reactiveepoxides).
o
II
COOH+ F C-NHCH,COOH

Haloneridol Paraflurobenzoic
acid Glycineconjugate

o o o o
!t il tl tl
C NHNH2 C -o H C NHCH.'
C -()H

Hydrolysis

Isoniazid Isonicotinic
acid Glycineconjugate

.a
Principlesof MedicinalChemistryflol. ll) c) DrugMetabollsm

cuH\ CH., cuH\ cooH

I
cHo- cHz
l-
-o_scH ,_C H
CoHi I
cooH HlC _ CONH
Diphenhydramine Mercapturic
acidconjugate
o o o o
il tl ll tl
/'c
cHs N CH.' NH CH,

CS H
CH

OH OH
Acetaminophen Mercapturicacidconjugate

(3) NH - CQCH-I
e I
CH'CI --.+ CHr ' + c H z -s -c H " - c H - c o o H

Benzylchloride Mercapturic
acidconjugate

( 4) c'Hsooc cooc'H5 ooc'Hs

\/
\,

C=C
tl
c-c
H,\
HH

NHCOCH.I
Diethyhnalcate Mercapturic
acidconjugate

I
I
I
I
I

I
I-c-g, I orH S -G

!--------______________J

Glutathione
Principlesol MedlcinalChemistryffo!. ll) 3l DrugMetabolism

( l) S
ll HSG
Noz GS - C F l . + G S Noz

MethylParathion Glutathione
conjugate

HSG
t)\ CHz- cH,-c
-l =Q GS-CH2 -

H H
Glutathione
conjugate
o
HSG il
(3) CH. - C H= CH - C H = O -CHz- cH
Crotonaldehvde SG conjugate
Glutathione

C
CH.

H
(4) I HSG
ocH"cooH c
/
=f GS_ CH' ocH,cooH
q R CL.
tl
o
Ethacrynic
acid adduct
Glutathione
SG
(5 ) coocH.l coocHl
H_SC

cHr
Arecoline Clutathione
adduct

Paracetamol,busulphanand azathioprinear6 acegl group is catalyseclby N-acetyltransferase

other examples of clrugs conjugated by this
pathway.Glutathioneconjugatesare polar and of
high molecularweight and are eliminatedas such in
dte bile. The glutathioneportion of the conjugate
may further be metabolisedvia the pepticlebond
io mercapturicacid that are the normal urinary
productsof this conjugationpathway.
{V) Acetylatlon reactlons :
Acetylationreactionsserve as an important
metabolicroute for clrugs containing lo-amino
groups, sulphonamides,hydrazinesand hydra-
rides. which upon conjugationget converteclto
1'dr correspondingamide derivativeswhich are
ccneraltyinactive and non-toxic. The transfer of
enzymes present mainly in hepatic reticulo-
enclothelialcells, which ctisplaybroad substrate
specificity. Thus aromatic primary amines
(e.g., sulphonamides)and hydrazinederivatiyes
(e.9., isoniazicl)are acetylatecl,utilising acetyt
coen4/me A. The acegl transferaseappearsto be
locatecl in the soluble fraction of reticulo-
endothelialcells presentin the liver and kidney.
Becauseof a lowereclsolubilityat aciclpH, there i_s
the clangerof injury to the kiclneyresultingfiom
precipitationof the conjugateclsulphonamidein
the renal tubular fluicl as the l<iclneyconcentrates
urineand lowersits pH.
Principles
of Medicinal
Chemistry
flol. lt) p DrugMetabolism

CH.,
(l) Aliphaticl" amines:
N. CH, NH) N-Acctyltransf'erase cll.' NH C OC H T

Histamin
e
cH.lo ClH.2 CH.
.C HrCO
H) N-Acctyltransti'rlsc CH,
I t-
cH30 NH, HlCO
I
N H C OC H I
ocH.l ocHl
Mescaline
(:2)A romaticAmines
N-Acctyltransl'crasc

N(C:Hi: N (C .H r).
O=C- NHC H,) O =C- NHC
Procainarnide

N-Acetyltransf'erasc

SO, NH, so., NH.

( )ne
Daps
(J) Sulphonamides
: NH' N H C OC T{1

N-Accty!translcrusc

Sulphapyridine .S ul phl pvri cl i nc

(4) Hydrazines
and CH,CH-'NHNH,'
Hydrazides: CH,CH.'NHNHCOC'H.

N-Acetyltransl'erasc

Phenelzine
CONHNH,'
coNHNHCOCHI
N-Acetyltransf'erase

trsoniazid
Prlnclples Ct|cmbw (vol.ll)
of Medlcinal 3 Drug llcttbolbm

NHCH\
OH OH
Norepinephrine Epinephrine

(Vl) Methylatlon Reactlons : or S-methylated respectivety.These enzymes are

Methylation differs from other conjugation
processesin that,
( I ) lt ts of greater significance in the
metabolismof endogenouscompounds.
. (2) In some cases,it results in the proclucts
having greater pharmacologicalactivity than the
parentmolecules.
In these reactions, methioninetransfersits
methyl group via the activated intermediate, S-
adenosylmethionineto the substrate under the
influence of methyl transferaseenq/mes. Drugs or
their metabolites containing primary aliphatic
amine, phenolicor sulflrydrylgroupmay be N-; O
(l) O-methy'atlon:
as follows :
(l) Catechol-O-methyltransferases(COMT)
They catalyseO- methylation of catecholamines.
(2) Hyclroxyindole-O-methyltransferases:
They catalyse O-methylation of substrateother
than catecholamines.
(3) N-methylationis catalysedby substrate
specificenzymes.e.g., phenyl ethanol amine-N-
methyl transferase,lmiclazole-N- methyl trans_
ferase.
(4) S-methyl transferases: They catalyse
S-methylation.

Hydroxyindole-O-methyl
COOH cH.ro COOH
transferase

4-hydroxy-3,5-diiodo
benzoicacid

Catechol
O-methyltranst'erase
HO COOH cooH
-

4-dihydroxy-benzoic
acid
Principlesof MedicinalChemistry(Vol.ll) s DrugMetabolism

Table 3.2
Mammalian Phase ll ConiugatlngAgents
Type of Coenzyme form Transferase
conjugate Enzyme
Uricline 5'-cliphospho-cr-D-gl ucuronic acid
GIucuronicle (UDPGA)
O
COOH
NH -oH, - cooH, -NH2 UDP-Glucuronosyl
Ho oo - NR,-SH, C_ H transfer,ase
HO

HO OH
Su lfate plratc NH'
.3'-Plrosphoaclctlrstnc-5'-phosplrosul
(PAPS) N
N
o o -oH, -NHz Sulfotransferase
tl
HO-S-O
ll I
o ol-l

H.,O.PO OH
Clu t at h i o n e Activatcdacylol aryl cocnzyme

o
COOH
+ GlycineN-
(Ar) acyltransferase

(GSH)
Cl ut at hi onc NH'
'',"',,cooH
Ar-X, areneoxicle,
epoxicle,carbocation Glurathione
S-transferase
t'lAcooH Acetvlcoenzvme
A
H
-OH, -NHz Acetyl transferase
H:C s/cuo
M et h y m e t h i o n i n( SAM
-Aclcnosyl e )

CH.1
-OH, -NHz,
heterocyclic Methyl transferase
HOOC

NH,
OH
Principles
of MedicinalChemistry(Vol.ll) s7 Drug Metabolisln

Metabolic oxldations catalysecl by cytochrome p - 450

{a)Ringhydroxylation
:

so"NH-C-NH
-tl SO,NH-C-NH
-tl
o o o o
Acetohexamide
(b) Olefinoxidation:

orJ
.o
I

HO
{c) Aromaticoxidation NIJCOCFI NHCO CHI NHCOCHT

-+

(d) N-Dealkvlation
:

N I\I

Ic'

I tttiprunrinc

'l\ t-

I
( c'H. J, - \H C II.
Dcsrpr i l mi r r c
(e)Deamination:

OH OH OH

N NH'' +
| _._>
Principleeof MedicinalChemlstryflol. ll) 38 DrugMetabolisn

3.5 TACTORSINTLUENCING METABOTTC The rate of elimination of many lipophilic

PAII|WAYS OT THE,DR,UG clrugs thus depends upon the activity of these
In most cases,the metabolism of a drug is a hepatic enzymes.Consequently,any alterationin
first order processwhich means that a constant the activitSlof these enzymes may result in the
fraction of the drug is metabolizedin unit time. fluctuationin the drug activi!. En4ymeinducing
Saturationof one metabolic pathway may allow for agents can causean increasein the rate of drug
a shift in the metabolic pattern of a drug. Thus metabolism. Such agents include phenobarbital,
after paracetamoloverdosage,the glucuronideand steroidal hormones (e.g., estrogen, androgens,
sulphate conjugation pathways become satu- progestins, and corticosteroids),p-naphtho'
rated, making available a greater fraction of the flavone, ethanol, 3, 4-benzpyrene, rifampicin.
dose for oxidation to a reactive and potentially p h e n yt o in, phenyl-butazone, glutethimide,
toxic metabolite where glutathione conjugation carbamazepine,etc. Enryme induction not only
playsan important role. reducesthe drug activit5rbut may also decrease
lmportant factorc that affect metabollc pattem toxicity in some cases. However, the effects ol
of the drug Include : enzyme induction and enzyme inhibition are
(1) Dose and frequenqyof administrationof reversible. As soon as the interacting agent is
withclrawn,the metabolizingability of enrymes is
drug.
brought to normal level.
(z) Speciesand strainof animal used.
(3) Diet and hutritional status of animal and Stimulation of clrug metabolism may result
the sex and weight of the animal used. due to
(41 Routeof administration. (i) an increased rate of synthesis of new
(s) Time of administration. en4/me proternsor
(6) Interactions with other drugs and (ii) decreased rate of clegr.rdationof drug
environmentalcontaminations. metabolizingenrymes,and
(7) Pregnancy and psychological abnor- (iii) an increasein the amount of smooth
malities. endoplasmicreticulumthat servesas site
(8) Inducersof drug metabolism. for drug metabolism.
(9) Inhibitorsof drug metabolism. Phenobarbital treatment increases the
Age of the patient govems the pattern of amountof microsomalproteinsper gm of liver and
drug metabolic pathways. For example, the extent also causesan increasein the amount of smooth
and types of drug metabolitesobservedin very olcl encloplasmic reticulumof the liver.
patient is different from that in very young The blockage of enzyme induction by
patient. Besidesthis, normal adult handles the actinomycin or puromycin (protein synthesis
drug in quite a different fashion inhibitors)suggeststhe role of inducersat the level
3.6 INDUCER,S OF DR,UGMETABOLISM of transcription,resultinginto an increasein the m-
Although the liver is the main site for drug RNA synthesis.Thus the microsomal enzyme
metabolism,other sites like placenta,skin, lung, inducers increasethe rates of protein and DNA
gut or white blood cells also offer platform for dependent RNA synthesis. Different receptors and
metabolism of drugs. The hepatic microsomal genes thus participate in the induction ol
P-45Omixed functionolygenasescatalysenume- microsomalenryme activity, that is reflectedin the
rous biotran.sformationsby simply inserting increasedrates of synthesisof cytochromeP-450,
o4ygen into drug skeletons.Certain chemically clrtochrome P-45Oreductaseand other en4ymes.
reactivemetabolitesmay produce a range of toxic An enzyme inducer, 3, 4-benzpyrene is
effects by reacting covalently with egsential present in kidney, adrenalglands, placenta,gastro
cellularcomponents.Hencethe microsomalP-450 intestinal tract, pancreasand skin, can also be
mixed functionenzymes,therefore,play a key role inducedto a limiteclextent.
in goveming drug toxicity.
 Principles
of Medicinal
Chemistry
(Vol.il) GI DrugMetabolism

3.7 INHIBITORSOT DRUG METABOI,ISM (ll) Dlsulflram :

The enzyme inhibitors may display compe-
titive ancl non- competitive kinetics.For example, S S
tr"r\ c:Hs
cimetidine. MAO-inhibitors (tranylcypromine,
tl tl
N-C-S-S -C -N
iproniazid),disulfuram(alclehydeclehydrogenase) CrHr/ crHt
anclallopurinol(xanthineoxidase).Novobiocin has
been reported to causejaunclicein the new bom,
Disulfiramis yet another inhibitor of clrug
arisingfrom its inhibitionof bilirubin conjugation
metabolism.lt is devoicl of any pharmacological
with glucuronicacid.
activity of its own. lt specificallyinhibits meta-
Since microsomal P-450 enzvmes exhibit bolism of ethyl alcoholand hence,is usefulin the
broaclsubstratespecifici\r, many substancestry treatment of chronic alcoholism.The conversion
to occupy the enzymes competitively. Hence any of acetalclehyde intermecliate to acetic acicl is
clrug may inhibit the metabolism of another clrug. inhibiteclby disulfiram.
Prominentinhibitorsof drug metabolisminclucle, The accumulation of acetalclehyclein bocly
SKF525A, clisulfiram,MAO inhibitors,ailylbarbi- results into violent unpleasant syndrome
turates, clicumarol, phenylbutazone, piperonyl inclucling,flushing,clyspnea,nausea,vomiting and
butoxicle,sulfaphenazole,etc. Similarly various hypotension.The clrug inhibits an enzyme, acetal-
disease conclitions, like hepatitis, obstructive clehyde ciehydrogenase. Due to the vicllent
i.rundice,aclvancedcirrhosis,diabetes,or hypo- syndrome
that resultsfrom (itq\(\tq\ \t\
thyroidism may lead to the interference
or \\t
suppression of microsomal enzyme activity. treatmentof chronic alcoholism.the treatment
Recentlyit has been founcl that the hepatic clrug must strictly be given uncler the medical super-
metabolizing activitV is inversely proportional vision.
to (lli) MAO Inhlbttors :
the plasmaglucocorticoidatactivity.
Mono amino oxidases(MAO) is a group ot
enzymes that metabolizes catecholimines.
lproniazicle,phenelzineancl isocarboxazic.le are the
inhibitorsof MAO enzymes.
c - c o o - CH) CH ,_ N ( C ) H s ) , Sincetheseagents inhibit the metabolismof
I catecholamineswhich act as neurotransmitters
in
CH, S K F 5 2 5A brain, these agents are useful in the treatment
of
f- psychotic clisorclers.They are effective
MAO
CH,- CH., inhibitors,both, in vivo as well as in vitro.
(lv) Pyrazole:
(i) The drug SKF525 A is pharmacologicaily
lnactive but when aclministerecl Thoughit is a potent competitiveinhibitorof
alongwith another liver alcoholclehyclrogenase
clrug, like hexobarbital, prolongs cluration en4/mes, it can not be
of usecl clinicallydue to its severetoxici!.
hypnosis. The prolongation of action of
other Several structurallyunrelateclbut lipophilic.
barbiturates,amphetamine, and analgesicagents
has also been reportecl. lt also inhibits the non_ clrugshaving an allyl group in their structure,
were
microsomal metabolism (e. found to inhibit and destroy cytochrome p_45O
S, hyclrotysis of
procaine) and some glucuroniclationreactions eDzymes.Allyl barbiturates(e.g., secobarbital,
which require microsomesbut are not oxiclative allobarbital)increase the cluratiin of action
in of
nature. other clrugsby this mechanism.
Besiclesstarvation and parenchymal liver
SinceSKF525 A cloesnot have activi$ of its
damage,some clrugson chroniclong terlr use,
own, it can be used as a tool to fincl out whether may
depress the m icrosomal clrug-metab=ol izing system.
the activigr is due to the drug or clue
to its Such drugs inclucle,oxyphenbut"ron.,
metabolite. nt.trip_
lline, methylpheninclateand allopurinol.
 Principles
of Medicinal (Vol.ll)
Chemistry 'o DrugMetabolism

Table 3.4
Therapeutlc actlvlty of drug metabolltes
Parent drug Actlve metabollte(s)
Acetanilide N-acegrl-p-aminophenol
Acetohexamicle Hydroxyhexamicle
Acegrlmethadol Nor-acetylmethadolancldinoracegllmethadol.
Aclriamycin(doxorubicin) Adriamycinol
Allopurinol Oxipurinol
Amitriptyline Nortriptyline
Amphetamine p-Hydroxyamphetamine
Carbamazepine Carbamazepine-10,
11- epoxicle
Carbimazole Thiamazole(antithyroicl)
Cephaloglycin Desacetylcephaloglyci
n
Cephalothin Desaceglcephalothin
Cephapirin Desaceglcephapirin
Chloralhyclrate Trichloroethanol
Chlorcliazepoxicle N-clesmethylchlorcliazepoxicle,
demoxepam
Chlorpromazine 7- Hydroxychlorpromazine
Chloroguanicle Cycloguanil(antimalarial)
Chlorpropamicle Z-Hyclroxymetabolite, 3-hyclroxymetabolite
Clofibrate Freeaciclmetabolite
Codeine Morphine, norcocleine
Cortisone Cortisol
Daunorubicin Daunorubicinol
Diazepam N-Desmethylcliazepam,
N-methyloxazepam,
oxazepam
Digitoxin Digoxin
Diphenoxylate Difunoxine(free acicl metabolite)
Ethynocliol Norethisterone
Fenfluramine Norfenfluramine
Floctafenin Floctafenicacicl
Flurazepam N-clesalkylrnetabolite, flurazepamN3-ethanol

\
I
Principlesof MedicinalChembtry(Vot.ll) /tl
DrugMetabollsm

Parent drug
Actlve metabollte(s)
Guanethidine N-oxide metabolite
lmipramine Desipramine
Lignocaine N-desmethytmetabolite, N_didesethylmetabolite (glycine4ylidide)
Ae-tetrahydrocannabinol | 1-hyclroxymethyl metabolite
Mephobarbitone Phenobarbitone
Methsuximide N-desmethylmetabolite
B-Methyt ctigoxin Digoxin
Morphine Nor-morphine
MiracilD Hycanthone(schistosomicide)
Nalidixic acid Hydro4ynalidixicacid
Naloxone 6-p-Hydroxynaloxone
Nor-ethynodrel Nor-ethisterone
Oxisuran Oxisuranalcohols
Pethidine Nor-pethidine
Phenacetin Paracetamol
Phenylbutazone Oxyphenbutazone
Preclnisone Prednisolone
Primidone Phenobarbitone
Probenecid Side chain hydroryl metabolites,N_despropyl
metabolite
Procainamide N-aceglated metabolite
Propranolol 4-Hydrorypropranoror,
propranoror
grycor,N-Desisopropyr
metaborite
Quinidine 3-Hydroxyquinidine
Rifampicin Desace\rlatedmetabolite
Thioridazine Mesoridazine
Trimethadione Dimethadione
VitaminD 1, Z5-dihydrorymetabolite
Warfarin Warfarinalcohols
Zoxazolamine Chlorzoxazone
 of Medicina'l
Princlples Chemlstry
ffol. ll) a DrugMetabollsm

Table 3.5
Toxlc metabolftes of drugs
Drug Metaboltte Toxlclty of metabollte
Chloroform Phosgene Renaltubularand hepaticnecrosis
Dapsone N-Hydroxydapsone Methaemoglobinformation
Diazepam N-Desmethyl-diazepam Adverse autonomic neryoussymptoms
Glutethimicle 4-Hydroxy metabolite Metabolitecontributesto the coma produced by glute-
thimide overdose
4-Hyclrory metabolite Metabolite is twice as potent as parent drug in produ-
cing drug inducedataxia
Imipramine pramine
Z-Hyclroxy-imi Cardiotoxic(clepressedcontractility)
lsoniazid Ace\rlhyclrazine lsoniazid hepatitis results fiom liberation of aceld-
hydrazinein the body.
Lignocaine N-desethylmetabolite MEGX has convulsant activigr.
(liclocaine) (MEGX)
Glycineryliclide(GX) Adversely affected mental performance, caused
heaclachesand
(GX)
Glycinexyliclide Potentiatesseizures produced by lignocaine ancl
MEGX.
Methoxy-flurane Fluorideion Nephrotoxicity.
Methsuximicle N-desmethylmetabolite Metabolite implicateclin production of delayed coma
after methsuximideoverdose anclataxia.
Norethy-nodrel 3p-hyclroxymetabolite Dysmorphogenic i'

Paracetamol N-acetyl-p-quinoneimine Hepaticnecrosis

Phenacetin p-pheneticline Methaemoglobinaemia
Salicylate Semiquinoneradical Ren.rltubular necrosis
Testo-sterone Etiocholanolone $rrogenic ancl inflammatory reaction

ooo
 4.1 INTRODUCTION
To exhibit the same pharmacological action,
INTRODUCTION the two clrugs must possesscertain structural
featuresin common along with the same spatial
TYPESOF RECEPTOR arrangementof such groups. Such requirements
cannotlogica.llybe explainedunlessit is assumecl
that for a drug, in order to produceits pharma-
43 RECEPTOR
SITETHEORIES cologicalaction,it must reactor interactwith the
complementaryr chemicalgroupingsof a biologically
importantintegralpart of the organismknown as
FORCESINVOLVED
IN DRUG-RECEPTOR receptor.
INTERACTIONS The term receptivesubstanceor, receptorwas
coined to denote a relativelysmall region of a
macromolecule vr,hichmay be an isolableenryme,a
45 FACTORSAFFECTING
THEDRUGRECEPTOR structuraland functionalcomponentof a cell-
INTERACTIONS membraneor a specificintracellular substance like
protein or a nucleicacicl.Enzymesare biological
SPARERECEPTORS catalysts.Most enzymes are proteins but the
activesitesoften containgroupsother than amino
acicls.There are metalloenzymesin which zinc,
SILENTRECEPTORS iron, cobalt,manganese or other transitionmetals
are the catalyticcenters.Many enzymesrequire
cofactors- smallmoleculesboundto the enzyme-
MECHANISM
OF CA++-DEPENDENT
HORMONE to becomeeffectivecatalysts.Forexample,all the
ACTION '54 vitaminsfrom B complex familyare all cofactors.
Some enzymesare complexesof protein anctRNA
in which the RNA also parficipatesin catalysis
NON-RECEPTOR-MEDIATED
ACTIONS
OF e.g. ribosomes.
D R UGS Ion channelsmecliateion permeationwith
both efficiencyand specificity.lon channelsmay
be classifiedby a number of criteria inclucting
electro;rhysiologicalproperties(i.e., conductance,
activationand inactivation),ion permeation(i.e.,
sensitivig to specificdrugs).lon ch.rnnelsthus
may be reg.rrdecl as pharmacological receptorsand

,,1n\
Principlesof MedlcinalGhemistry(Vol.ll) 6 Receptar

(b) Rcccptors acdng through second The pharnnacologicalresponse of a drug

messcngcr : molecule is a function of dose. number of
Receptorsfor a number of hormones and receptors available and its intrinsic activigr. The
autacoids function by regulation of the concen- rate of combination of drug and receptor can
tration of the intracellularsecondmessenger,qyclic thereforebe expressed
adenosine3', 5' monophosphate (cyclic AMP) as K1[R] x [A]
through the activation of intracellularadenylate
qyclase.In this system,the receptor- drug binding where,
sites and enzymes catalytic sites are clearly on K, = association constant
separateproteinse.g. p-adrenergicreceptors.
R = concentration of the receptors not
(c) lntracellular receptors : occupiedby drugs and
Intracellularreceptorsplay a dominant role in A = concentrationof drug moleculesor dose.
the actionsof the steroid and thyroid hormones.
The steroid receptor complex undergoes a confor- Similarly,the rate of dissociationof the drug
mational change and is thereby activated. This receptorcomplex is given by the expression
activated complex then enters into the nucleus KzIRAI
and binds to acceptorsites on chromatin(actualor
true receptors),resultingin an increaseor decrease where.
in the productionof certain RNA'sand m-RNA's h = dissociation constant
along with the correspondingenqymesand other
proteins wlrich cause the steroid-hormone IRA] = concentrationof receptorsoccupied by
response. the drug.
4.3 R,ECEPTOR, SITETHEOR,IES At equilibrium
(a) Occupatlon theory : K1[R] x [Al = Kz[RAl
This theory, proposedby Gaddumand Clark, This relationship can be more conveniently
states that the intensity of the pharmacological expressed by taking account of the fact that
effect is directly proportional to the number of
receptorsoccupiedby the drug.

Adenylate
Cyclase Membrane
boundenzyme

Inactivation
ATP-Mg CyclicAMP 5'-AMP
complex I
I Phosphodiesterase
I
I
Proteinkinases + ) ActivatedProteinKinases

Biological
resPonse

Elg.4,2: H = Hormonc or A drug molcculc; R, R' = Rcceptor sltes

GTP= Guanoslnc trlphosphate
Principlesof MedicinalChernistrygol. ll) Receptor

IRI + [RA] is equal to [r] = total concentrationof occupation rather than to the proportion of,
receptors.Thus, . receptorsoccupied,equation (5) of rate theory is
important.
Kr [A] [r] - [RAj = Kz[RA] (c) The lnduced-fft theory of enzyme-substrate
... ( 1)
lnteractlon :
tRAI Kr [A] The induced-fit theory of Koshlandwas
Or
lrl K1[A] + K, originally proposed for the action of substrates
ancl enzymes. According to this theory the
1 + KzlKr[Al
,,,(z) receptor (enzyme)'neecl not necessarilyexists in
K2 the appropriateconformationrequiredto bind the
can be replacedby, KA = equilibriumconstant. clrug (substrate). As the clrug approaches the
Kl
receptor, a conformational change is induced
It is reciprocal of the clrug's affinigl for the which orients the essential binding sites. This
receptors. confortnational change in the receptor cou\d be
The term IRAI representsthe fraction of the responsible for the initiation of the biological
Irl response.e.g., acetylcholinemay interactwith the
total number of receptorsoccupied by the drug. regulatingprotein and alter the normal forceswhidr
WhenIRAI= [r], i.e. all the receptorsare occupiecl stabilise the structure of the protein, thereby
ancl the response is thus proportional to its proclucing a transient rearrangement in tire
intrinsicactivity,Xn. membranestructureancl a consequentchange in
its ion regulatingproperg.
RA] X
RelativereSponse = . . . ( 3) The receptorwas suggestedto be elasticand it
trI I + KA/IAI coulcl return to its original confcrrmationafter the
This theory cloes not rationalise partial clrug was released.The clrug may also undergo
"lgonists. conformationalchanges.
(b) Rate Theory: Accorcling to the inducecl-fit theory, an
Paton ancl Rang in 1965 proposed that the agonistwould inclucea conFormational change(i.e.
most important factor determining drug action is intrinsic activity) and elicit a response,but an
the rate at which clrug-receptorcclmbinationtakes antagonistwould bincl without a conformational
place. change (i.e., devoicl of intrinsic activigr). The
Therefore,the rate theory suggests that the macromolecularperturbation theory and the
pharmacological activigl is a functionof the rate of activationaggregationtheory are extensionof the
associationancl dissociationof the drug with the induced-flrttheorv.
receptor, ancl not ttre number of occupied (d) Macronnolecularperturbatlon theory:
receptors. Accorcling to this theory, Belleau proposecl
At equilibrium,the rates or comDtnatlonano that interaction of small molecules of clrug or a
Cissociation of drug-receptorreactionsare same substratewith a macromolecule(such as the
anclequation(l) can be rewrittenas protein or a drug receptor) may lead either to
Kr tAI(lrl- tRAl) K2 [RAI specific conformationalperturbations(SCP)or to
... ( 4 )
lrl trI non-specificconformationalperturbation(NSCP).
By simple mathem.rticalmanipulationfrom A SCP(specificchange in structure or confor-
equation(3), it can be shown that mationof a proteinmolecule)would resultin the
Kz specificresponseof an agonisti.e. the drug would
Rateof receptoroccupation = ...(s) possessintrinsicactivity.
l+
tAI lf a NSCPoccurs,no stimulantresponsewould
When the response is proportional to the be obtainecland an antagonisticor blockingaction
numberof receptorsoccupied,the equation(3) of may be procluced.lf'a drug possessesfeatures
occupation theory is important ancl when the which contributeto formationof both a SCPand a
responseis proportionalto the rate of receptor NSCP,an equilibriummixtureof the two complexes
 Principleeof MedicinalChemistry(Vol.ll) 4l
may result, which would account for a partial
stimulant action e.g. alkyl trimethyl ammonium
ions. Lower alkyl trimethyl ammonium ions (C1to
Co) alter the receptor structure in a specific
perturbation,thus stimulating the muscarinic
receptor.With a chain of 8-12 carbonatoms,the
antagonistic action is observed due to non-
specific conformational perturbation while the
intermediate, heptyl and octyl derivatives act as
partial agonists.
(e) Actlvatlon-Aggregatlon Theory :
It was proposed by Changeux and Karlin.
Accordingto this theory, even in the absenceof
drugs, a receptor is in a state of dynamic
equilibrium between an activated form (Ro),whictr
is responsiblefor the biologicalresponseand an
inactiveform (To).Agonistsshift the equilibriumto
the activated form, antagonists bind to the
inactive form and partial agonists bind to both
conformations.In this mode, the agonist binding
site in the Ro conformation can be different from
the antagonistbinding site in the To conformation.
If there are two different binclingsites anclconfor-
mations,then this could account for the structural
differencesin these classesof compouncls.
4.4 IORCESINVOLVEDIN DRUG.RECEPTOR
INTERACTION
Drug-receptorinteractionsinvolve one or more
of the following glpes of bonding :
(a) Covalent"-bondlng:
The stability of this type of bond harclly
permits the formation of an easily reversibledrug-
receptor complex. Only when the receptor is
inactivated by an irreversible antagonist, there is
the formationof covalentbond e.g. acetylcholine-
sterasesare irreversiblyinactivated by a number of
phosphate esters. The nitrogen mustards are also
ineversibleinhibitors of certain receptors.
(b) Hydrogen bondlng :
An important type of bonding between drugs
anclreceptorsis a weak and easilybrokenH-bond.
Since many drugs contain hydroxyl, amino,
carboxyland carbonylgroups, they can form H-
bonds with the receptorscomplex. The recluced
potency of many sulphur analoguesof oxygen-
containing drugs has been attributed to the
-, reducedability of sulphurto form H-bond.
Receptor
H-bondsare a gpe of dipole-dipoleinteraction
formed betweenthe proton of a group X-H, (where
X is an electronegativeatom,) and other electro-
negativeatom ffi containinga pair of non-bonded
electrons.X removes eleciron densigl from the
hydrogen so it has a partial positive charge, which
is strongly attracted to non-bonded electrons of
Y. The interaction is denoted as a dotted line, -X-H
... Y-. to indicatethat a covalent bond betweenX
and H still exists, but that an interaction between
H and Y also occurs.
The hydrogen bond is unique to hydrogen
because it is the only atom that can carry a
positivechargeat physiologicalpH while remaining
covalentlybonded in a molecule,and hydrogen
also is small enoughto allow close approachof a
second electronegativeatom. The strength of the
hyclrogenbond is related to the Hammett (o)
constants. There are intramolecularand inter-
molecularH-bonds;the Formerare stronger.
(c) Electrostatlcbondlng :
The charged ions produced by the clrug
moleculesmay be attracted to chargeclgroups
within the receptor site. For example, acetyl-
choline.
+
x - (cH3)3
N - cH2- cHz-ooc - cH3.
The positivelychargeclquaternarynitrogenof
acegllcholinemay be attracteclto the negative
chargeof an ionisedcarbo>qylgroup in the receptor
site.
(d) Dlpole-dlpole antl lon-dlpole interactions :
These forces are generally associateclalong
with electrostaticbondings.
o
il
-rl l
n4N ............N& R-9 - R
I
NRt
Ion-clipole Diple-clipole
The C-X bonds in clrugsancl receptors (where X
is an eldctronegativeatom) will have an asymmetric
distributionof electrons;this produces electronic
clipoles.The dipoles in 4 drug moleculecan be
attracted by ions (ion-dipole interaction) or by
other dipole (dipole-clipoleinteraction) in the
receptor, provided charges of opposite sign are
properlyalignecl.Sincethe chargeof a dipole is less
than that of an ion, a dipole-dipole interactionis
weakerthan an ion-dipoleinteraction.
Principlesof MedlcinalChembtry(Vol.ll) tA
(e) Charge transfer complexes :
When a molecule(or group) that is a good
electrondonor comesinto contactwith a molecule
(or group) that is a good electron acceptor,the
donor may transfersome of its charge to the
acceptor.This forms a chargetransfercomplex,
which, in effect is molecular dipole-dipole
interaction.Electrondonors containn electrons,
e.g. alkenes,al$nes and aromaticmoietieswith
electrondonating substituentsor groups that
have a pair of non-bonded electrons,such as O, N
andS moieties.
Acceptorgroups contain electrondeficientn
orbitals, e.g., alkenes, alkynes and aromatic
moietieshavingelectronwithdrawingsubstituents
or weakly acidic protons.
(fl Hydrophoblc forces :
ln the presenceof a non-polar molecule or
region of a molecule, the surrounclingwater
moleculesorient themselvesand, therefore,are in a
high energy state than when only the H2O
moleculesare around.When 2 non-polargroups,
suchas a lipophilicgroup on a drug and a non-polar
receptorgroup, eachsurroundedby orderedH2O
moleculesbecome disordered in an attempt to
associate with each other, this increase in
entropy, therefore,resultsin a clecreasein the free
energy that stabilisesthe drug-receptorcomplex.
Table 4.1
Forces Involved ln drug-receptor lnteractlons
Bond type Strength
Kcal/mol
Covalent 40 - 140
lonic (in solution) 5- lo
Hydrogen l -7
Dipole- dipole 1- 7
Hyclrophobic
Recoptol
This stabilisation is known as hydrophobic
interaction.lt is a reversibletype of bonding that
liberatesener$/.
G) van der Waals or London Dlsperslon forces
van clerWaalsbonds exist between all atoms,
even those of noble gases, and are based on
polarizabilityor the inductionof asymmet4tin the
electron cloud of an atom by a nucleus of a
neighbouringatom. Such forces operate within an
effective distance of about 0.4 to 0.6 nm and
exert an attractive force of less than 2 kJ/mol.
Therefore, they are often overshadowed by
strongerinteractions.
Atoms in non-polar molecules may have a
temporary non-symmetrical distribution of
electrondensity which resultsin the generationof
a temporary dipole. As atoms from clifferent
molecules(sudr as a drug and a receptor)approach
each other, the temporary clipolesof one molecule
incluce opposite dipoles in the approaching
molecule. Consequently, an intermolecular
attraction, known as van der Waals forces
results.Thus,every CHz-CHzinteractionliberates
0.7 kcal/mol of free energy. e.g. Acetylcholine-
sterasecombination.In this, methyl groups or
acetylcholineare attached to acetylcholinesterase
through van der Waalsforces.
Example
H H
I I
c
H
otl
c- Receptor
Receptor
Receptor
-1G]H]l]E]d}-Receptor
 gol. ll)
Prlnciplesol MedicinalChernisfrY e Rcceptor

4.5 FACTORSATFT,CTING THE DN,UG-R.ECEPTOR (b) When a group is present in a part of a

INTERACTIONS molecule where it may be involved in an essential
The basis of attempts to design compounds interaction or may influence the reactions of
of similar biologicalactivity not only involves the neighbouring groups, isostdric replacement some-
presence of common functional groups in times produces analogues which act as anta-
gonists. In the field of antineoplastic agents.e.g.,
compounds but also such groups should be in
same specificspatial relationshipto each other.
This consideration has lecl to the study of 3 H
following important factorswhich affiectthe drug- N9
receptor interactions.
rN
(l) lsosterlsm :
Groupsof atoms which impart similar physical R
or chemical properties to a molecule due to
similarities in size, electronegativity or stereo- AdenineNH2
chemistrylare referred under the general term of Metabolites
HypoxanthineOH
isostere.For example, the moleculesN2 and CO,
both possessing14 total eiectronsand no charge 6-mercaptopurine SH - Antimetabolite
show similar physical properties. Examples of On the similarlines,the hydroryl group of folic
isosteric pairs which possesssimilar steric and acid, if replaced by the amlno group leacls to
electronic configurations are sulphonamide aminopterin, an antagonist usefulin the treatment
(SO2NR-) and the carboxylate(COO-) ions, ketone of certain types of cancer.
(C = O) and sulphone(SOz)groups;Divalentether (2) Sterlc features of drugs ..
(-O-), sulphide(- S -), amine (-NH-)and methylene
(-CHt-)groups. Although dissimilarelectronically, In order to evoke the pharmacologicalaction, a
they are sufficientlyalike in their stericnatureto be drug must approach the receptor and fit closely to
frequentlyinterchangeable in drugs. its surface; hence a drug must possess a high
Appllcatlons In structure-acttvlgrrelatlonshlp : degree of structuralspecificity or stereoselectivity
(a) Compounclsmay be alterecl by isosteric to initiate a responseat a particularreceptor.e.g. in
replacementof atoms or groups in orclerto develop cliethylstilbestrol,only trans diethylstilbestrol is
analogues or to act as antagonists to normal estrogenicwhile cis-isomeris almost inactive.Just
metabolites.e.g., like geometric isomers, in certain rigicl systems
(where rotation around the bonds is clifficult).
conformational isomers also show significant
differencesin biological activity clue to clifferences
(U
in affinity as well as intrinsic activigl to the
receptor.
Antibacterial In open chaincompouncls,all possibleconfor-
mations are not equally manifested by the
X = S,Se,O, NH,CHz, compounds (due to steric complications)at all
times. Hence, by virtue of the ability of such
compouncl to interact in a clifferentand unique
(ir) R -X- C H 2- conformation with different biotogical receptors
may result in multiple biological effects e.g.
Antihistamines : X = O, NH, CHz
Ace$lcholine may react in its extencleclconfor-
Cholinergic blockingagents; mationalform with the muscarinicreceptorand in
X = - COO-,-CONH-. - CO S- quasi-ringform, may reactwith nicotinicreceptor.
 Chembtryryol.ll)
of Medlclnal
Prlnclples E' Recaptor

sites. The logarithm of thls ratlo ls termed as

eudlsmlclfidex(El).
lf two enantiomers of dlsopyramlde are
adminlsteredlndependently,they have the same
cHr pharmacodynamic anclpharmacoklnetlc profile.lf
admlnlsteredtogether, they have dramatlcally
dlfferent pharmacoklnetlcproflles. Thls ls the
Acetylcholinein extended conformatlon
,,\ ,r" Tablc 4.2: Plasma-protclnblndlng of cnantlomers
/cHt Drugs 96 unbound
\a",
Acldlc Drugs :
lndactlnone R(-) O.eO
Methobarbltal RH 2.29
Moxalactam R (+) 47.00 s (-) 32.00
AcetylcholineIn Quasi-ringconformatlon Pentobarbltal R (+) 36.6O s (-)26.so
flg. 4.3 (-l
(3) Optlcal lsomers and blologlcal actlvlty : Phenprocoumon s o.7z
Stereochemlstry,enantiomers, symmetry, Warfarln s H o.9o
asymmetry ancl chlralit5tare lmportant concepts Baslc Drugs :
that help us to understandthe therapeutlcand Amphetamlne
toxic effectsof drugs. The word 'chlral' ls derived
from the Greekword cheir which means 'hand'. A Chloroqulne (-) sl
chiral drug consistsatleastone asymmetrlccarbon Disopyramlde H3e
atom and has fwo enantlomers.Although each Fenfluramlne (-')z.e
enantiomerhas ldentlcal chemicaland physical Methadone (-t tz.z
properties, lndlvidually they may Interact
clifftrentlywith receptors,enzymesand proteins Propoxyphene H 1.8
in the body. A number of mechanlsms(e.g. Propranolol (-) 1l
metabolism,proteln binding,clearance)in the body Tocalnlde (-) 83-8e
can be stereoselectivewhlch nnay account for (-) ll
pharmacokinetic among,enantiomers, Verapamll
dlfferences
Formulation factors such as the rate of Slmllarly,the stereoselectlveclearanceaffiects
cliss ol uti on , m e lt ln g p o in t , p o wd e r f lo w the plasmahalf-lifeof the drug. Upon admlni-
characteristics and solubilityare all diffierentfor the stratlon of leucovorin calclum enantlomers,/-
racemateand to be taken Into account to ensure leucovorlnls rapidlyclearedftom the body and has
bioequivalence of the formulations. a pfasma half-life of 32 mlnutes, whereas
Becausethe isomers have dlfferent three d-leucovorlnls slowly clearedand has a plasma
dimensional structures, they have dlfferent halFlifeof 45 mlnutes.
affinitiesfor receptorsand enzymeswhlch are also S (-) Tlmolol ls one of the few adrenoceptor
threedimensional.Thlso<plainsthe reasonfor the blockers marketedas the pure enantlomerused
different therapeutlcand toxlcologicalproperties
exhibitedby differentenantlomers. cllnicallyto treat systemlc hypertension, angina
pectorls and glaucoma. When thls forrn is used
Generallyone enantlomeris more potent than
the other in exhibltlngpharmacological response. toplcally ln eyes for treatlng glaucoma, severe
The more potentenantiomeris calledas eutomer bronchoconstrlctlon ls noticed.ln contrastR (+)
and lesspotent gnantlornerls termedas dlstomer. timolol lowersIntraoccular tenslonwlthout causlng
The ratio of actlvltiesof eutomerand dlstomeris slgnlficantbronchospasm.R (+) form ls therefore
calledas eudismicratiowhich ls a usefulparameter safurficrtreatlngglaucomathanS (-) form.Slmilarly
to assessthe relatlvepotenqyof the enantlomers. humansprefurentlally metabollse(+) funfluramine
Thls ratio is normallydlfferentat diffierentreceptor whlle ratsfavourthe (4 enantlomer.
Principles Chemistryflol. ll)
of Medicinal 51 Receptor

Table4.3(a) ( 1) DexchlorpheniramineI S highty ste(eo-

Wottdwidesalesq( sisgtecnantisnret {rugs selective; the (S) - (+) - isomer I S about 2OOtimes
Single more potent than the (R)- (-) - isomer.
Total enantiomer (Z) d-Ketamineis a hypnotic and analgesic
market($) drugs($) agent;the /-isomeris responsiblefor the unclesired
$ Billions 1 9 9 9 2000 1 9 9 9 2000 side-effects. In the case of local anaesthetic
Analgesic 21.5 23.0 1. 0 1. 3
prilocaine,although both isomersare active, only
/ Antilungals zY.,t 31.7 23,9 23.9
Antibiotics
Antiviral 17,7 19.1 6. 2 one isomer contributesto the toxicity.
Anticancer 13.7 15, 6 9. 4 10. 4 (3) Both isomers of bupivacaineare local
Cardiovascular 42.7 46. 6 24.8 26. 9 anaesthetics,but only the l-isomer shows vaso-
Central
nervoussystem 4 7. 7 (eo 8. 6 9.0 constrictive activitSl.Indacrinonehas a uric acid
Dermatological 17.9 1 8 .4 1. 3 1. 2 retention side-effect.The d-isomer is responsible
Gastrointestinal 4 3 . 9 47.2 3. 0 aq for both the diuretic activity and the side-effect
Hematology 1 6 . 5 1 5 .4 8. 6 9.1 while the l-isomeractsas a uricosuricagent.
Hormones z u , v 22.0 13. 8 1 4 .6 (4) lt also, is possiblefor the enantiomersto
' f1
Ophthalmic 7 .4 1. 8 2 . 0 have opposite effects. The l-isomers of some
Respiratory 3 6 . 5 4 0 .5 5.1 6.1 barbituratesexhibit clepressantactivigrand the d-
Vaccines 7.3 2. 0 3 .0
?qn 4 1 .9 5. 5 5.6 isomershave convulsantactivigr. Similarlythe cl-
Others
isomer of the narcotic analgesicpicenadol,is an
Total 360.0 390.0 115. 01 2 3 . 3
opiate agonist, the /-isomeris a narcoticantagonist
Table4.3(b) anclthe racemateis a partialagonist.
Pharmacological effectsof Racemic drugmixtures
H.1,C
Drug Biological response Enanliomer
cHlcH?cH"
Terbutaline Trachearelaxation (-)

Propranolol p-blockade (s) cH,

Amosulalol cr-blockade ( +)
B- blockade (-)

Warfarin Anticoagulation (s)

Verapamil Negativechronotropic
---\uocrer
(-)

OH
(s) Picenadol
Ca++channelblocker (s) (5) (+) - Butaclamolis a potent antipsychotic,
Zopiclone Sedation (R)
Terfenadine (s) but the (-) isomer is essentiallyinactive. The
Antihistaminic eudismicratio (+/-) is 125Ofor D2-clopaminergic
Albuterol Antiasthmatic (s receptor. (-) Baclofen is a muscle relaxant that
Flurbiprofen Anti-nflammatorv (s binclsGABA B receptors.The eudismicratio (-/+) is
Ketoprofen Anti-nflammatory (s 800.
Thalidomide lmmunosuppresive (s
Tetramisole Anthelmintic (S)-form
(levamisole)
Proporyphene Analgesic Dextro form
Antitussive Laevolorm
Tranylcypromine Antidepressant (-)

in
lmprovement (+)
performance
Antihypertensive
Antiarrhythmic l."t""to,l slto, qt
Butaclamot

"u elt.: i-
Prlnclpleof Medicinal
Choinlstryryol.ll) 52 Rec€ptor

HO CH]NH,CHl HO CFI)NH,CH1
-o - -e-
OH I
I
I
HO I
I HO
I
I
I

I I
I I
I I
e e

R-(-)-epinephrine S-(+)-epinephrine

tlg. 4.4 : Effect of stercochemlcd featurcs on drc blologlcal acttvlty

(6) The eudlsmlcratio (/d) for propranololis
about 1OO.However, propranolol also exhibits
local anaestheticactivlt5rfor whlch the eudismic
ratio is l.O. Labetalol,as a result of two
asymmetriccarbon atoms, exists ln four
stereoisomericforms, having the stereochemistries
(RR),(SS),(RS)and (SR).This'drughas a-and p-
aclrenergicblockingproperties.The (R& - lsomeris
predominantlythe p-blockerand the (SR)- lsomer
is mostlythe a-blocker.'While other 50 % of the
isomers,the (SS)- and (RS)-isomers, are almost
inactive.
(7) lf you considertwo enantiomers,such as
R-(-) ancl (S) (+) epinephrine,interactlngwith a
receptorthat hasonly two bindingsites(Fig.4.4),
it becomes apparent that the receptor cannot
clistinguish betweenthem. However,if thereare at
least three binding sites, the receptoreaslly can
clifferentiatethem. The R - (-) - isomerhas three
points of interactlonand is held in the confor-
mation shown to maximisemolecularcomple-
mentarity.Ihe (S)- (+) - isornercan haveonly two
sites of interaction(the hydroxyl group cahnot
interactwith the hydro4yl binding site, and may
even have an adversesteric Interaction);conse-
quentlylt hasa lowerbindlngenerS/.
The chiral interactionshelp us to discover
which partsof the moleculeare Involvedln primary
receptorintqraction.Chiralitymay also be usedto
distinguish different states of activation of ion
channelreceptors.
Generallyin a recemicmlxture,one enantiomer
ts bioactivewhile other remainseither inactiveor
possessesdiffierentactivit5l.Hencein caseof clrug
containingone asymmetriccarbon,administration
of a racemicform permits the deliveql of 50 9o
activecompound.At presentonly about 12 % of
synthetlcchiral drugs are availablein pure chiral
form in the marketwhile remalnlng88 9oare sold as
racemates,
An effort to make the drug commercially
availableln pure chiral form, add to the cost of the
synthesis.Variousoptions llke, to reduce the
number of asymmetrlc centers, replacing
asymmetric carbon with nitrogen, adding
symmetryto the molecule,are henceused to save
this added cost.
Pdnclplerof liledlclnalChemlstry(Vol.ll) 53 Reco@l

When a drug exlsts ln stereolsomerlcforms,

Table4.4 the rate and routes of metabollsmmay dlffer
drugs
Slereolsomeric betweenthe enantlomers.The rate of metabolism
Agentr:
Gardiovascular of two enantlomerswould be expected to diffier
Acebutolol Alprenolol Atenolol where they form dlastereomerlccomplexeswith
Betaxolol Bisoprolol Bopindolol the metabollzlngenryme. Extracomplicatlonsmay
arlse becauseof ablllgl of metabollcprocessesto
Butefolol Bufuralol Interconvertchlralcenters.
Bunitrolol Bupranolol Butofilolol (4) Confiomailonal factors r
Carazolol Carvedilol Curteolol Varlous conformatlonsare posslble for a
DisopynamideDobutamine lndenolol flexibledrug structure.Besldesdrug, the receptor
Mefiin&bl Metipranolol Metroprolol sites also exhlbit flexlble nature and can acquire
Nadolol Oryranolol Pindolol conbrmatlonin adaptationto the mutualeffectof
drug. However,suitablesterlcbatures need to be
. Propranolol Quinidine Sotalol presentIn a drug moleculelf lt ls to havesignificant
Toliprotol Verapamil Xibenolol affinlgr and Intrinslcactivlty at receptorsite. The
system
Centralnervoug : X-ray crystallographic spectrophotometry ls
Butaclomol Butoryhanol Buprenorphine routlnely used to determlne conformationof a
Cocleine Dihydroer- Dobutamine drug moleculewhile NMR spectraprovidesinfor-
gotoine matlonbr geometrlclsomerswhen the compound
ls In llquld state.
Fluoxetine Kehmine Lorazepam Optlcal lsomers,particularlydlastereoisomers
lvledizine Nalbuphine Nalfename (1.e..compoundswith two or more asymmetric
Naloxone Nallrexone Oxaprotiline centres),exhlbit slmllar chemlcalreactlonsbut
O(yntorptpne PhenylpropandPhysostigmine different physlcal properties. Slnce the physlcal
.IIIE propertles are lmportant in drug distribution,
Thioddazine Toloxatorr
Chloramphetamine metabollsmand lnteractlonwlth the receptor,the
biologlcalpropertlesof such lsomersmay also be
Tomoxetin Vasopressin Viloxazin different.
Anti-lnflammatory :
rnd analgeslcs We may expect from the deffnitlonof optlcal
Bedomehasone BehmehasoneCicloprofen enantiomers(that compounds havlng ldentlcal
CorticosteroidDihydroxy- Fenhphen physlcaland chemicalpropertlesexcept for thelr
abllity to rotatethe planeof polarisedlight) that
hebane they may have the same blological activlgl.
Fenoprofen Flurbiprofen lbuprofen However, thls is not the case wlth many of the
Ketoprofen Indoprofen Minoxiprofen enantlomers.
Norlevophanol Oqrcodone Pirpolen 4.6 SPARI,R,ECEPTORIi
Stanozolon Steroids Suprofen In most of the cases,the blologicalresponsels
Tdamcinolon a functlon of total number of receptorsthat are
occupled or activated by drug molecules.But in
Anlicancer: certalncases,lt hasbeenobservedthat a relatively
Bleomyejn Cytarabine Doxorubicin small fractlon of the avallable receptors, lf
Methotrexate MitonrycinC occupled,may resultInto the maximalblologlcal
Antiblotlcs,
antl-lnfectlves, :
antivlral responseof whlch, the tissuels capable.Furchgott
(1954)showedthat only t% of the ldeal receptors
Ciprofloxacin Norfloxacin Ofloxacin haveto be occupledin order to get the maximum
Genitourlnary
Hormones
: response.Herethe remalnlng99Voreceptors,even
BromocriptineButoconazole
Benzylglutamate lf occupied or unoccupled,do not make any
difference.Such receptorsare known as spare
Calcitonin Estradiol Flurogesterone receptorsor reseruedreceptors.Thesereceptors
Gonadorelin Ketodesogestrel are not qualltatlvely dlfferent from non-spare
Norgestrel Prednisolone receptors.Myocardlumls sald to contaln a large
Progesterone Testosterone number of spare receptors.They are not inactive
receptors.An agonlstcan easllytum on the sparc
Principle
of Medicinal
Chemistry
Uol. ll) 55 Receptor

inositol
Membrane
Phospholipids

- 1,4,5,
l nosi tol Diacylglycerol
triphosphate

Activationof proteinkinaseC

ationof different
Phosohorvl
chainsol targetproteins

++
Extracellular
Ca Ca Inactive
influx CytosolicCa Protein Enzyme
kinase
Active
EiEnle
// \\

reactons
Chemical

++
Complex
Ca - Calmodulin

Protein
kinases

Inactive Adive
Enzyme Enzyme(phosphorylated)
[*nmptiRcationof
chemical
reactions
Ilg.4.5 : Mechanlsmof Ca++- dependent hormone acdon
 s Receptor
Cham|swOol' lD
ot Medlclnal
Prlnclple

FamilY
i-Protein
(mGluRt to mGluRs)

acid
NMDA : N-methyl-D-asPartic
acid
AMPA : cr-Amino-3-hydroxy-5'methylisoxazole-4-propionic

ted(L, T, N, P'Q andR)

EstrogenrecePtor
receptor
Glucocorticoid
(3)Intracellular--+ (Steroids) ProgesteronrecePtor
receptor AndrogenrecePtor
recePtor
Mi neralocorticoid

RetinoicacidrecePtor
RetinoidX recePtor
Thyroidhormone receptor
VitaminD recePtor

ATP-sensitive
i4) K-channe-l Larseconductance

Smallconductance

(e.9.'Hcart)
Resistant
Tetrodotoxin

IetrodotoxinSensitive
(Brain,SkeLetatmuscle)
Ilg. 4.6 : TyPes of recePtols
lsreguIatethepasHgeoflon5ofvadoustypes.|onchannelscontro1le
are
(a) chemtcalmessengers calted lon
tlgand-gated (b)
cliannels. trans-m*:i:^:,-P:::i11:j.t::.11";,*l
receptor
ronchannet,
iil"no--gut.a changes
glvcoproteln lts shapeupon
*i,.J'rrffi#;'il-;;;J;.;" process better known as gatlng' The receptor
blndlng wlth llgand. ,Ihls leads to openlng of a
lon-channel,
domalns (ZTM' 3 TM' 4 TM) Present ln them'
glycoproteinsare classlfledby the nurn'b",oitr.nrm.*brane have
the electricaland chemlcal gradients that
The passageof lons acrossthe cell membranels dictated by or effiux of such (Ca**'
drlven lon pu-pt e.g. NaYKi - ATPase' The Influx 'ions
beenestabllshed by metabollcally nervous and neuronal
provldes the basls of most
Na+,l(+, Ct-) modulatesthe transmernbran.potintr.iwhlch nucreotrdes and lnorganlc lons'
transmrsslon processes. Thesechannersmay be moduratedby neurotransmltters,
ooo
 5.r NTnODUCTTON
5.1 INTRODUCTION 5l
The reversible binding of drug with non-
A2 BODYPROTEINS 58 specific and non-functional sites on the body
proteins without showing any biological effiect is
53 FORCESINVOLVEDIN DRUG.PROTEIN
called as Protein Binding.
INTERACTION
A drug molecule, to less or more er-tent,has a
FACTORSAFFECTING DRUG.PROTEIN capacity to enter into specific combination with
BINDING s plasma-proteins.These molecular interactionsplay
an important role in deciding the intimate nature of
55 MATHEiIATICALOERIVATIONS c)
drug action. For example, using parameciaas test
5.6 METHODS EMPLOYED TO DETECTTHEDRUCr. organism,Busck,in 1906, observedthe inhibitory
PROTEININTERACNON d) effiectsof serum on the photodynamic and other
toxic properties of certain dyes. This inhibition
17 PHARMACOLOGICAL SIGNIFICANCE 6l
was attributed to the formation of dye-albumin
5A EFFECTOFDISPLACEMENTOFBOUNDDRUG 63 complexes. Moore and Roaf reported that protein
binding of volatile anaesthetics,ether and chloro-
59 DRUGPERSISTENCE & form make them more soluble in plasma than in
5.10 DRUGALLERGY 64
saline' Rabbitserum has excellentbinding proper-
ties towards various drugs.
5.11 SUBSTANCES THATDONOTINTEFACT Drug molecules in blood are present in two
WTTHPLASMA.PROTEINS fiorms :
(a) tree form : This form is pharmacologically
active. lt is difrrsible and available for both.
metabolismand excretion.
(b) Bound fonn : lt is non-diffirsible(being
complexed with plasma-proteins)and hence
inactive.lt acts as reservoirof drug.

(57)
Principles
of Medicinal flol. ll)
Chemistry $ ProteinBinding

secondary receptors in the body tissues. In the Thereare usuallyone or two primary binding
plasma,plasma-proteinsplay the role of secondary sites availableper protein moleculewith several
receptors. possible secondary sites. The characteristicsof
Drug molecule binds with proteins through each such site depend not only upon the
two different modes. properties of its ionic residues but are also
(a) Prlmary blndlng : A firm binding results influenced by the properties of neighbouring non-
through primaql binding. This is an ionic interaction ionic groups, and upon surfaceconfigurationancl
in which an ionised form of the clrug molecule steric hindrances offered to approaching mole-
interactswith the charged molecule of the plasma- cules.
proteifi. 5.4 TACTOR,SATIECTINGDR.UG-PROTEIN
(b) Secondaryblndlng: The primary binding BI NDI NG
alone, is not sufficientfor plasma-proteinto hold Thesefactorsare categorisedas :
the drug molecule.lt is to be supplementecl with (a) Physical factors,
other secondary binding forces. These forces (b) Chemicalfactors,and
mainly operatebetweenthe non-ionicpart of drug (c) Physiologicalfactors.
and non-polarportion of protein molecule. (a) Physlcal factors : The pH of blood, ionic
The forcesinvolved in secondarybinding are :
(1) Hydrogenbonding strength and temperaturetop amongst the list of
(2) Hydrophobicbonding physical factors. They affect the degree of drug
(3) van der Waalsforces. bincling in plasma by affecting the number of
(l ) H y dro g e n b o n d ln g : A so rt o f bindingsitesavailableper proteinmolecule.
electrostat!c union always exists between a (b) Chemlcal factors ! Polarity of drug
hydrogen atom and an electronegative atom. This molecule increases its affinig for protein. For
bonding can be illustratedas : example, salicylicacid binds more strongly with
A-F H-B protein than benzoic acro oue to lncrease tn
A_O H- B numberof sitesfor primarybinding.
The hydrogen atom may be a part of drug
Table 5.2
moleculeor the plasma-protein.Thisis an example
of intermolecularhydrogan bonding. No. of blndlng Assoclatlon
(2) Hydrophoblc bondlng : According to the Drug sltes per constant
principle of 'like dissolves like', the hydrophobic proteln Kx lOa
portion of drug molecule always has a tendency to molecule(n)
avoid an aqueous phase. Hydrophobic bonding Phenol Negligible Negligible
results through this tendency. Actually bond Benzoate 0.3 1.5
formation does not take place but association of Saliqylate o.4 3.0
two hydrophobic portions occur to form micelle
Similarly,an increasein non-polar portion of
like structuresin order to avoid water.
drug molecule through addition of non-polar
Thus an attraction of non-polar portion of
substituent or by lengthening the side-chain
drug molecule towards non-polar portion of
results into more firm binding due to lncreasetn
anothermoleculeresultsthrough their unwelcome
numberof sites for secondarybinding.
reception to water, is known as hydrophobic
bonding. Table 5.3
(3) van der Waals forces : This force Compound n Kx lO4
operates mainly between dipole and inducecl Octanol 4.5 3.O
dipole portions of the molecules. This is cate- Ocgd sulphate 4.5 60.o
gorised as a weak binding force. All the above
Dodecanol 4.5 15.0
mentionedsecondarybinding forceshelp a non-
ioniseddrug moleculeto bind with plasma-protein Dodecyl 8.5 120.0
e.g. steroidaldrugs, like hydrocortisone. sulphate
Principles
of MedicinalChemistry(Vol.ll) s) ProteinBinding

Such enhancementis due to an interaction then, the equilibriumconstant k, can be calculated

between the lipophilic portions of drug ancl b y,
protein. k1 (PD)
k=
k2 ( P u )( D u ) .. (z)
Usingexperimentalmodels. the concentration
of bound and free drug can also be determinedor
may be known.
The averagenumber of drug moleculesbound
per protein molecule (r) can then be calculatedby:

Thyroxine;R = - CHz-CH -COOH

TH' Moles of drug bound
Total moles of plasma-protein
Plasma-proteins, while interactingwith small (PD)
molecules,exhibit a high degree of structural (PD)+ Pu
specificigl. The specific structural features of k (Pu)(Du)
thyroxine analoguesnecessaryfor binding with . . . ( 3 )
thyroxinebinding albuminfractionhave beenwell k (Pu)(D.,)+ (P,r)
characterised.The following structural features k (Du)
r : ...(4)
favout more efficient binding with plasrna- k ( D u ) +l
proteins. lf 'r1' equals to total number of binding sites
(1) A diphenylethernucleus. on each protein molecules, then equation (4) can
(Z) A free phenolic hydro>qylfunction. be rewritten as :
(3) An ionised moiety separated by about
three carbon atoms away from aromatic l 'k ( D u )
. . . ( 5 )
nng. I + k (Do)
In general, the extent of binding of any This is the expressionthat is identicalwith the
substanceto plasma-proteinsis greatly influenced Langmuirisotherm.
by its partition coefficient value. Other factors Similarly,the fraction of the total bound drug
which determine the extent of protein binding in plasma(F) can also be calculated by
include decreasein albumin concentration,dose of IDPI
drug given, route of administration,pathological ID]
conditions and genetic factors. These factors
affect the number and t5rpe of protein binding ...(6)
lDul
sites. For example, the protein binding of l+ +
phenytoin founcl to increase two times in a \k (Pr) \ ll',rl
heal\ person than'that in nephrotic or uremic where,
patient. tDPI Concentration of bound drug tn
5.5 MATHEMAIICAL DERIVATIONSR,ELATED plasma,
TO DR.UG.PR,OTEIN COMPLEX IDl Total drug concentration,
In most of the cases, the drug-protein lPrl Total protein concentration.
complex formation is a reversiblereaction. and 5.6 METHODSEMPTOYEDTO DETECT
henceis by the law THE DRUG-PN.OTEIN INTER.ACTION
-eoverned Sometimes,the activity of a drug may change
kl
Protein+ unboundclrug q=-\ Protein: Drug ...(1) suddenly in its magnitude.This may be due to
k2 either:
I (a) Fluctuationin the concentration of free
t f Pu = Unboundplasma-proteinconcentration drug due to its binding to, or releasefrom
plasma-proteins, or
Du = Unboundor freedrug concentration,ancl (b) Changein the thermodynamicactivity of
PD .=Protein-drugcomplex concentration. drug.
Principleeol iledicinalChemisFy(Vol.ll) 6l ProteinBinding

Differentmethods have been documented tn (2) When only unboundor ftee drug is active,
literature to demonstrate the presence of an then protein bindingmay :
interactionbetween drug and plasma-protein"Atl
(a) act as a reservoirof drug and prolong the
are coiledaroundthreebasicprinciples:
duration of action,
(l) Methods based upon reductlon ln free
drug concentratlon : (b) facilitate the distribution of drug through-
(a) Dialysis, out the body,
(b) Ultra-filtration, (c) retard the excretion of drug,
(c) Differential adsorption, (d) lower the therapeuticconc€ntrationof the
(d) Osmotic pressure,surfacetension, vapour drug by not allowing a sufficientconcen-
pressureand freezingpoint, tration of free drug to develop at the
(e) Biologicalactivig. receptorsite,
(ll) Methods based upon dteratlon of drug (e) unbound drug is freely diftrsible and the
popertles : drug-protein complex is generallyconfined
(a) Solubility, to the circulatingplasma.
(b) Diffusion, IAI Effcct of proteln blndlng on drug dlstrl-
butlon
(c) Stabiiisation,
(D Proteinbound drug is unableto penetrate
(d) Electrophoresis,
membranesand is confined to the circulating
(e) Spectrophotometry.
plasma.It cannot diffi.rseto the site'of action or
(lll) Methods based upon alteratlon of metabolisein other compartments.
proteln propertles or behavlour :
Only free drug can crossbiologicalmembranes.
(a) Precipitation,
This transfer is mainly influenced by partition
(b) Stabilisationof protein,
coefficientand concentrationgradient of the free
(c) Viscosi!, electrophoreticmobility, sedi- drug. Protein binding, therefore, by acting as
mentation rate and other related reservoir of drug, can decreasethe rate of drug
properties. disappearanceftom general circulation. When
The chemical reactivity of many plasma- required it dissociatesto releasefree drug and
proteins diffierand is dependent largely upon their maintainsa steady state concentrationlevel of
amino acid compositions and physical chara- free drug. It
thus compensatesthe loss of free
cteristics.
drug by excretionor metabolisme.g., the affinigr
5.7 PHAR.MACOTOGICAL SIGNIFICANCEOt and extent of binding of differentsulphonamides
DR,UG-PR,OTEIN TNTER,ACTION enablethese drugs to be classifiedinto long and
Depending upon their structural features, short acting categories. Sulphamethoxydiazine
most drugs interact at their therapeuticconcen- stronglybindswith plasma'proteins. Henceit is a
tration with one or more of the plasma-proteins. long acting drug, whereassulphathiazole weakly
Thismay give riseto differentpossibilitieslike : binds to proteinsresultinginto its short duration
(1) Drug boundto plasma-proteinis pharma- of action.
cologically active and can penetrate the sites of (ii) Proteinbinding of drug slows the rate of
drug action.
distributionof drug into penpiiri-: . ,\mi "-rtmen6.
Princlplerof lledldnal Ghemistry(Vol.ll) e ProteinBinding

*Protelns Investlgated' : S, serum (or whole plasma);F, plasma

fractions;A, albumin ftaction
(impure);A crystallinealbumin,(b) bovine;(c) cat; (ch)chicken;(d) dog; (0 frog; (g) goose;(ho) horse;
(h)human;(p)pig; (r) rabbit;(s)sheep.
"ltf,edrods': B, biological action; C, conductivity; O, diablsis;DA, differentialadsorption; Di, diffi.rsion;
E, electrophoresis;EA, enzyme activity; EM, electrophoreticmobility; FP, freezing point; OP osmotic
pressure;P precipitation; Sb, stabilisation(of drug); So, solubility; SP, stabilisation(of protein); SR,
sedimentationrate; ST,surfacetension, Sy, spectrophotomet4l;U. ultrafiltration;V, viscosity;VP, vapour
pressure.
(bac.)bacteria;(c.9.)cat gut; (cl.)clotting time; (f.h)frog heart;(hem.)hemolsis; (ma.)mouseassay;
(r.h.)rabbitheart.
O, none; S, interaction,in an experimentwith serum, where the specificprotein interactingwas not
further identified;A, A*, interactionwith albumin (impure)or crystallinealbumin; G interaction,with
globulinfraction.
'fasc of Rcverslblllt/ : +, definitelyreversibleby simplemeans,e.g. dilution; (+), probably reversible
by simple means,not proved definite$;-, apparent! not reversibleby simple means.
"Complex dlssoclated by" : Lists special reagents which seem to dissociate the complex without
denaturationof the protein.
Table 5.4
Substance Proteln Method Prlmary Ease of Complex
lnvestlgated lntcractlon wfth reverslblllty dlssoclated by
1. lron F (h),s (h) B, (bac) G (Br-pseudo) (-) p H <5
ln t v-7
z. Glucose S (b)
(h)
3. Cholesterol ,s(h)
4. Oestrogen (b, r, h) P,D s (+) Vigorousacid
hydrolysis
5. Ascorbicacids (h) A (+)
6. Vit. K (h) A
7. Nicotinamide (h) E G
8. Riboflavin s(h) G (eu-)
9. Thiamine (h) o
10. Barbiturates (h) A (+)
11. Heparin (h, ho) E, B (cl.) A (+)
12. PAS s (h),A (b) u A (+)
13. Saliqylate s (h,b) D S (+)
14. Atropine S (b, r) D,B (c.g) S (+) Citrate,peptone
15. Caffeine S (ho) D s (+)
16. Cocaine S (b, ho, r) D s (+) High pH vt'ith
ether
1 7 . Epinephrine s (h) SB s
1 8 . Morphine (h) S (+) Citrate,peptone
Principlesof MedicinalChemistry(Vol.ll) B ProteinBinding
(iii) Placentais a demarcationline between the
matemaland the foetal circulation.Hormonessuch
as thyroxine, is not required in foetus befiorethe
appearanceof fioetalendocrine glands. Since the
placentais not permeableto the proteins,protein
binding of thyroxine limits its accessto the foetal
circulation.
(iv) Ferrousions are transported to the bone
marrow with transferin, a p-globulin. They are
utilised in the formation of haemoglobin but are
toxic when they are not bound in the plasma.
(v) Protein binding of a drug may project
misleadingconclusions,if two drugs of the same
pharmacological category, are compared on the
basisof concentrationof drug in the plasma.
lBl Effect of proteln blndlng on drug meta-
bollsm :
'ln general, the drug present in the unbound
form is available for metabolic processes.Hence
the rate of metabolism is inversely proportional to
the extent of protein binding of a drug.
ICI Effect of proteln blndlng on drug ellml'
natlon :
Even though renal blood supply consistsof
both, bound and free drug, only the free drug is
filterablethrough the glomerular filter. The concen-
tration of free drug in the glomerularfiltrateequals
to the concentrationof free drug in the plasma.
Hence, the drug eliminationvia the kidneys is
influenced by the extent of plasma-protein
bindingof a clrug.
Glomerularfiltration rate of a drug
1 plasma-proteins
Extentof protein binding
It means that increased protein binding
decreasesthe rate of elimination of a drug,
resultinginto prolongedbiologicalhalf-life.But it
does not hold true. if the rate of dissociationof
drug-proteincomplexis high. Forexample,the rate
of dissociationof penicillin'proteincomplex is
considerablyhigh. Hence, penicillin can be
completelyremoved from the blood during single
passagethrough the kidneys.
5.8 EFFECT OFDISPTACEMENT OF BOUND DR,UG 5.9 DN,UGPEN,SFTENCE
There are obvious occasionswhere drugs
bound with plasma-proteinscan be partiallyor exhibit an affinity for certain drugs. They thus
complete\r liberated by another drug. This leadsto
increase in pharmacological response of the
displaced drug due to an increase in the
concentrationof free drug in plasmaand biophase.
In such cases,the dissociationconstant and the
apparentvolume of distributiondeterminethe rate
of excretionof the displaeeddrug.
The effect of-displacementcould be sudden if
the binding exceedsX)-95%. For example, in the
caseof a drug which is 98olobound, a displacement
of 2olodrug will lead to a substantiall0oo/oincrease
in the unbound drug concentrationin plasma. In
such cases,if the volume of distribution (VD) is
large the effects may be minimal. Serious toxic
effiectsmay appear if VD is small. This is due to a
significantrise of drug concentrationin plasmaand
biophase.
Some drugs may exert an indirect biological
effect by displacing other drugs from plasma-
proteins. This can reasonably be attributed to
competition between the drugs that are known to
act on same physiological receptors or that share
some common structuralfeatures,
(t ) Sulphonyl urea anti-diabetic agents
displace insulin from its complex with
protern.
(z)Atropine displacespilocarpine.
(3) Salicylatesand sulphonamidesdisplace
bilirubin.
(4) Acetltlcholine displaces carbonic ester
inhibitors from their complex with the
plasma cholinesterases.
(5) Similarly, benzoatep and salicylates
displacethyroid hormone.
The impairment of the binding capacit5rof
(e.g., hypoalbuminemia) may be a
significant factor in justiffing an unusual sensi-
tivitSror resistanceto drugs. Moderate hypo-
albuminemiamay be caused by a number of
diseasesand conditions such as cancer, myo-
cardial infarction, pregnanq,r,prolonged immo-
bilisation, G.l.T. disorders, etc. Severe hypo-
albuminemiais observedin severeburns,liver and
renal impainfients.In renal impairment,clecreased
bindingof acidicand neutral(but not basicdrugs)
drugs to plasma-proteinis fiound.
Beside plasma-proteins,tissue proteins also
Princlplccof McdlcinelChcmlilry (Vol.ll) 6f
provide drug depots outside the plasma. This
process obviously is reversible. The effiective
intracellularprotein concentrationis considerably
higher for certain body organs, e.g. liver, lung,
spleen, muscles,etc. They have much higher
affinity for certain drugs which include emetine,
suramin, quirlacrineand organic arsenicalsand
antimonials.For example, quinacrine and anti-
malarial drug, after 4 hours of administration,
shows a 2OOOfold concentrationin liver than in
plasma.After 14 days of daily administration,the
concentrationof drug in liver touchesto 2O,0OO
times to that in plasma. lt is not entirely clear
whetheralbuminor a globulinis primarilyinvolved
in it.
5.IO DRUGAILEN,GY
An allergy arises clue to antigen-antibody
interaction,which itself can be interpretedin terms (c) Thiamine
of protein-protein interaction. Landstrlher has
clevelopeda method of producingan arfficiat drug
antigen (by coupling particular drug to protein
through diazo-linkage)which can be utilisedto get
specific antibody responses in experimental weaklyif at all.
t
Plobln Blndlng
animals.Strydrnine,eplnephrlne,aspirin,sulphon-
amidesare amongthe drugswhich havebeentried.
In many cases,only albumins qualiff themsehues
to act as antigensbut purified globulins could not
give expectedresults.
5.TI SUBSTANCESTHAT TIPPAN,T,NTI,Y
DO
NOT INTEN,ACT
W|It{ EAIiMA-PN,OIEINS
Though most of the drugs bind wlth plasma-
proteins, there still remain a short list of sub-
stances which are least interested in forming
associationwith plasma-proteins.
Thislist includes:
(a) Sodium and potassium ions
(b) Nitrousoxide
(d) Histamineand droline
(e) Streptomycin
These agents interact with plasma-protein
ooo
6.1 lNTROOUCTION 66 6.r NTnODUCTTON
Cellular systems for the transduction of
62 NERVOUS
SYSTEM 65 external stimuli into intracellularsignals are
a3 NEUROCHEMICAL
TRANSMITTERS 6l essentialcomponentsof the plasmamembranes.
According to the theory of neurohumoral
6.4 AUTONOMIC
NERVOUS
SYSTEM transmission, specific chemical agents are
responsiblefor transmissionof nerve impulse
65 OFAUTONOMIC
DIVISIONS SYSTEM 68
NERVOUS across most synapses and neuro-effector
6.6 ACh ANDNE AS NEUROTRANSMITTERS 74 junctions. These agents are known as neuro-
humoral transmitters.The concept of "chemical
6.7 NEUROTRANSMITTERS
PRESENT
IN CNS E neurotransmission" was first proposed by Dale
and co-workers, instead of "electricaltrans-
6.8 ACETYLCHOLINE n mission"hypothesis.The releaseof transmitter
69 CYCLICANALOGUES
OF ACh 79 substances occurswhen the nerve impulseelicits
the responsesat smooth, cardiac and skeletal
6.10 CHOLINERGICRECEPTORS g) muscles, exocrine glands and postsynaptic
8l
neurons. These neurotransmitters cross the
5.11 METABOLISM
OF ACh
synapseor the neuro-effectoriunction to initiate
6.12 CHOLINERGIC
AGONISTS e activi! in another neuronor in a muscleor a glancl
cell by 'rrteractingwith the postsynapticreceptors.
6.13 ANTICHOLINESTERASES A clear understancling of the impulse transmission
6.14 STRUCTURAL
FEATURES therefore, is essential to study the pharmacology
OF CHOLINESTERASE
ENZYME of the drugs acting on autonomicnervoussystem.

6.15 CLASSIFICATION
OFANTICHOLINESTERASES 6.2 NER.VOUS SYSTEM
Principally the neryous system may be
6.16 THERAPEUT]C
USES sl clescribedas a cleviceof,
(l) receivinginformation(i.e. sensoryinput),
6.17 ANTIDOTES
FORNERVEGASES sl (2) processinginformation (i.e. integration)
and
(3) transmitting information (i.e. motor
o u tput).

(65)
Principlesof MedicinalChemistry(Vol.ll) 66 Gholinergic
Drugs

, Nervoussystem

Lentratnervoussvstem Peripheral
nervous
sYsrcm
(brainandspinalcord)

Et-fbrent
system Afferentsystem

Autonomicnefvoussystem Somaticnervous
s ystem
(Involuntary
nervoussystem) (Voluntary
nervous
system)

Ilc. 6.1 : Classfficatlon of newous svstem

The fundamentalunit of a nervoussystem is
the neuronor a nerve cell. Eachneuronconsistsof
a nucleusand a cell body from which, stems an
extensive network of branches,the axon - (long
process)and the dendrites(short process).
The surfacemembraneof a neuron consistsof
a semipermeablelayer of lipoproteins. The
compositionof salt solution inside the membrane
is usually diffierentfrom that on the outside. This
is due to differencesin the permeabilityof the
membraneto the various ions like Na+, K+, Ca++,
Cl-, HCQ, etc.
In the resting state, the inside of neuronal
membraneis more negativethan the ouiside.This
normal situation is known as resting state or
polarisedstate. When any exogenousstimulusis
applied; a change in the electricalactivity occurs
within the neuron.At the point, where an exoge-
nous stimulus occurs, the inside of neuronal
membranebecomespositive than the outside. As
a result, Iocal action currents are set up, which
have the effiectof transferringthe area of reversecl
polarisationto an adjoining region of the nerve
while normal resting conditionsare re-established
in the previouslystimulatedarea.

dendrites
boutons
Terminal
r

t
a)(On

Flg. 6.2 : Nerve cell or Neuron

 Principlesof MedicinalChemlstry(Vol.ll)
When the transmitter substance reacts with
the post-synapticreceptors,it may produce either
excitation or inhibition. The action of the trans-
mltter results in selective increaseor decreaseof
ionic permeabili! of membrane for ions. In
inhibition,there is a negligible changein the ion
potential and the fibre remains at near to the
resting potential, thereby preventing the fibre to
get in an excited position.
The transmitters in the neurons are in a state
of flux, being continuously biosynthesised,
released and metabolised, thus producing pro-
found changes in the activity of the nerves. The
nerves in the peripheral nelvous system are
classifiedon the basisof their functionsinto.
(1) Sensory(afferent)neuron,
(Z) Motor (efferent)neuron and
(3) Intemuncialneuron.
Sensoryrneuronstransmit impulsesfronr CNS
to or towardsthe muscleor tissues.
lnternuncialneurons are located in CNS and
they transmitimpulsesfrom sensoryto the motor
neuronS.
Many neurotransmittersplay an important role
ln the propagation of the nerve impulse in the
sensory neurons. These include substance p.
somatostatin,vasoactive intestinal polypeptides whole body. The area of functioning of
ancl choleqystokinin.
H-Arg-Pro-Lys-Pro-Gln-GIn-Phe-Phe-Gty-Leu-Met-NH2
SubstanceP
The efferent (motor) nervous system of ANS
can be broad! categorisedinto,
(a) Parasympathetic(or craniosacral)division emergencies.lts stimulationresultsin a generalised
and,
(b) Sympathetic(or thoracolumbar)division.
This classificationis mainly based upon the
type of neurotransmitter that predominatesin
each division.
The cholinergic nervous system consists of
preganglionic and post-ganglionic fibres. The
preganglionicfibres have their origin in midbrain,
medulla oblongataand the sacralpart of the spinal
cord. Thus, the principal site of control and co-
ordination of both sympathetic and parasym-
pathetic nervous system is hypothalamus. The
hypothalamusalong with cerebralcortex servesas
a locus of integration of the entire autonomic
nervous system. Hypothalamus also plays an
important role in the regulation of gastrointestinal,
cardiovascular,sexual, emotional and the
functioningof limbic systern.
e Cholinergicl)rugs
In contrastto other cholinergicallyinnervated
organs, the cardiac impulse conduction system
(i.e. S-A node, atrium, A-V node and the His-
perkinje system) has its own activigr where the
conductionof impullsecan be influencedbut not
initiated by autonomicnervoussystem. ln cardiac
cell, cholinergicinfluenceresults into inhibitory
responsedue to hyperpolarization.The hyper-
polarization results due to the increasedperme-
ability of the a<on membraneto potassiumions.
In parasympatheticdivision, a preganglionic
fibre synapseswith one or at the rnost two post-
ganglionicneurons.The synapsesare located very
close to or within the organ innervated.Due to the
Iimited distribution, paraslmpathetic preganglionic
neurons can affect only specific organ and do not
influencea wide region of the body. In contrastto
this, sympathetic synapses are located in the
vertebral and prevertebralganglia. Hence, a single
sympathetic preganglionic fibre may synapsewith
6O to | 89 post-ganglionic neurons provided to a
widely separatedregion.sof the body. Naturaily
upon activation, sympathetic nervous system can
evoke and influencethe biological activities of the
parasympatheticdivision is thus limited and
involves accumulationand preservationof body
resources.While sympathetic division regulates
body compartments of vital importance and
prepares the person in conditions of stress and
rcmatic or m€rssreflex action.
(a) Parasympathetlc nervous system :
Acetylcholine is the neurotransmitterwhich
propagatesimpulse transmissionin the parasym-
pathetic division. Besidesthis, acetylcholinealso
functionsas a neurotransmitter in,
(i) Motor neryesto sketetalmusclesand
(ii) Certainneuronswithin CNS.
Reid Hunt and Taveau ( 1906) were first to
report the properties of acegrlcholine.ln 1921,
Otto Loewi, a German pharmacologistidentified
the nervoui stimulation of the heart as a
chemical! rnediatedevent. Loewi then, along with
Navratildemonstratedin 1926 that acellcholine
functions as a neurotransmitterin cholinergic
nerves. This was later confirmed by Dale and
Fefdebergin 1934 on stimulationof vagal fibresto
the stomach.
Principlesof MedicinalChemistry(Vol.ll) 7t) Cholinergic
Drugs

The three important responsesmediated by neuronsthat releaseacegllcholineand norepine-

acegdcholinein man or laboratoqlanimalsinclude
l . Contractionof smooth muscles.
z. Cardiacinhibitionand
3. Peripheral vasodilation.
- -Since upon stimulation, parasympathetic
nerve fibre liberatesaceglcholine, the parasym-
pathetic division is also termed as cholinergic
nervous system. The terms cholinergic and
adrener-qicwere first presented bv Dale to denote
phrine respectively.
Acetylcholineis biosynthesisedby the acety-
lationof cholinemolecule.Cholineitselfhasa weak
parasympathomimetic activigl and upon injection,
causesa fall in blood pressure.Acegllcholine is
about IO,OQOtimes more active than choline
molecule.
Acetylcholine is biosynthesisedtn tne nerve
terminalsas shown in Fig. 6. 5.

Heart
Bloodvesscl
Smoothmuscle
Clands
ganglia
Autonomic
CNS

SYNTHESIS STORAGE

Choline RELEASE
CHOLINE+ ACETYL- CoA Acetylase ACh a

Clucose
Cocnzyme A N i c o ti n i c
Pyruvate receptors
UPTAKE
muscle
Skeletal
DISPOSAL Autonomicgenglia
Choline + Aceticacid Adrenalmedulla
Cholinesterase
CNS

tlc. 6.5 : Blosvnthesisof Ace Icholine

Slte I : Acetylcholine,synthesiscan be blockeclby styryl pyridine derivatives such as NVP.
Sfte 2 : Ace$lcholinetransportinto vesiclesis blockeclby vesamicol(AH 5t83). (t) Vesamicolis a potent
inhibitorof vesicularACh storagewith L (-)-Vesamicol beingmore potent than D(+)- Vesamicol.
Sfte 3 : Releaseis promoted by p-bungarotoxin,blackwidow spider venom, and Ca++.Releaseis blockecl
by botulinumtoxin, clrtochalasin B, collagenasepre-treatment,anclMg**.
Site 4 : Postsynapticreceptorsare activateclby cholinomimeticdrugs and anticholinesterases. Nicotinic
receptors, at least in the peripheral nervous system, are blocked by rabies virus, curare
hex amethonium,or clihyctro-p-eryrthroicline; n-methylcarbamylcholine and climethylpheny
piperaziniumare nicotinic agonists.Muscarinicreceptorsare blockeclby atropine, pirenzepine
anclquinucliclinylbenzilate.
Slte 5 : eceptorsmay be blockeclby AFDX- 116 (an M2 - antagonist),atropineor
Presynapticmuscarinicreceptors
quinucliclinylbenzilate.Muscarinicagonists(e.g. oxotremorine)will inhibit the evoked releaseof
acetylcholineby acting on these receptors.
Slte 6 Ace$lcholinesterase is inhibiteclreversiblyby physostigmine(eserine)or irreversiblyby DFP.
Sfte 7 Choline uptake competitive blockersincluclehemicholinium3, troxypyrrolium tosylate.
Prlnclples
of Medlclna!
ChomlslryUol. ll) 73 Gho{ncrybDrugE

stimulation and malntenanceof tone of the Dopamlnels a predomlnanttransmltterIn the.

skeletalmuscle.Theseactionsare not antagonlsed humanextrapyramldalsystem,mesocortlcaland
by atropine.Nicotlnlcreceptors(Nl) at the neuro- mesolimblcneuronalpathways.Theffrstevldence
muscular lunction are activated by phenyl-tri- for noreplnephrlne as a prlnclpalneurotransmltter
methylammonlum and are blocked by deca-
methonium,succinylchollne and d-tubocurarlne. in ANS was given by Eulerln 194.6.The sympa-
Nicotinic receptors(Nz) in autonomlcgangllaare thetic systern ls dlstrlbuted to effector cells
activated by tetramethylammonlumand are throughoutthe body. lt ls also called as thora-
blockedby hexamethonlumand trimethaphan. columber dlvislon becausethe pregangllonlc
neurons of sympathetlc nervous system have
Hq their cell bodlesIn the thoraclcand lumbarreglons
of the splnal cord. The sympathetlcgangllaare
categorlsedlnto,
(a) Paravertebral,
Vesamlcol(AH5183) (b) Prevertebral and
o (c) Termlnal.
_CH,,
Thls classificationis basedupon thelr sltes of
)NCH2c -cHz location.The termlnalgangllaare few In number
HzC-CHz
and conslstespeclallyof those connectedwlth
Oxotremorine the urinarybladderand recturn.
HO The sympatheticsyltem ts normallyacflve at
!tl
N{ all times and by stlmulating mental alertnegsr
resplration,ener$/ productlonand heartacfivlty.lt
preparesthe person for 'fight or fllght' sltuaflon.
N
I Receptorsfor a number of hormonesIncludlng
noreplnephrlneand autacolds, functlon by
cHzN regulatlonof the concentratlonof the Intracellular
secondmessenger, qycllcadenoslne-3', S'-mono-
cH'N(C2H5)2 phosphate(cyclicAMP) through the acflvaflonof
AF- DX I I6 adenylatecyclase.CyclicAMP was dlscoveredby
Suderlandand co-workersln 1956.
HO Eplnephrlne
ttl and noreplnephrlne catalysemany
N-C of the responsesof the autonomic nervous
system.The blosynthesisof eplnephrlneoccursIn
the nerve termlnals uslng grroslneas a starfing
N
I material.Thls schemeof blosyntheslswas ffrst
co-cHz- - CHr proposedby BlaschkoIn | 939. Phenylalanlne ls
converted to dopamlne In cytoplasmvla two
Plrenzepine lntermedlates.The hydroxylatlonof grroslneto
flg. 6.8 : Stnrctures of some drugs that affect DOPAls generallyregardedas the ratelimltlngstep
the chollnerglc newous system In the blosynthesisof catecholamlnes.
(b) Sympalhetlcdlvlslon : To meet
Eplnephrine, noreplnephrine and dopamlneare increaseddemands for noreplnephrlne,acute
the principle neurotransmltterspresent In the regulatlon nnechanlsms are avallableat nerve
sympathetic nervous system. In many cases, termlnals to actlvate glros!ne hydroxylase
synaptictransmlsslonmay be medlated by the enryme.
releaseof more than one neurotransmltter.
Princlplesof MedicinalChemlstry(Vol.!l) 75 Drugs
Gholinergic

Table 6.1
Parasympathetlc dlvlslon Sympathetlc dlvlslon
division.
Craniosacral Thoracolumbardivision.
Acetylcholineis a principalneurotransmitter. Epinephrineand norepinephrineare principal
neurotransmitters.
3 . Emergesat segmentallevel 52 to Sa of spinal Emergesat segmentallgvel T1to L2or L3of spinal
cord. corcl.
Ganglia are small ancl suitecl verlr close to the Ganglioncontainsneuronsthat are distributed
organs innervated. to a numberof organs.
5. Eftcts are localisedand limited and affectsonly Influencesa wide region of the body.
a smallregionof the body.
6. It is involveclmainly in storageand preservation Preparesthe personto faceemergenqycises.
of body resources.
ln rare cases, c-GMP is used as second Operatesthroughc-AMPwhich acts as second
messenger. messenger.
In the organs, innervated by both these divisions, effiectsupon stimulation of paraslmpathetic
system is exactly opposite to that obtained after the stimulation of sympathetic qystem.
In most instances,the sympatheticand para- drug given. lt can be decidedby developingsuch
sympathetic divisions act. as physiologicalanta- specificagents that will block the specificfiormof
gonists.Exceptionis male sexualorgan where both the nervousactivity in CNSthat was supposedto
divisions act to promote sexual function. The be operatedby the drug which was claimedto be a
sympathetic fibres to sweat glands and to certain new neurotransmitter.
blood vesselsprovided to skeletalmuscles,release Acegllcholine has been searched out in the
acetylcholineand hence the effiectof stimulation brain cortex, limbic system, extrapyramidalnudei
of both the divisions at these target sites is similar. and reticularformation. lt regulatesthe senson
For example, in salivary glands, both divisions functions,short term memory, the classicalphase
upon activation leads to an increase in saliva of sleep and eliminationof hormones,especially
production. vasopressrn.
Norepinephrineacts as a neurotransmitterin
Some organs are innervatedonly by sympa- limbic
system,reticularformation,locuscoeruleus,
thetic nervous system. These include, most blood hypothalamusand medulla oblongata. lt is
vessels,spleen, sweat glands, etc. involveclin thermoregulation,memory, motor
6.7 NEUR.OTR,ANSMITTEN,S PR.E!'ENTIN activigl and vegetative functions.
CENIRATNERVOUSSYSTEM: Dopamineis presentat higher concentrationin
Along with acetylcholineand norepinephrine, the extrapyramidalnucleiand limbic structures.It
other neurotransmitterswhich function in the CNS regulatesmotor activiql, emotionaltonus, memory
include,dopamine,epinephrine,serotonin,glycine, and releaseof hormones.
gammaamino butyricacid, asparticacid, taurine, Serotoninis a mediator which influencesther-
histamine,substanceP, enkephalinsand ATP. moregulation,learning,classicalphase of sleep,
It is usual! difficult to establishan identitlr of analgesiaand sensorylfunctions. lt is present in
any other substanceas a candidateto function as limbic system, hypothalamus,spinal cord and
neurotransmitterin CNS.Many drugs affiectCNS Raphenuclei. Lysergic acid diethylamide ([SD)
functioningby influencingthe release,action or interfuresin and reducesserotonintumover in the
metabolism of the neurotransmitter.In such brain. This explainsthe basis of hallucinogenic
cases,it can not be judged easilywhether the actionof LSD.The depresslonof serotoninactivity
alteredCNSpattem is due to involvementof new resultsin the inhibitionof visualand other s€nso.y
neurotransmittersor due to modulating effect of lnputs.
Principlesol MedicinalChemisryryol. ll) E Cholinergic
Drugs

Table 6.2
Some of the ncurotransmlttens present ln CNS

o OH
ll o_ I
cHr-C - o - CHz - CH2 - N (cH3)3 CII - CH. - NFl2

Aceglcholine
Norepinephrine

OH
I
CH- clt" - NHCHr C H ,- C H ,- N H 1

Epinephrine Dopamine

N cH2cH2NH2 CH, - CH,

N
I
I I
H H

Histamine (Serotonin)
5'Hyctroxytryptamine

NHz-CHz-COOH - cHz-cooH

Glycine
Asparticacid

HzN-!n- CHL-CHL-COOH HzN-CHz-CHz-CHZ-COOH

cooH y - Amino bugric acid
Clutamicacid
-Tyr - Cty - Gly - Phe- Met - OH H - Tyr- Gly Gly- Phe- Leu- OH
-
Methionine enkephaline Leucineenkephaline
H - Arg - Lys- Pro- Pro- Gln- Gln - Phe- Phe- Gty- Leu- Met - NH2
SubstanceP
CNSexcitationoccursas a result of the release (b) Release of inhibitor, neurotransmitte
of excitatoryneurotransmitters like acefrlcholine, which then stimulatesinhibitory responses.The
catecholamines,dopamine, glutamic acid etc.
SimilarlyCNSdepressionariseseitherdue to, inhibitorylneurotransmitters
include, serotonin,
glycine, taurine and gamma-aminobulric acid
(a) Inhibitionof the releaseof CNSexcitatory
(GABA).
neurotransmitter,or
Principlesof MedicinalChemistry(Vol.ll)
Glyclne :
lf acts as an inhibitory neurotransmitter
predominantly in the reticular formation.
Strychnineappearsto antagoniseselectively the
glycine responses but fails to antagonise the
effectsmediated bv GABA.
Taurlne :
It uniformly depressesthe functioning of CNS
except the cortex where it has very weak
depressantaction.
G A BA :
Though it has widespread depressantaction
on the various regions of CNS, its main sites of
action involve local intemeuronsin the brain and
presynaptic sites within the spinal cord. lts
presencein brainwas first reported in 195O.
Many drugs lead to excessiveCNSstimulation
(convulsantaction) mainly due to the blockadeof
inhibitorylnerve-channelsmediated by GABA. For
example, the action of benzodiazepinesis linked
with the potentiation of the functions of receptor- present at cortical and subcortical site within the
chloride ionophoresystemsthat are regulatedby
GABA. The activation of chloricle ionophore
causesinflux of chloride ions which causesthe
hyperpolarisationof the nerve tract.
6.E ACETYTCHOLINE
Acetylcholine was first synthesisedby Baeyer
in 1867. In general, stimulationof parasympa-
thetic nervous system induces constriction of
pupil and bronchi,decreasein heart activity and an Pharmacologlcal
increasein the activig of digestive system i.e.
salivationand other GIT secretionsare promoted.
Motility of the intestineis also increased.
Chemlcal features of acegilchollne :
Followingare some of the importantchemical
featuresof aceQrlcholinemolecule:
(i) Chemicallyit is an ester of acetic acid and
choline,an €uninoalcohol.
(iD On the structuralbasis.it offersthree sites
for molecularmoclifications:
(a) acetylgroup,
(b) ethylenebridgeand
(c) quatemaryl ammoniumgroup.
v CholinergicDrugs
cHz- cH2
Acetyl Ethylene Quaternary
bridge ammonium cation
(oniumgroup)
. 6 . 1 O : A c e lcholine
(iii) The quaternary ammonrumgroup ( i . e .
onrumgroup, is linked by an ethylene bridgeto an
estergroup.
(iv) Acetylcholineis stable in acidic solutions
but it is verylunstablein alkalinemedia.
(v) Free acegllcholine present in the tissue
fluids and circulation, is rapidly hydrolysed to
acetic acid and choline molecule by cholinesterase
enryme.
(vi) Acetylcholineexhibits some of its actions
via muscarinicreceptorswhile remainingactionsare
propagatedthrough nicotinic receptors.
Muscarinic receptors are also reported to be
CNSand in autonomicganglia.Nicotinicactionsat
autonomic ganglia are antagoniseclby hexa-
methonium and related drugs whereasat neuro-
muscular junction of skeletal muscle, they are
antagonisedby tubocurarine.At nicotinic receptor
sites, aceglcholine produces stimulant effects in
small doseswhereas large closesof acetylcholine
lead to receptorinhibition.
actlons :
Qrrdlovrccular system :
et5llcholineis injected intravenously,the
mOsg\rinic effects of acegllcholine are predo-
m inantly seen on cardiovascularsystem. These
effiectsinclude :
(i) Vasodilation.
(ii) Decreasein the force of heart contraction
(negativechronotropiceffiect)
(iii) Decreasein the force of heart contraction
, i ..
(negdtiveinotropic effect).
Low doses acetylcholineare sufficient to
produce vasodilationincluding the pulmonaryand
coronaryvasculature. This is broughtabout mainl-v-
by the stimulationof muscarinicreceptorspresent
tn the endothelial cells of vasculature.The
Prlnciplesof llediclnalChemistryPo!. ll)
vasodllatoqreffect of acetylcholine on peripheral
vasculature is very. marked but is quickly
terminated. The latter two effucts of acetylcholine
can be observed only in higher doses. In heart,
cholinergicinnervation is providecl mainly to the
sinoarterial node. atrioventricular node and the
atrial muscles.The activation of this innervation
leads to an increasein the permeabili$r of cardiac
fibresto potassiumresulting into a decreasein the
activigr of S-A node.
The effects of acetylcholine on cardiovascular
systemjust described,sometimesmay be reversed
by the releaseof catecholar*rgs from the adrenal
medullaand from sympatheti- anglia.Thisrelease
may be due to the stimulation of nicotinic
cholinergicreceptor sites present in these organs.
(b) Smooth muscle :
At moderate doses, acegllcholinestimulates
the muscarinicreceptors present on the smooth
musciesof GIT,urinogenitaland respiratorytract,
and eye resulting into contraction of these
muscles.The increasedmuscle tone of GIT may
lead to nauseaand vorpiting. The lacrimal,salivaryl,
gastric, pancreatic, and sweat glands are also
stimulated.The motilig of gall bladder and bile
ducts is also increased.
The stimulatory effects of acetylcholine can
be explained on the basis of an increase in the
permeabiliglof the muscle cell to Na+ and Ca++
ions which resultsinto a depolarisationof the cell
membrane.When aceglcholine reacts with the
post-synaptic receptors, it may produce either
excitation or inhibition. The action of the
transmitterresultsin selectiveincreaseor decrease
of ionic permeability of membrane.The ratio of
permeabilityfor K+ to that of Na+,if increasedmay
lead to hyperpolarisation(asin cardiaccells)and if
decreases,may causedepolarisation(asin smooth
musclecells).For example,high concentrationof
78 CholinergicDrugs
acetylcholinemay lead to the complete heart blod:
due to hyperpolarisation.
Thus, enhanced permeability to monovaleni
cations, an increase in the concentration of
intracellular calcium ions, an increase in the
concentrationof guanosine- 3', 5' -monophos-
phate (qyclicGMP) or the inhibition of adenylate
cyclase enzyme are some of the mechanisms
associatedwith muscarinic receptor stimulation.
Investigationsin the role of c-GMP starteclfrom
1960. It is widely distributedin the tissues.lt is
presentat higher concentrationin cerebellumand
particularlyin retina.
Due to the quaternarycationic nature, ace$rl-
choline, at low doses, can not readily reach the
skeletal muscles embeclcleclby the fatty layers.
Hence at low closes, the nicotinic actions of
acellcholine are not prominent. At large doses,
acetylcholinecan stimulate nicotinic receptors
presentin both, sympatheticand parasympathetic
ganglia.
Ace\rlcholineis poor therapeuticagent sinceit
gets easily hydrolysed by cholinesteraseen4y'me.
Clinically, its use as acellcholine chloride, is
restrictedin ophthalmicsurgeryto obtain rapicland
complete miosis during cataractremoval. For this
purpose,0.5 to 2.O ml of 10 mg/ml solution oi
acegllcholinechloridecan be applied locally.
Slructure-Acttylty Relatlonshlp :
(i) Any change in the ethylene briclge may
affect the chemical stabili\l of acetylcholine
molecule.
ammoniumgroup is essentialfor
cf both muscarinicand nicotinic
receptoractivities.lf one or more of the methyl
groupson nitrogenatom are replacedby hydrogen
or ethyl group, both activities are reduced.
I
Principlesd mfyffof f) E Gtolcr1ic Orugr

H.\'
N N
N

N N

o- H2

CvclicGMP
6.tt :
(iii) The quatemary nitrogen atom itself may Examplesinclude, benzillcholine, tropyldroline,
be_replaced by arsenic, antimony, phosphorus or
sulphuratom without the loss of all acegllcholine-
like activities.
(iv) Ing in 1949 proposed that for m.ximal
muscarinic'activi!,there should be not more than
four atoms between the nitrogen and terminal
C-atom.
(v) lf bulky substituents are placed on the
terminal C-atom of acetyl group, through a firm
binding and 'Umbrella effect,' these substituents
block the accessof acetylcholine to the receptor.
This results in the antimuscarinic activigl.
o-l
CyclicAMP
lk nrclcoddcs
etc.
(vi) C.arbachol
and acetyl-p-methylcholineare
the cholinergicagonistsacting chieffy at muscarlnic
receptors while propionylcholine and acetyl
c-methylctrolineact driefly at nicotinic cholinerglc
receptors.
6.9 CYCLICANALOGIIEIIOT ACETYTCHOLINT,
Muscarineis a cydic analogueof acregdcholine,
devoid of nicotinic receptor activlty. It has a
quaternaryammonlum group but does not
possess an ester function. Hence, it is not
+
-cHz-cHz-N (CH-r)r

Benzilylcholine Tropylcholine
Cycllc andogues of acegdchollne :

Hrc cHr-N (CH3)3 H H

H3 Ha- N (CHlh
Cis-L-(+)muscarine 2-methyl-4-trimethyl
ammonium
- methyl-
1,3-dioxolone

6.12
 of itodlclnalGhemlstryflol. ll)
Prlnc-lples e Cholinerglc
Drugs

Citrate Glucose coocH3

r'
AcetyI CoA Choline ,

CHr
cHr
Phosphorylcholine
Ar€coline Ir{iodne
(lD Phosphonium, sulphonlum,arsenonium or
substances largerthan methylon the nitrogen,had
lessactlvlt5land not usedcllnlcally.
olinefrom the (b) Modlflcadonsof the EthylcnlcBrldge :
culation (l) In studyinga serlesof n-alkyltri-methyl
l-boundandfree)
ammonlum salts, Ing noted that for maximal
muscarlnlcaciivity, there shouldbe not more than
fls. 6.18 r Ac chollne metebollsm four atoms between the nltrogen and terminal
carbonatom. This rule was rcfuned to as five atom
6.12 CHOL|NOTUMEflCSOn CHOLTNEnGTC rule.
AGTONISt!5
0D Replacementof the hydrogenatoms of
The chollnomlmetlcshave as thelr primaql the ethylenlcbrldge by allqylgroups producesfar
actlon the excltatlonor lnhlbitlonof autonomlc less actlve compoundsexcept when a single,
effector cells that are lnnervated by post- methyl group is placed elther at c or p to the
gangllonic parasympathetlcnerves.They differ quatemarynitrogenatom.
ftom acetylcholineIn, (ill) The presenceof a methyl group p to the
(l ) Thelr selectlvlgl on muscannlc ano quatemarlrnltrogenatom lncreasesthe muscarinic
nlcotlnlcreceptors. activlty,e.g. Methachollne.
(2) Theirchemlcalstablllty. The hlgh selectlvemuscarlnlcactlon is due to
(3) Their resistanceto hydrolysisby chollne- orlentatlonof methylgroup of methacholineln the
sterasesand sameposltionasa methylenegroup ln muscarine.
(4) Theirdurationof actlon. OH
On the structuralbasls,the chollnomlmetlc
agentscanbe divided into,
(a) Acetylcholine and several synthetlc
Hgc
o
cholineest cH2N(CHJ3
(b) Naturally Hcc
alkaloids. Muscarlnc
(c) Chc,linesterase inhibitors (S)- itcdnchollnc
sterasesancl Moreov yl group hindersthe
added methvl
(d) Ganglionicstimulants. attack of esteES enzyme, thus slows down
The last two categoriesdo not act at postgan- enrymatic hydrolysis.
glionic cholinergiceffiectorsites'andproducetheir (iv) A methyl group alpha to the nitrogen
effiectsby acting in an lndlrectway. Increasesnlcotinic actlvlty e.g. Acetyl Methyl-
Structure-ActtvltyRelatlonshlp choline.
(c) Modlflcatlonsof the Acyl Gtoup :
(a) Modlflcatlons of the onlum (Quaternary
ammonlum)group : fif Wnen the aqyl group ls substitutedby lts
higher homologues(1.e.the propionyl,butyryl
(D The trlmethylammoniumgroup is the etc.),lessactivecompoundsare brmed.
optimal functlonal requirement for activlty, (,i0Choline esters of aromatlc br higher
althoughfollowlng are the exceptions. molecularweight acidsare chollnerglcantagonists
czH ratherthan agonists.
cHz (!ii) When the termlnal methyl group ls
replacedby -NH2group, the resultlngcompound,
(the carbamicacid ester), however, is a potent
cholinergicagent wlth both muscarinicand
Pilocarpine nlcotinicactivities.
 Pdttclpbsol l{edlclnalChomlstryryoL il) B GhollrcrylcDrugs

A CHa ftlLThe conceptthat the esterl.e. carbonylor

ilI
HzN- C - O- CH- CHz-N+ (CHr)s
Ct- other group ls not essentlalfior actlvlty but may
Bethanechol
drloride enhance lt by Increaslngthe afflnlty of the
o moleculefor the receptorwas conftrmed by a
il
HzN - c - o-cHz -cHz-N" (CH3)3Ctr study of the muscarlnlcpropertlesof N-alkyltri-
Carbacholchloride methylammonlum salts.
CHr - (CHz)n-N+ (Ctlt3)(-
Carbacholis certalnlystableto hydrolyslsand
hasthe right sizeto fft the cholinerglcreceptor.The N-dlqyltrlmethylammonlumsalts
carbamicacid esterof p-methylchollnels also a In thls serlesshowed muscarinlc
stable therapeutlcagent. The measuredInter- = l, 2,3 or 4. Compounds wlth
prostheticdistancesIn acet5llchollne are 7.O A groupslargerthan pentylwere partlalagonlstsand
ketoneorygen to methyl and 5.3 A ether olygen
to methyl. Obvlously, the interprosthetlcdis- those wlth groups larger than heptyl were
tances for ace$llchollne,methachollne,carba- antagonlsts.Thls appears to belleve the hypo-
minoylcholine.and urecholineare the.same,Appa- thesis that slze rather than functlonalgroups ls
rently, if the lnterprcsihetlc
lnterprcstheflcdlstan@a*e
dlstai Optlmal, necessaryfur the Intrlnslcactlvlty.
the receptors on the cell do not dlffierentlate Advcrsc roec{pgts r
between ether, ketone, ester" or ace$ll oxygen
atoms. All synthetk chollne esteni should never be
rbaehol,the termlnalmethyl group of adminlstered by Intravenous route. They are
is replae€d by -NH2 group, whlle size usually admlnlstered preferably
of the molecule remainsthe same as that of subcutaneousroute. The usl
" acetSllcholine. So lt becomesapparentthat the slze lnclude,sallvatlon,vomltlng and severegastro-
of the moleculemay be more lmportantto lts intestlnalcrarnps.
activitythan the aqylgroup present.Slmllarly,the Confia lndlceflonr r
, _ -- -<(Rerorygen appearsto be of prlmarylmportance
t* for high muscarlnlcactlvlt5l.As a result of such These synthetlc derlvatlves of acetytchollne
reasoning,ethers of choline and alkylamlno- are contralndlcated ln patlents sufferlng from
ketoneswere examlnedfor activity. peptlc ulcer, bronchlalasthma, hypotenslon,
CFl3- CHz-O - Cllz- CFl2- N+(CHr)rCtr presenceof organlcurlnarytract or gastrolntesflnal
chollneethyl ether obstructlon.
(Hlgh muscarlnlcactivlgr)
6.13 ANTTCHOLTNI,SnRASE,
t"'
cH3- cFt2 o - cH- cHz- N(cHt3 The chollnesterase enzyme termlnates the
-
'p- methylclrohne ethyl ether blologlcal actlvlty of acetylchollne by hydrolysing
(High muscarinlcactivig) ace$rlchollnelnto a9 cld and a chollne
(rc)The reduced biological actlvlty of molecule,thus llmltlng the tumovertlme of acetyl-
compounds In whlch oxygen ls replaced by choline to l5O mlcroseconds. The hydrolyslsof
sulphur(e.g. thlomuscarlne) suggeststhe presence acetylchollneoccurs through deacetylatlon
of H-bondlngor dlpole-dipoleinteractlonbetween reactlonwhlch ls catalysedby cholinesterase
.the drug and the receptorbecausesulphuratom enzyme.
has a le'ss qblllty to form H-bonds wlth the The chollnesterases present In the human
receptors. body can be broadlycategorlsedInto,
(a) Acetylchollnesterase or e-chollnesterase
HO or true chollnesteraseor speclfrcchollnesterase
and
Hrc cH2 - N (cH3)3x
(b) Butyrochollnesterase or s-chofinesterase
or pseudochollnesterase or non-speclflccholine
Thlomuscarlne sterase.
(
7
*ncirls Chemistryffol. ll)
ol Hecficinal
Ttrespecificor acegllcholinesteraseis found in
R-8.C..in the brain and other nerve tissues.lt is
pr€s€fit in high concentrationon presynapticsites,
pos-qynaptic membrane sites and at motor nerve
errd plate regions of cholinergic nenrous system.
-\r presynapticsites, its role is to regulate the
acerylcholine levelsin cholinergicnerueterminals.
r s also located in autonomic ganglia and certain
<frclinergic synapses in the CNS. The non-specific
or buglrocholinesterase is present in plasma,glial
cells, intestine and other organs. The choline-
sterasespresent in different species or organs
so{netimesbear basic differencesand need not be
identical.
Theseenrymes are mainly locatedinih-tQute r ---6.14STN,UCruRAL
basementmembraneof the synapsesand in the
neuromuscular junctional cleft. They are also
reported to be present in the cisternae of the
endoplasmicreticulum.
Sometimescholinesteraseen4/mes have been
located in such regions where they can not claim
the role of 'aceglcholine-killer'.ln such cases, cationic and esteratic site. The anionic site is
they are supposed to be tiecl up with some
independentactivities like,
(a) to control the membranepermeabilityancl
(b) to control the blood level of fatty sub-
stances.
Cholinesteraseinhibitors, as the name
indicates,increasethe concentrationof the acetyl-
choline at the receptor sites by inhibiting its
metabolism by cholinesterases,resulting into
prolcngation and potentiation of acetylcholine
activity at both, muscarinic and nicotinic
rec-eptors.They do so mainly through competitive
antagonismand hence often resemblewith acetyl-
cholinein structure.
The unhydrolysed acetylcholineaccumulates
and exerts its actions. Hence. cholinesterase
inhibitorsare .also termed as indirectly acting
cholinomimeticagents.
The activationof muscarinicreceptorsresults
into various muscariniceffects which include
miosis, contractions of smooth muscles,
diarrhoea, vasodilation, bradycardia, nausea,
vomiting, salivation,perspiration,lacrimation,etc.
All these effectscan be blocked by administration
of muscarineblockerlike,atropine.
4 chdkulff
The activation of nicotinic receptors by'
levels of accumLrlatecl acetylcholine results
generallsed muscle twitchin.g followed by tne
muscle weaknessand ganglianic stimulation.The
activation of nicotinic receptors present in the
autonomicgangliaand adrenalmedulla leadsto the
releaseof catecholamineswhich may further alter
the cardiovascularfunction.
Some anticholinesterases have an indepen-
dent direct cholinomimeticaction of their own
while some may causeneuromuscularblockade.
The toxic effects of sonne drugs may be due to
their in vivo metabolismto toxic metabolites.
FEATURES OI
C}IOLINTSTERASE ENZYME
Cholinesteraseconstltutes an example of one
of the most effectiveen4yme systemspresent in
the body. lt is a tetramerhaving a molecularweigiit
of about 3,2O,OOO. The cholinesterasemolecule
consistsof three important sites namely, anionic,
formed by an ionisec'lgamma-carboxylategroup of
a glutamic acid resiclueancl is stereospecific.
cationic site possesseshyclroxyl group probably
that of tyrosine resiclue.While the esteraticsite
consistsof two imiclazolegroups (lm1 and Im2)
from histidinemoietiesand a serineresidue.
o
- CH,-o
(CH.1,-- N - CH,''
tl
C - CH:
I
I
I
I
I
I
I
I
6 I
I
Antonlc Esteratic
site slte site
Flg. 6.19 : Posslble Interactlons between
ace$chollne and chollnesteraseenzyme
The process of hydrolysis of acetylcholine,
thus occursin the followingsteps:
(i) The imidazole group lm2, of histidine,
acceptsa proton from a serinehydroryl group at
the esteraticsite, creating a strong nucleophile
while OH - from grrosinejust servesas binding site
to ether oxygen of the acetoxy group of ace$ll-
choline.
Principlesof MedlclnalChemlstry$ol. ll) 6 Drugs
Chollnerglc

6.15 CIASS!flCAT|ONOt ANTICHOUNE-

Aniouicsite
STERASES
The anticholinesterases are classifiedlnto :
L reversibleanticholinesterases
R
*v* | | . irreversibleantichollnesterases.
(I) Reverslbleantlchollnesterases :
They bear a structuralresemblanceto acetyl-
choline, hence capableof comblningwith the
anionlcand esteraticsites of cholinesterases and
receptors as well. They have a great affinigl for
active sites but no Intrinsicactlvi$1.This procluces
"-o the temporaryrinhibition of the enzyme. In
contrastto other reversiblecholinesterases, edro-
phonlum forms reversiblecomplex only with the
anionicslte and hence has a shorterdurationof
-o-H action.
N AN C,H 5
-
Jer tJ l +-
H:c- N,- ctH3
tr.l

CI
Flg. 6.2O : Chollnesterasemolecuie and
lchollne OH
(li) The anionlcsite of the enryme bindswiih Eclrophonium chloride
the quatemary nltrogen of the acetylcholine Thesecan furtherbe divldedinto
through both ionic .rnd hydrophobic forces"The (al Naturally oceurrlng I e.g. physostigmine
latter bincling ft6rcels provided by the presenceof (b) Synthetlc : e.g. Neostlgmine, pyrido-
three methyl groups which are presenton the stigmine,ambenonium, miotine,demacarlum, edro-
phoniumand benzpyrinium.
nitrogeri.The activateclserine, being a strong
nucleophile, then attacks on the. C-atom of
carbonylgroup of acetylcholineresultlng Into a o
CFI
tetrahedralintermediate.This intermediatersvery
short-livedand its collapseresultsinto the release cHl
of choline molecule,leaving the aceglated senne
residueon the enryme. r
(iii)Thecholinemoleculereadilydissoclatefrom CHr
the anionicsite, slnceit is boundonly by van der-
--E-..-\ Physostigmlne
Waals forces and hydrophobic forces. The acetyl
group, however,forms a covalentbond with the
nucleophilicgroup (activatedserineresidue)of the o
en4/me. The acetylatedenryme then unclergoesa tl o (CHJs
conformational change which brlngs the - c -o
(cH3)2N N
acetylatedserine In close proxlmigr to the second
imidazole (lm1) resldue.In presenceof a water
molecule,the secondlmidazoleresiduecatalyzes
hydrolysisof acegllatedserineto give aceticacid Neostigmlne
and serineresidue.This step is rate limltlng step ln neostigmine, increased stability to
whichoccursat a very rapidrateand the enzymels hydrolysis is achieved by using dimethy
thereby efficientlyregeneratedback. carbamateIn place of methyl carbamategroup
The cholinesteraseenzyme from a purified Becauseof chargednitrogen,neostigminecan nc'r
sampleof OX red blood cell is frcundto hydrolyse crossthe blood-brainbarrierand causeCNSs',cer
3 x t Osmoleculesof acetylcholineper mlnute. effects.
Principlesof MedicinalCh€rflistry(Vol.ll) s Drugs
Gholinergic
(

of this drug b eliminated. leaving the carbamoyl

o group attached to th€ enzyme. The rate of
tl hydrotysis of carbamoyl group is about 60 times
(c H 3 )2 -NC less than tre rate of trydro\sis of aqyl group of
BF acegrlcholine.
(ll) lrreverslbte rdcholhestereses :
Organophoeptprus compounds combine only
CH, with esteratic site of cholinesterases and the
esteraticsite is phosphorylated.The hydrolysisof
this phosphorylatedsite, however. is extremely
tlridostigminebromide slow which produces a long term inhibition of
cholinesterases.In contrast to other organc-
o phosphorus cornpounds, echothiophate forms
t! complex with both anionicancl esteraticsites and
(cH-j)''N-C hence is much more irotent.
@
o
T I
N (CHs)r- N -cH z-cH z-s-P - (ocz H5)z
I Echothlophate
CHz
A number of phosphate, pyrophosphate and
phosphonate esters apparently react irreversibly
rvith cholinesteraseby forming phosphate ester
with the esteratic site. Because the rate of
Benzpyriniumbromide hydrolysis of the phosphorylated enzyme is
measured in hours, these compounds have long
o C H, duration.of action. These compounds esterifu the
il I serine resicluein the cholinesteraseen4yme. The
H3C- NH --c C H-N( cHr)"
hydrolysis rate of the phosphorylatecl serine is
extremely slow ancl hydrolysis to the free en4yme
ancl phosphoric acid clerivative is so limitecl that
Miotine the inhibitionis consideredirreversible.
The following are the examples of organo-
phosphorus compounds which are irreversible
anticholinesterases.
o o
t
I
(c2H5o)z- P P - (OCzHs)z
cHz _ * N H- CO 2Cl Tetraethvl pyrophosphate
c:Hs s
orN o-
tP_ (oc?H5)r
R = Cl:Ambenoniumchloride
R = OCH:; Metho4yambenoniumchloride
Parathion
Structure-Actlvlty Relatlonship :
(i) The distance across the ether oxygen and S o
nitrogen atom approximately same as that (cHro)2
-
IP- S- CH -
tc - oc,Hs
between the ether orygen and nitrogen atom in I
I
aceWlcholine. CH,
(ii) The two heterocyclic rings of physo-
stigmine are not essentialfor anticholinesterase
activigl.During hydrolysis,the phenolicfragment Melathion
 Prindpbsof Medlclnal flol. ll)
Chemlstry sl Drugs
Chollnerglc

(iv) In alkoxy series, compounds which

contaln fluorine are more active than those
containlngiodineor other raclical.
These organophosphoruscompounds are
lsofluorphate nervepolsonsand usedas :
(1) Nervegasesin warfare.
(2) As agriculturalInsectlcidest n which the
o death of insectscan be attributed to the inactl-
orN o-
tP- (oc2H5)"
vation of their acegllcholinesterases.
(3) In the treatmentof glaucoma.
Thesecompoundsare very toxic.to humans
and must be hancllecl with extremecaution.Toxic
Paraoxon symptoms are nausea, vorniting, excessive
oc l sweating, salivation,miosis, bradycardia,low
blood pressureand respiratorydifficulty that is
-- cl usuallythe causeof death.
lt
tl 6.16 TIIERAPEUTIC USES
OH CL
Dlpterex The reverslblechollnesteraselnhibitors find
oo their cllnlcal uses mainly due to their following
basicpropertles
[(cH])2N12-P - O - P - [N (CHr)u]z (1) They actlvate muscarlnlc receptors by
Schradran accurnulatlngacetylcholineat the receptorsites.
o (2) Activationof nicotinicreceptorsites leads
t to stimulation,followeclby depressionor paralysis
(cHs)zcFI- O - P -O - CH(CHr;t of skeletalmuscles.
I
F
(3) Actlvation of muscarinlcreceptorsin the
CNSleadsto stimulationfollowedby clepression of
Di-isopropylfluorophosphate
the centrallygovernedchollnergiceffects.
Sfructure-ActtvttyRelaflonshlp :
Thecholinesterase inhibitorsare recommended
A general formulafiorthesecompoundsls as
follows: underbllowing condition,
A (D in glaucoma,in which high intraocular
t t pressurecan lead to permanentclamageto the
& - P-X optic disk,iesulttng.inlllndness,
I (iD in myastheniagravis : They increasesthe
R2 acetylchollneconcentrationand excitationoi the
whereRr = alkoryl neuromuscularlunction. Dlseaseis characterised.
Rz= alkoryl,allqylor tertlaryamlne. by muscularweaknessand abnormalfatiguethat
X = Agood leavlnggroup, patientscan not even keep thelr eyes open. These
e.g. F,CN, thlomalate,p-nltrophenory. drugs increasethe strengthand endurance,and
(D A is usuallyo4ygenor sulphur,but may
(iii) as curareantidotes becausethe increased
dso be selenlum.When A is other than orygen,
blologlcalactlvatlonls requiredbeforecompound acetylchollnelevels displace the blocker more
becomeseffiective. readily.
(ii) X ls good leavlnggroup rrrhenthe molecule 6.17 ANTIIX)TESfOR NERVEGASES
reactswlth the enryme. When an lrreversiblecholinesterase is used, it
0il) The R mole$r lmpartslipophllicltyto the comblneswlth cholinesterase and the OH gro,io of
moleculeand contrlbutesits absorptionthrough the serlne gets phosphorylated.lt W d S U S i 2 ' '
skln. conslderedthat water in body fluids anacts ::e

l1
Princlplesof MedicinalChemistry(Vol.ll) 88 Cholinergic
Drugs

phosphorylated serine residue and causes its

hydrolysis. But the rate of hydrolysis is very slow
and that a more effiectiveagent was required for o
rapid hydrolysisi.e. it involvesthe administration ll
N C- NHOH
of a better nucleophilethan water to attack the
phosphorusatom and thereby eliminate or liberate
IcHr
the enqyme back to its original form, as shown
below: Z-tlridine hydroxamicacid
(l) Enryme-Ser-CH2-OH+ N-atom of methiodide
imidazole(lm2)
ofhistidine

N CH= NOH
Enzyme- Ser-CH2
- (lmz)
HN-imiclazole
ICH.
(Z) En4yme
- Ser-CH2
-d* nO- -oR Dihydro Z-Ilridine aldoxime methiodide
irreversible !
o
cholinesterase tl /R
H. C- C- C= NO H
o
f R = CHs;Diacetylmonoxime
Enzlnne-Ser-CH2-O-P(OR)z
Phosphoqllateclserine resiclue R = H; Slruvaldoxime
of cholinesteraseenzvme Hydroxamic acid or aldoxamine part of the
ot structure is known for zinc (metalloenzymes)
(3) Enqfme-Ser-CH2-O-P - (OR)z binding properties.
+ Nu (betternucleophile) To potentiate the action of Z-PAM, atropine is
J, also usecl along with it. Atropine acts as
ot competitive antagonist for the accumulated
aceglcholineat muscarinicsites.
- (oR)z
En4yme-Ser-CH2-O- P@
a
The effiectivenessof the oximes as antidotes
t is not entirely attributeclto their reactivatingaction
Rapicl a on cholinesterases.They may also alter the
hydro\sis Nu distributionof the inhibitor,diverting it to the liver
o as well as exerting a curare like action sufficientto
t effect a partial relief to the neuromuscular
Enzyme- Ser4H2OH + Nu - P - (oR)z
Regenerateden4/me blockade.
The effective antidotes for irreversibleanti- Llmltatlons of oxlmes as antldotes :
cholinesterases
developed are as follows: (i) These reactivators (antidotes) are only
effectiveif they are given immediately before or
soon after the exposure to the inhibitor. The
- phosphorylatedenryme unclergoesa fairly rapicl
N CH = NOH process, called as 'ageing' (which probably
IcHr cfe involves the loss of an allqylpart of alkory group)
as a result of which it becomes resistant to the
2-pyridlnealdoxlmemethchlorlde action of the antidote.
(Pralldoximechlodde)
 Principlesof MedicinalChemistry(Vol.ll) E Gholinergic
Drugs

(ii) Use of agents that block the acegrlcholine

o o from reactingwith the receptors.
Enz.-O -
t I
Enz-O- P- CH,, Compounds that inhibit'acetylcholinesyn-

o
Ageing
H ,O OH
I thesis have been discovered but have not proved
to be clinically useful while drugs that block tile
I Resistant to the interaction of acegllcholine with the receptor,
actionof antidote however, are widely employed in medicine.These
clrugsare of three glpes :
Phosphorylated
enzyme (a) Those who block the transmissionat
parasympatheticpost-ganglionicnerve terminals
e.g. Atropine.
(b) Thosewho block transmission,at sympa-
(ii) The reactivatorsare not very successfulin thetic and parasympatheticganglia e.g. hexa-
restoringcholinesteraseactivity in CNS. methonium.
(iii) They are not effective against all organo- (c) Thosewho block neuromuscularjunctions
phosphoruscompounds, the toxicity of few of in skeletal muscles e.g. d-tubocu(arine. Such
wtr-rch'rsac\ua$rncreasedby \Yreoimes. compounds shou)dhave the opposite eltects ol
Parasympatholytlcs or Antlspasmodlcs or cholinergic agonists and their administration
Chollnerglc Blocklng Agents : should be characterisedby decreased secretion of
They are anticholinergicdrugs that inhibit the saliva and gastric juices, decreasedmobility of GIT
effects of acegllcholine released from postgan- ancl unnarytract (antispasmodic)ancl dilation of
glionic parasympathetic nerve endings.They block pupil.
muscarinic actions of acetylcholine including
Because of their ability to relax smooth
smooth muscle contractionsancl exocrine gland
secretion.Atropine is the prototype of this class. muscle, they are referreclto as antispasmodic.
Two obvious approachesare there, to treat Such compound should have an affinigr for
the conditions characterisedby overstimulation of cholinergic receptor but should lack intrinsic
cholinergicnerves. activity.
(i) Use of agents that inhibit the synthesisor The interaction of atropine with muscarinic
releaseof aceqllcholine. receptorswas found to be loose and reversible.
I

HON = 911 -CHr-cHr-cHr_ CH= NOH,2HBre

1, 3 bis (pyridinium.4- aldoxime)propanedibromide

A
HON= CH - C H '- O- C H ,- N CH = NOH.2Clv

Obidoximechloride

t
Prlnciplesol MedlclnalChemlstry(Vol.ll)
Classlffcatlon:
Chemically,antlspasmodicdrugs are classlfied
as:
l. Atropineand its synthetlcanalogues
Z. Syntheticaminoalcoholesters
3. Aminoalcoholethers
4. Aminoalcohols
5. Aminoamldes
6. Papaverineand lts syntheticanalogues
7. Miscellaneous
agents.
Structure-Actlvlty Relatlonshlp :
(A) Anticholinerglccompoundsmay be consl-
clereclas chemicalsthat have some structural
similarig to acegdcholinebut contalnaddltional
substituentswhlch enhancethelr blndlnc to the
cholinergicreceptors. tsr-
-L
C acetic acld ester of amlnoalcohol,many substl-
H l C -N C H - O- C - C H.i
"-''"--'-t-"'---1"'---""-""""--"t'."-l
cH : cH? -cH2 cH2oH
Elg. 6.212 Atroplne
Thecircledportion of atropinemoleculereveals
the segmentresembllngwith acetylcholine.
Atropa belladonnawas namedby Llnnaeusln
1753,after Atropos,the eldest of the three Fates
of Greekmythology and the one whose dutSlwas
to cut the thread of life. "Belladonna'does refer to
an ltalianname("handsome woman")for the plant,
which was useclby Venetian ladles to glve them
"sparklingeyes"..The greater molar potency of
atropine helps it to block severalmoles of acetyl-
choline. The umbrellathe umbrella-likeatropine
molecule may mechanicallyor electrostatically where
inactivateadjacentreceptorson the cell surfaceso
that these receptorsare also unavailablefor acetyl-
cholineor other parasympathomlmetic
stimulants.
Atropine and scopolamineare estersof tropic acid
with the complex organic basesfropanol (troptne)
and scopine,respectlvely. Scoplnediffersfrom not be largerthan butyl, if the compoundis to be
tropanol only by the orygen brldge between C-6 an effectlveantagonist.
anclC-7. The alkaloidatropinewas first lsolatedby
Mein anci also by Geiger and Hesse ln 1832. not be always quaternlsed.Slnce the pH of the
Laclenburg,who, in 1880, produced the
semisyntheticderivativehomatropine,which is
stillwldely usecl.
I Drugs
Chollnerglc
CH qH -_cH2
(7) ol
o -o-c o-c
IH
2
Scopolamine
The actlon of scopolamlnediffersfrom that of
atroplneIn one lmportantrespect: when given by
injection, In ordlnary doses, scopolamine,In
additlonto lts cholinergicblocklngeffect,exertsa
powerfulsedativeor hypnotlcactlon.
To reduce CNSside-effiects,quaternarysalts
of atroplnelike, ipratroplum(bronchodilatoO and
atroplne methonltrate(to lower Gl tract motillty)
are usedclinlcally.
(B\ Slnceacet5llchollneand atroplneboth are
tuted acetlc acld estersof amlno alcoholswere
preparedand evaluatedfor biologlcalactivity.Such
esters of phenylacetic acld had llttle actlvlty.
Slmllarestersof diphenylacetic acid are found
therapeutlcallyuseful.
cHz-cHz-N(R)2
R= allq',lgroup
Therefore,the minlmum structurenecessary
for pureantagonlstlcactivlty ls :
C H z-C H 2-N (R ')2
R= hydroryal$d,allqyl,qycloallqyl or heteroglcllc
R= allqyl
(a) ln the above general formula, the anta-
gonlst may contaln largergroups than methyl on
the nitrogenatom. In general,thesegroupsshould
(b) The nitrogen atom In an antagonlstneed
receptorls acldic,this amlno group gets proto-
nated and carrlesa posltive chargethat Interacts
wlth the anlonicslte of the receptor.
FrfirEilsr d Hclnal Chemlstry(Vol.ll) 9l CffilinergicDrugs

(c) The aqyl group in an antagonist'ls always

anger than thl icyl group in ace$lchollne.The
,oSer aq/l group ensuresthat the compoundis not
a Dartiala.qonist.
(C) Th--e acetylcholinemolecule does not cover
a* the area of receptor. The area of a receptor,
*,hich is not covered by a acetylcholinemolecule HsC CHs
apfars to be chiefly hydrophobic in nature.
r'{ence,hydrophobtc substituentslncrease the
affiniry of the ar ling to thls area. chloride
Propantheline
li'Nowcryer, this a ,rm'in its hYdro-
:'dmbicnature. The fact that esters of trlphenyl
acedc acid have low potenq/ can be justiffed only
1l'rhe hydrophoblc area does not accommodate
bdMing by a third phenYlring.
(DI Tire hlgh potencyo-festersanclamidesof HO- C-
A"
CHr-N N (cH3)"
iloSri€acid result from their ability to H-bond with a
zufiablegroup on the receptor, surroundedby the
Sdrophobic area.
o
tl
Hexocycllum
//C-N - CH2
c
Tropicamide o
(E) Sincea number of alcohols,estersand ll -c-
Hr N- C
erhersresemblingcholine are less potent than
aceglcholine,but still demonstrateappreciable cH,
agonistproperties,it might be expectedthat the
addition'of two large groups to these molecules
n"ould produce cholinergicblocking agents.The
r-easoningwas correctand yielctecttherapeutically Aminopentamide
usefulcompouncls. This is an indication for the' need of at least
one portion of the molecule to have the space
occupying,umbrellalike shapewhich leaclsto firm
binclingat the receptor.
rt
(F) Sizealone,is not the solecriteriafor potent
blockipg agents. The spacialarrangementor the
CH, -c- o- cH 2- C H z- N ( C Hj)2 stereochem-lGal-'{ nolecule are also
important presul f a good fit of its
prostheticgroup with the receptorsite.
Mocle of Actlon :
The main differencein cholinergicand anticho-
Chlorphenoxamine linergicagents appearsto be the size of the acyl
group.
oll
R- c -O-CHz- CH2-N (R)z
H O - C- compoundsR = smallgroup.
In cholinergic
compoundR = largegroup'
In anticholinergic
Bre The large (alkyl or aryl) group may not cnly
increasethe affinity of the blocking agent bur
throughan 'Umbrella effect' may also block tfte
Tridihexethylbromide approachof acetylcholine to the recePtor.
Principlesof MedicinalChemietry(Vol.ll) I Cholinergic
Drugs

Adverce effects : Adverse effect of the anti- the seriesof compoundswith cholinergicactivity,
spasmodicdrugs are dose dependentand include there is not an abrupt change from cholinergic to
dry mouth and skin, flushing, tachycardia, anticholinergicactivigl.
pupillary dilatation with blurred vision, cerebral [e. g. CH3(CHJnN+ (CHJr]
excitementand clelirium.The quaternaryammo- when (1) n= l to4potenqyincreases
nium compounds may also cause postural hypo- (2) n = 5 to 7 partialagonists
tensionand impotencebecauseof their ganglionic (3) n = more than 7, compound is
blockingeffects. antagonist.
Uses : The anticholinergicdrugs have been Bellaeu's concept can be representecl as
widely used in the treatment of peptic ulcer shown in Table6.3.
diseaseand irritable bowel and functional dis-
In this table, compound l (ACh) can exactly fit
orclers, including diarrhoea. The main contra-
on the receptor to provide orientation favourable
indicationsto anticholinergicdrug use are narrow
for agonist activity. Some molecules like
angle glaucoma, pyloric outlet obstruction and
\-*.rr-_-, compound 2 and 3, when in an unfavourable
reflux oesophagitis.
orientation[i.e. 2(a) and 3 (a)l exhibit antagonistic
Bellaeu's concept of enzlme p&urbaflon : activity, while remainingmoleculescan assumea
This concept views that the receptor alters its confonnationi.e. 2 (b) and 3 (b), that will fit on the
conformation to fit the acetylcholine or its receptor to give an orientation favourable for
agonists. Since it is bound to the membrane, it agonist activigl. Therefore,the combined effect is
sufficientlychanges membrane structure to alter being partialagonist.Molecule4 is too largeto fit
the transpert of ions through the membrane to the receptor in such a way as to provicle a
generatemusclecontraction. favourable contormation. lt acts totally as an
The applicability of this concept is further antagonist.
enhanced by the fact that as the size increasesin
Table 6.3 : Belleau's conce to fe n erturbatlon
Favourable Orlentatlon Unfavourable orlentatlon

2(a)

o)5
-..t
ftl
t liv

(a)6 CHr

(b) 6

HtC-H2G

4 9
 Principles
of MedicinalChemistry
(Vot.lt) 94 Cholinergic
Drugs
Cllnlcally useful antispasmodlc agents

o
tl
o
tl
Br€ c-o-cH2(

e
Br

Glycopyrrolate Methantheline;R = 4-zHs

R = isopropyl
Propantheline;

o -r*a+_
tl
/..C - o ./CH- - CH,
C
\ oH IcH,{n -.,,^^o
cHrso; NH,
i - crHT
,\o ^ \ ll
o

polclineMethylsulphate lsopropamicle
Papaverlneand lts synthetlc analogues
:
This is a group of antispasmodicagents Hrco CH,
. that
do not act by interfering with cholinelgic H3CO
nerve
transmission.
CH, oc.Hs
Hrco
ocH.r
H.rCO
Dioxyline
CH, ocH.3 H.co
Hsco

CH, ocH-3
Papaverine

ocH.r
H5C. o
Tetrahyclropapaverine

HrC_.o

CH, oc?Hs
( c H2) 3 - N_( c H2) 3

Ethaverine
Alverine
Princlples
ol Medlclnal
Chemlstry
ryoL[) s Drugs
Cholinergic

cHl

cHj o
facrine
Tacrlne hydrochloricle ls a reversible
Neupaverine cholinesteraseinhibitor, used in the treatmentof
Mechanlsmof actlon : mild to moderateAlzheimer'sdementia.
Since cholinerglcnerve stimulationincreases
peristaltic movements of GIT (spasmodlc),
adrenergicnerve stimulationwlll produceanti- cclr
spasmodiceffect through the stimulation of p-
adrenergic receptors.Cyclic-AMP (cyclic-3', 5'- H.,c
adenosinemonophosphate)ls the actlve factor OH
which is a product of the responseof p-adrenergic
receptors. Papaverine and its analogues are Metrifonate
csphodiesterase, an enryme that
AMP.

.--
B-adrenergic CvclicANlP
receptor Strmulatlon H.rC
I I
I I
I I
t I
I I
I
I
I
HuperzineA
I
analogs
analogs i I
I
!------------l I
I
I
I
I
I
I
aa I
t
J
Antisoasmodic
etl'ect N- czHs
I (cHJ2N
Inactive
5'-AMP
i..------*-----rl
-E_- Rivastigmine
flg. 6.22 z Mechanlsm of actlon of Papaverlne
analocues
Chemlcal structures of AChE Inhlbltors and
nlcotlnlc aggnlsts under.lnvestlgatlon as thera-
peutlc agents ln Alzhclmer's dementla :
(a) AChElnhlbltors r H3CO
OH
cHz - cHz
H3CO

o Donepezil

It is a reversiblenon-competitive
actingchollnestraseinhibitor.
Galanthamine
 Princlplecof iledicinal
th"ri"ry(vor.D
Ntcottntc@ !!!19rercer

H,rc
Xanomefine
(tlt$fi
N Phenyltrimethylammonium
(N1)
I Muscarine
(M)
cHt cH.l
CH2-C= C-( IN

Nlcotlnlc antagonlsts : O Oxotremorine

1M) Nicotine(N1+ Nr)
ff
c
cHr- N- cHr
Hc c H
Hz9
fl
cHz
OH iY:
H2
Trimethaphan
(Nr)
d_T[rbocurarine

CHI CH,
Hexamethonium
(Nr) CHs CHr
.
Muscanlnlcantagonlsts
z ' Decamethonium
(N2)
o
H ff
N- c,
/c -o Br

Clidinium
bromide
(M3) /o-cHz(
Pirenzepine
(M,)

CHs Orphenadrinc
(M1)
HO-si_ CHt CH,_cHz
- _N

exahydrosiladiftnidol
LMr)
ooo
 7.r TNTRODUCTTON
i7.1 TNTRODUCTTON The sympathetic nervous system controls
various important systems inclucling cardio-
72 BIOSYNTHESIS
OF NEUROTRANSMITTER vascular,bronchialairway tone, muscular,rneta-
bolic etc. lt preparesthe organismagainstthe
conclitionsof stress,either of physicalor physio-
73 SYNAPTICINTEBACTIONS logical origin. In adclitionto epinephrine,a large
number of agents can mimic the responses
7.4 PHARMACOL9GICAL
ACTIONS obtaineclas a result of stimulationof adrenergic
CATECHOLAMINES neryes.They bear structuralresemblancewith the
neurotransmitter, epinephrine.Hence,they can be
useclto mimic or alter the functioningof sympa-
75 METABOLISM thetic nervoussystem in severalclinicalclisorders
like hypertension,asthma,arrhythmiaanclvarious
7,6 ADRENOCEPTORS 't@ allergicconditions.Majori! of these substances
contain-an y substitutedamino
group ancl ts sympathomimetic
7.7 CLASStFtCATtON
amlnes.
These drugs are divided into two broad
78 DESIGN
OFDRUGSAFFECTING
THE categoriesaccorclingto their structures.
ADRENERGIC
NERVOUSSYSTEM (a) Compouncls-wlth 3, 4-dlhydroxyphenyl
nucleus or a catechol nucleus : Thev are termed
as catecholamines.

cH,- cH,- NHt

Dopamine

(e7)

I
Prlnclplesof ltledFlnalChemlfi (Vol.ll) s AdrcnergbDrugs

A large number of synthetic amines, 4. Dopaminep.oxldase

structurallyrelated to epinephrlnewere prepared 5. PhenylethanolamIne-N-methyl-transferase.
and evaluatedfor the activityby Bargerand Daleln Theseenzymesare syntheslsedwlthin the cell
l9lO. They clescrlbedthe activlgr of these bodies of the adrenerglcneuronsand are then
sympathomimetic.The racemic transported along the axons to thelr nerve
rmed, was resolvedby Tullar ln
1948. Upon resolrrtion,dextro-eplnephrlne was termlnals.The activlty of groslne hydrorylaseIs
found to be about one twelfth potent as laevo- low and converslonof glroslneto DOPAis a rate -
epinephrine.Its role as a neurotransmltter In the limiting step in neurotransmltter synthesis.The
sympathetic nervous system, was proposed by remainingenzymesare of generallylow speciffclty.
Elliottln 19O4. StepsI to 3, takesplaceIn qltoplasm,Dopamine,
Dopamine,a third naturallyoccurrlngcatechol- the end- product of step 3, then enters Into the
amine, acts as a neurotransmitterIn the basal synaptic vesicles where it ls converted Into
gangllaof CNS.Dopamlne-p-hydrorylase enzyme norepinephrlne. Noreplnephrlne thus syntheslzed
converts dopamlne Into norepinephrlne.Thls ls then storedinsidethe nerveendingswithin the
enzymeis not presentin the dopamlnerglcneuron. synapticveslcles.
Hencedopanrineremainsin lts orlginalformto carry
out the functlonof ;':eurotransmltter.
Forexample, 7.3 SYNAPTICINTERACTIONS
dopamineacts through dopamlnergicneuronal ( I ) When the impulse 'reachesto the nerve
mechanisms to dilatemesentericand renalvascular termlnals,the membranebecomesmorepermeable
becls.
7.2 BIOSYNTHEIiIS O] NEUR,OTRANSMITTER, for the lnflux of C-a++ions.Thlscausesthe release
The Flg. 7.1 representsthe biosynthetic of neurotransmltterfrom the synaptic veslcles
pathwaybi noreplnephrine and epinephrineln the through exocytosis. The transmitter mlgrates
nervetermlnals. acrossthe synapseand blnds to lts receptorsltes
The enzymeswhlch catalysethe intermediate upon the targdt organ. The neuro-transmitters
steps of biosyntheslsof sympathetlc neuro- being hlghly flexlble molecules,can swltch on
transnitterare denotedby the numberpresenton different receptorsto glve different blologlcal
ihe arrow.Theyare llsted as below : responses.Hencebody takes care to releasethem
Enzymespartlclpaflng : close to thelr target receptors, then qulckly
1. Phenylalanine hydroxylase lnactlvatlngthem to avold thelr loumey to other
Z. Tyrosineh5ldroxylase receptors.
3. DOPAdecarborylase
I Tlramine
Impulse I
DOPA
I
Dopamin
ionophore

Synapticvesicles aa

\
\
I Presynaptic
I
recePtors
I
() Release
(.)
I
I
I U Glial
cell
(n

\ \
\\

receptors
Postsynaptic

tlc. 7.2 : Schematlc representatlon of adrene c svnaDse

 Principles
of MedicinalChemistryPol. ll)
(2) After its interaction with receptor, nore-
pinephrine may be removed by the following
routes :
(a) Norepinephrine is rapiclly ancl efficienrly
'reabsorbecl'into the neuron i. e. nerve terminals
and then into its storage sites. The maximum
quanti! of norepinephrineis removed in this way.
This type of uptake (uptake-l) has strict ionic
requirements,being completelyclependenton the
presenceof Na+ ions (and low concentrationof K+
ions)in the externalsurrounclingmeclium.Similarly
this uptakeexhibitshigh stereochemical selectivigl
ancl operates against concentration graclient.
Certain clrugs Iike cocaine and imipramine
selectively block this neuronal uptake and avail
high concentration of -ccggpl4ephrine in the
synaptic cleft.
(b) Extraneuronal uptake :
In aclclitionto neuronaluptake, there exists a
second uptake process of norepinephrinefrom
synapticcleft to supporting tissues(glial cells).
This process is not stereo-selectiveancl is not
inhibiteclby usual inhibitorsof neuronaluptake.
This extraneuronal uptake is reported to be
inhibiteciby metanephrineancl corticosteroicls.
This extraneuronal uptake can be regarded as
transportand metabolismwhile neuronaluptakeis
transportand retentionof neurotransmitter.
(c) Part of the neulotransmltter may also be
lost due to lts dlffuslon across the synaptlc
cleft:
In the adrenergicsynapses,diffilsion mecha-
nism is a route of minor importancein removing
OH
I MAO
CH- CHt NHz
Vir.86
Norepinephrine
OH
I I
WhereR OH CH
flc 7.3 : Metabollc lnactlvatlon of noreplnephrlne by monoamlneoxldase enzyme
L
1q) Adrenergic
Drugs
norepinephrine.The blood vessels,probably stancl
as an exceptionwhere the immecliateclisposition
of releasednorepinephrineis accompaniedlargely
by a combination of extra-neuronal uptake,
diffusion and enzymatic breakdown of neuro-
transmitter.
The other routes of removing norepinephrine
are metabolicin nature.
Forexample,norepinephrinethrough its inter-
action with cytopl.lsmic monoamino oxiclase
(MAO) enzymes, is converteclto the correspon-
cling alclehyclewhich then non-enrymaticallyget
further oxiclisecl.Similarly, catechol-O-methyl
transferase (coMT) enzyme methylates the
m-hydroxy group of the phenyl ring of the
catecholamines, rencleringthem lessactive.
7.4 PHAR.MACOTOGICAL ACTIONSOf
CATECHOLAMINES
(1) They exert excitatory effects on smooth
musclespresent in blooclvesselsand on salivatr'
as well as sweatglancls.
(2) They initiate inhibitory responses on
smooth muscles of GlT, bronchial tract ancl of
blooclvesselsprovicledto skeletalmuscles.Thus
the blooclvesselsget clilatedto supplythe skeletal
muscleswith more bloocl.
(3) Dependingupon the clrug employecl,the
secretion of various endocrine glancls either
increasesor decreases.
OH
I
CH-CH NH
Imine
OH
CH-cH
Aldehyde
 Ctunlstry (Vol.ll) Adrcnerglc
Drugs

S TFrq/cxert excitatory effects on cardlac

EdmE into an increaseIn force of contra-
rroilm ifli'c poriitive ionotroplc effect) and an o OH
|ffire rt the rate of contractlon(i. e. posltlve ll
d@rr. cffect). - c -o
(cHJ3C NHCH3
5 Tih ixreased level of catecholamlnesin
(cH3)3c
, firlcinErrrcin psychomotor actlvltSl and a
ma@! in +petiG. o
(!b C.cdplamines promote glycogenolysls
I m hrr and skeletal musclesand cause a
rffiMD dl€ production of ftee fatty aclds Dlpiveftln(Pivallcacld ester)
r ,@e -r tissJe.
E+lphrine reducesIntraocularpressure. I,IETABOLISM
t*tartrate,dipivefrln and eplnephqd Monoamino oxldase (MAO) and catechol-o-
t ccnplex between borlc acld and
qpil@lrrrnrc are prefienedpreparatlonsused In the methyl transferaseare the maln enrymeswhlch
[!mliE'1rt cf open-angleglaucoma.In the lacrimal metabollsethe sympathomlmeticdrugs. About
il[lru. arcptr4d borate readlly dissoclates to 60% of the adminlstereddose of epinephrineor
tur drqg. OH norepinephrinein man remalnsuntouchedby
NHCH3 these maln enrymes whlch then ls excretedin its
N d r c-B /o original form or ln tts con\ugatedtorm w\th
sulphuricor glucuronicacid. Conjugationusualiy
Epinephrylborate occursat phenollchydroryl groups.

OH OH
I COMT I MAOA/it.86
CH- cH, - NH, - CH-CH"-
-_'
S-Adenosvl-
L-methionine
Norepinephrine Normetanephrine
I
I
I Oxygcn
t
Freeor conjugated
form
I
I
\,
-. \J
J-m
r olvc
D-J
] -
I
I
I
I
YI
I
I
i H.co
)H \- oH
rH- cooH Ho{ V l" - cH.,
oH
\:/

)xy 3-methoxy-4-hydroxyphenyl
II acid(MOMA)
mandelic glycol(MOpEG)
ettrylene
il
Y )=Aldehydeoxidase
Urine<----a @
- i= Aldehyde
reductase
Fls,74 r Mctebollc rn of norcplnephrlnc
 $ol. ll)
Principlesol MedicinalChemastry 1@ AdrenergicDrugs

OH
The maior fractionof naturalcatecholaminesis
attackedby MAO and / or COMT.At periphery,
they are preferentially oxidisecl to the acicl ancl in
the CNS,they are reduceclto glycol.
Thus the principal metabolites of norepine-
Pyrogallol Tropolone
phrine (MPOGAL, MOMA ancl MOPEG) are
excretecl through urine alongwith a free or 7.6 ADRENOCEPTORS
conjugateclform of unaltereclnorepinephrine.Of Upon dischargefrom nerve terminals, nore-
these, 3- mettioxy-4-hydroxymandelicacicl is the pinephrine reacts with post-synapticreceptor
principal metabolite and the estimation of its sites to evoke its pharmacologicalresponse.ln
content in urine can be taken as an index of 1948, Ahlquist observeclthat, the tissues he
catecholarninemetabolism.On an average,about examined, carried two kinds of aclrenergic
responses,i.e. alpha ancl beta responses,as
shownin the table7.1.
Table 7.1
Results of Ahlqulst experlment
'ugs which inhi Group 2 responses
s, the duration (p-responses)
effects can be raisecl.For exampl ple, so{ne agents
Vasoconstriction Vasodilation
can specificallyblock the MAO enzymesland are in
clinical use under the name of MAO linhibitors, Contractionof Uterus Relaxationof Uterus
while only few agents can block the lactivity of Contractionof Ureters lncreased rate and
COMT enzymeson circulatingcal force of heart beats
clid not fincl clinical applicabilit Constrictionof Pupil
pyrogallol ancl tropolone clerivatives. Relaxationof Intestine

Table 7.2 : DlsHbutlon of receptor sub-types

p-receptor predomlnance c-receptor predomlnance aand p
cells(Fr)
Carcliac Blooclvesselsto Coronarybloocl Vessels
Metabolic effects skin Skeletalmuscle
lipolysis(p1) visceralregion Bloocl vessel
glycogenolysis(02) brain region Mucous membraneof alimentarv
tract
Bronchialmuscles(p2)
Ciliarymuscles(02) - renalregion
Blacldermuscles Intestinalsphincter
Sweatgland
Blaclders phincter
Dilateclpupils

b
rlree of MedicinalChemistryflol. ll)
:-rm the table 7.1, it can be easilyseen that
,i,i,-- rhe last response as an exception)
._.sns€s are malnry excitatoryin nature,while
: ---+3nses are inhibitory in nature. ln general,
rrL--,r3t' 3-receptorscan be activateclat quite low
I :r:enriation of catecholaminesthan that is
-e.r:,ei to activa :ceptors.
-"nds and c< !7, based on the
;rf-ences in the carcliacancl bronchial responses
:f -e sympathomimeticagents, proposed a
'i=e. suMivisionof the p-receptorsinto :
3 -receptorswhose activation accounts
r:- ::'Ciac stimulation,lipolysisancl intestinal
r?":.r::on effectsof sympathomimeticdrugs, and
. B2-receptorswhose activation accounts
'elaxation in vascular becl, bronchial tree,
-"
-i=--s and ureter alongwith metabolic effects of
r,"- :a*rom imetic agents.
Table 7.3
!-ector Receptor
resDonses
l.gan cr Ft 9,
constrlction dilation
constrictiondilation dilation
decreaseddecreaseddecreased
motility motility motility
increased
]itr[it,: c0nstriction relaxation
tilsfE
.i.':h an exception of pr-receptors present in
:;-- -:e:s ,which have excitatory response),the
c-j-'.iaoo of most of the pr-receptors is linkecl
',,,r- :he inhibitoryresponses.While the activation
:," . -receptorsleaclsto the excitatory responses
- a-eral. Thetype of responseis mainlygoverned
:.. l=-- ion ffuxesat the nerveenclings.
3n rhe same line, d-receptors can be catego-
'*e: inro a'- and c[2-receptors.ctI -Receptorsare
:r=-r:1,ron post-synapticreceptor sites of smooth
- --ies of blood vesselsand glancl cells. While
---e.eptors are present on pre- ancl post -
r. -;:ric sites on the nerue terminals and are also
:r-:st in the CNS.
\r increasedprominence of c[2-receptor
*:s:,3nses accompanies hypertension and may
:--r-eute to the elevatecl blood pressure. The
:r--s:-synapticsites of ct2-receptor include the
rs-i-leslike brain, uterus, paroticlglanclsancl extra-
;.-€itic region at some bloocl vessels.The pre-
,,-.::r:ic o1-receptorsare present on the nerve
-:- ial. Their activation leacls to inhibition of
1(B Adrenergic
Drugs
neurotransmitter release(norepinephrine or acegl-
choline) through negative feeclbackinhibitory
mechanism.Theirfunctionis :
(i) to govern the releaseof neurotransmitter,
and
(ii) as per neecl,to alter the rate of synthesis
of neurotransmitter.
Thus the activation of o2-receptors on the
cholinergicnerve terminalswithin the intestinalwall
leadsto the inhibitionof releaseof acellcholine.
Clonicline,yohimbin and c-methyl-norepine-
phrine are more effectiveagonistson g2-receptors
than cx1-receptors. While phenylephrine, prazosin
ancl methoxamine act prominently on c 1-
receptors.
Thus in tissues, the overall effect of the
aclrenergicnerve stimulation depencls upon the
population of cr ancl B-reCeptors present in that
organ.
For example, in carcliac cells, positive
ionotropic ancl positive chronotropic actions are
due to the activation of p-receptors whereas
G,-receptoractivation leads to ectopic excitation
inclucedby sympatheticstimulation.
Further subclassification suggests the
presenceof four c[r (clra to c[lD) ancl four az Kxza
to cr2p) receptors.In case of B-receptors, the
presenceof thirct (91) type is postulatecl.All four
crq-receptorsproduce vasoconstrictorresponses
through clifferent biochemical mechanisms for
increasingcytosolicfree Ca++ions.
Tachyphylaxis or reclucecl response is a
common problem encountered in the prolongecl
treatment of adrenergic clrugs. Upon continuous
exposure, the receptors lose their efficiency
resulting inte-a e magnitucle of
biological respc f,wn as clesensi-
tisation, refractoriness,down regulation or
tachyphylaxis.Various mechanismsare proposecl
to account for this event. Thus, tachyphylaxis
may be clue to following processes:
(a) Feeclback regulatoryrmechanismsgovernecl
by cyclic-AMP.
(b) Somereceptorsmay undergodegeneration
causingdecreasein total numberof receptors.
(c) Receptorsmav be inactivateclor blocked
due to irreversiblephosphorylation, or
(ct) The correlation between the receptor anc
adenylatecyclasemay get paralyzed.
Principlesof MedicinalChemistry(Vol.ll) 1(X Adrenergic
Drug*

fable 7.4 : Adrenergic responses

cr-receptor medlated responses p-receptor mediated responses
Vasoconstriction Vasodilation
Mydriasis Bronchialsmooth muscle relaxation
Releaseof ACTH
Uterine myometrial contraction Uterinemyometrialrelaxation
Retractorpenis contraction Intestinalsmooth muscle relaxation
Seminalvesiclecontraction Positiveionotropiceffect on the heart
Pilomotormuscle contraction
Orbital contraction Positivechronotropiceffiecton the heart
Nictitatingmembranecontraction
Intestinalsmooth muscle relaxation Hepaticglycogenolysisand Lipotysis
Norepinephrineis the most active agent at remains unaffected by the use of reserpine
d-receptor and the lattei esponsiveto cocarne or lmrpramrne.
isoproterenol.The responsesmediated through (b) Indlrect-actlng drugs :
o,-receptorsare blockeclby antagonistslike phen-
Tyramine cloes not act clirectly on the
oxybenzamine or phentolamine. The excitatory
aclrenoceptors.The fact that reserpine depletes
nature of c-receptors and inhibitory nature of (Bertler et al, 1956)
p-receptorscan easilybe seenfrom the table 7.4. tissues of norepinephrine
indicated that glramine acts by releasingendo-
The p-receptor is most responsive to genous norepinephrine.Many sympathomimetic
isoproterenolwhile the least responsiveagent is agents exert a large fraction of their effects by
norepinephrine. The p-receptor mecliated releasing(through displacement)norepinephrine
responses remain unaffected by the usual from storagesites. The responsesof this released
o-adrenergicblockersancl are blocked by agents norepinephrineare prominently cr-receptor
likenaclololor timolol. mecliatecl,slower in onset and generally long
7.7 CLASSTHCATTON lasting.
Norepinephrine,epinephrineor isoproterenol- Examples of indirect acting drugs include
like drugs mimic the responsesof adrenergic tyramine,amphetamine,etc. Thesedrugs= usually
stimulation by acting directly on the receptor sites. lack catecholnucleus. Indirect acting agents have
While some agentswhen administered,do not act little or no actionin reserpinized
animals.Cocaineor
on the aclrenergic receptors. They enter the imipraminealso lower the intensig of activigl by
adrenergic nerve terminals and cause stoichio- inhibiting the drug-induced displacementand
metric clisplacementof norepinephrinefrom the releaseof norepinephrine. Since these drugs lack
synapticvesicles.Their pharmacologicalresponses the phenolic hyclroxyl groups, the increased
are thus due to this displaceclneurotransmitter. lipophilicity imparts pronounced central effects to
The adrenergic agonists can be conveniently these drugs. lf given repeatedly, tachyphylaxisis
dividedinto: likely to occur due to the depletion of
(a) Dlrect-actlng drugs : norepinephrine stores.
{c} Mlxed actlon drugs :
These amines produce their pharmacological
responsesby their direct actionon adrenoceptors. Many sympathomimetic drugs exert their
Theactionsproducedare of rapid onsetand short- actions partly by acting directly on the receptor
lived. Most of the agents can influence both sites and partly by their effect on the norepine-
q- and p-receptors,thus ranglng ftom pure cr- phrine release.They are termed as mixed action
agonist (phenylephrine) to pure p-agonist drugs.ExamplesInclude:
(isoproterenol).The intensig of their effects
Principles
of Medicinal (Vol.ll)
Chemistry 1(F Adrenergic
Drugs

Thus,examplesof direct-actingdrugs include:

(predorninantly
norepinePhrine on 0(-receptor)
OH
I epinephrine
CH cH-.- NHCH.T (on a, p1anctp2receptors)
isoprenaline
Ephedrine (on p1anctpr receptors)
Tazolol
(predominantlyon p1-receptor)
OH Salbutamol
I (preclominantly
on F:receptor)
CH cH- NH,
Phenylephrine
Metararninol (preclominantlyon a-receptor)
Prototypeof indirect- acting clrugsis amphe-
tamine. Prototype of mixecl action clrugs is
OH
I epheclrine.
C H-cH - N H " The commonly usecl alpha blocking agent is
clibozaneor 1, 4- (bis- 1, 4-benzoclioxan-Z-yl-
methyl) piperaz-inewhile the commonly used beta
Pheny
lpropanolamine blockingagent is propranolol.
They sharestructuralfeaturesof both classes. 7.8 DESIGNOT DRUGSATTECTING THE
The presenceof cocaine, reserpineor imipramine ADRENERGICNERVOUSSYSTEM
only lecluce(anclnot abolish)the intensigrof their Developmentof a new drug can be done in the
effects,where higher closesof these clrugswill be following dr€ds :
needed to proclucecomparable eftects. (A) Drugs that affect the biosynthesis of
Thus if we assume the following skeleton norepinephrine.
essentialfor sympathomimeticactivity, (B) Drugs that affect the storage of
norepinephrine.
(C) Drugs that affect the metabolismand/or
R, r€moval of norepinephrine from the area
t- surrounclingthe rec€Ft*---
CH-CH,-NH, (D) Drugs that mimic the effectsof norepine-
0tt
phrineat the receptorsites(agonists).
(E) Drugs that block the interactionof nore-
then,
pinephrinewith the receptor(antagonists).
(D Direct-actingdrugs will have R3= & = OH (F) Drugs that affect post-synapticregulation
or OCH3and Rz= OH. of hormone action.
(ii) Indirect acting drugs will have only a (A) Drugs affectlng blosynthesls of norc-
hydroxyl group at p-carbonatom or no substi- plnephrlne :
tution at Rr, R3and &. They retain the phenyl- The key enzyme is grrosine hyclroxylase,
ethylamineftamework,and which requiresa tetrahydrofolatecoenzyme,02
(iii) Mixed action drugs share the structural ancl Fe++and is quite specific.DOPA-decarboxy-
fieaturesof both the above classes. laseacts on all aromaticamino acids and requires
vitamin 86 as cofactor.Dopamine-p-hydroxylase,
Principles
of Medicinal
Chemistry
Uol. ll) 1(F Adrenergic
Drugs

locateclin the membranesof storage vesicles,is a
copper containing protein, a mixecl function
oxygenasethat uses 02 and ascorbicacict.Finally
phenylethanolami ne-N-methyl transferaselocatecl
in the aclrenalmeclulla(the main site of aclrenaline especially the p-OH clerivative of tyramine,
synthesis) and in the brain, uses S-aclenosyl-
methionineas a CH3-clonor.
(i) cr-Methyltyrosine effectivelyinniLits tne
action of lrosine hydroxylasein the first step of
biosynfhesis,which is rate cleterminingstep.
HO
tl
H NH)
ct-Methyltyrosrne
Unfortunately,the compounclis not clinically centraladrenergic,dopaminergic
useful.
(ii) DOPA-clecarboxylase may be inhibitectby
cr-methylDOPA. Since the rate of clecarboxylation concentration of norepinephrine at the receptor.
of ct-methyl DOPA 'is consiclerablyslower than
that of DOPA,it ties up the enzyme for a longer
period of time anclacts as an effectiveinhibitor.
HO c-c-cooH
tl
H NH,
a-MethylDOPA
(iii) Dopamine hyclroxylasemay be inhibited
by a variegr of compoundsincluding disulfrram.
Disulfiram inhibits dopamine hyclro4ylaseprobably
by breakinginto 2 moleculescliethvlcl ithiocarba- of inclirectactingclrugs.
mate which forms a chelate with Cu++ - ion of
enzyme'sprostheticgroup.
(B) Drugs affectlng the release of stored
noreplnephrlne (Indirect actlng agonlsts) :
(a) False neurotransmltters : Tyramine,
produced by decarboxylation of grosine (and
octopamine), can be taken up through the pre-
synaptic membrane by the not very selective
uptake:1 mechanism.Tyramine then enters the
storage granulesto a certain extent and displaces
neurotransmitternorepinephrinewhich, when
released causes post-synaptic effeCts. Octo
pamine, is taken up even more readily into storage
vesiclesand is, in turn, releaseclwhen the neuron
fires.As an agonist,it is only about l/lO activeas
norepinephrine.Compounclsthat behave like
- neurotransmitters of low potency are callecl as
false newotransmitters.
(b) True uptake Inhlbitors : They block the
amine pump of the reuptake-l mechanismin
neurons.e.g., tricyclicanticlepres
(i) Cocaine interferes with
uptake at the neuron and thr
Reserpineclepletesthe neuronal storage sites.
Releaseclnorepinephrine is then metaboliseclby
MAO.
(ii) number of antihypertensive agents
exert their activity by affecting the storage ancl
release of norepinephrinee.g. Bregrliumand
Guanethidine.
o
CHz-
czHs
Bretylium
(iii) The following structure rs representatrve

CH-CH- NHR'
C,Hr- N-C - S C N - C:Hs I
Hll R
S
tl5 H
R= H orOH
Sulfiram R = H, CH3or hetelocyclicring
 Drugs
Adrenergic
ll)
(Vol' 1$
of
Principles chemistry
Medicinal

Nasal tlecongestants
OH
I
CH-CH' - NHcHr
Ephedrine
PhenylePhrine

I
, z H2SO4
cHr
lPloPanolamine
Pheny sulPhate
Mephentermine

NH,.,
I
C H ,_ C H - C H I

ne
HydroxYamPhetamr
nol
Metarami

NHt

TuarninohePtane

Metlroxamine

cHz- cH- NHCH.T

cH- cH-cHr
I
NHCH,l
Propylhexedrine
Cyclopentamine

TetrahYdrozoline
Naplrazoltne

CH:

cHr H H
cHr CH,
Xylometazoline Oxymetazoline
(Otrivin,Ciba) Merck)
(Nasivion,
Principlesof MedicinalChemistry(Vo!.ll) 1(B Adrenergic
Drugs

OH OH OH
I I H2o- I
cH-cH2-NH2 HO CH-CH = NH Ho CH-CH =o
Norepinephrine Imine Aldehyde

(C) Drugs lnhlbltlng the metabollsm of
Noreplnephrlne :
MAO oxidises norepinephrine through the
removal of two hydrogensto give an imine, using
pyridoxal phosphate (vitamin 86), and then the
non-enzvmauc hydrolysisof this imine resultsinto
an aldehyde.
Inhibition of these enzymeswill increasethe
concentrationof norepinephrineat the receptor.
ThusMAO-inhibitorswill be usefulin the therapy
of clepression.Theyare divided into three types.
(a) Hydrazinesand hyclrazides.
C_NH- NH - CH( CHI ) "
il
o soz\
lproniazid
(b ) The rigid analoguesof phenylethylamine
e.g. tranylqypromine.
(c) Structuresnot clirectlyrelateclto norepine-
phrine.
cHr
Pargyline
(D) Drugs that mlmlc the effects- of
noreplnephrlne at receptor sltes (Dlrect actlng
agonlsts) :
The structural requirements for agonist
activigrat aclrenergicreceptorsare :
(I) A phenylethylamineparent structure.
(il) 3, 4-dihydrory substitution on the phenyl
n n g:
tl
ll
ll
PhenvIetnvIamrne stnrcture
Although the catechol group is of major
importance for agonist activigr, the phenolic
groups can be successfullyreplacecl by alkyl or
arylsulphonamiclefunctions.Actually a variegr of
substituentscan replacethe m-phenolicgroup of
catecholaminesand still retain high agonist
activity.
H
I
o
N-H
flg. 7.5 : Schematlc representatlon of blndlng
of sulphonamldo analogues of catecholamlne,
showlng productlve blndlng
(a) The aminogroup shoulclbe separatedfrom
the aromaticring by two carbonatoms for optimal
activity.
(b) Direct acting agonist activigr is enhancecl
by the presenceof a hydroryl group of the correct
stereochemicalconfiguration(i.e. laevorotatory)
on the-ft-carbOnbut is redr.rcecl
by the presenceof
a methyl gidEp-.en cr-carbon. The presence of
a-methyl group increasesthe duration of action
by making the compound more resistant to
metaboliccleaminationby MAO.
(c) Small substituents(H, CH3,C2H5)may be
placecl on the carbon without affecting agonist
activi\l significantly.
(cl) Small substituents(H or CH3) may be
placed on the nitrogen atom, without affecting
agonist activity.
(e) The nitrogen atom must have at least one
H-atom.

/,
Principlesqf MedicinalChernistry(Vol.ll) 110 AdrenergicDrugs

(0 The highly critical factor in the interaction
of adrenergicagonistswith their receptor is that of
stereoselectivig.Stedmanand Eassonproposeda
three point interactionof the catechol,p-hydroxyl
and amino group as shown for norepinephrine.
acting chiefly at the cr-receptor, whereas
isoproterenol acts most specifically at the p-
receptor.
Selectlve Pz Agonlsts :

p a
C H r - CH,- NHR

tbrmula
General
(i) Only one aromatic hydroxyl group ts
necessary(usuallyat the para, but sometimesat
meta position).
(ii) An a-methyl or ethylgroup is preferredfor
vascular eFects.
!-

OH
C H
NC(cH])r
I

I
NH,
o'
Pirbuterol
Iig. 7.6 : Representatlon of the stereoselectlve OH
three-polnt blndlng of noreplnephrlne
For epinephrine, norepinephrineand relatecl H
NC (CH3)3
compounds,the more potent enantiomerhas the
R (-) configuration.None of these compouncls Hrc
(Table7.5) can be considered totally specific for
either receptor and that they interact to some ozc cHr
extent with both. Of the compounclslistecl in Bitolterol
table 7.6, phenylephrineis the most specificdrug
Table 7.6 : Dlrect-actlng adrenerglc agonlsts

OH

Compouncl Prlmary receptor sfte

1. Norepinephrine - cliOH (I,

z. Epinephrine - ctiOH p
3. Phenylephrine 3 -O H c[
4. lsoproterenol 3, 4, - ctiOH -cH (cH3)z p
5. Isoetharine 3, 4, - ctiOH - cH (cH3)2 p
6. Metaproterenol 3, 5,- cliOH - cH (cH3)2
p
7. Metaraminol 3 -O H ([
Prlnclpbl of lledlclnalChomlstryOol. ll) 111 Adrenerglc
Drugs
OH
H o=S=
N-(CH2)6-0-(CH2)a

CH-,

Salmeterol Sulfonterol
OH H
N
CH
I
OH CHl
\l
ocH3
NHCHO Formoterol Ritoclrlne
H
Two clinically useful compounds of this N
categoryare isoxsuprlneand nylidrin.

CH-CH-NH-CH-CH"_O OH
Selectivep2- agonistFenoterol
Salmefamolis 1.5 times more active than
lsoxsuprine salbutamol.It hasa longerdurationof action.
OH H
N
cH-CH-NH-CH_cH,_cH2 HO

ocH3
Nylidrin
Salmefamol
lf the a-CH3group is dropped, more selectivitSr (E) Drugsthat act as d,z-adrenoceptoragonlsts
I
for bronchialp2-receptoris obtained.Thephenolic
groupsin nonpinephineare involvedIn.H-bonding CHz
to receptor.The COMT enzymescausemetabolic
methylation of one of these I N
which accountsfor its shorterdi H
Replacingone of these phenolic groups by a Naphazoline
hydroxyethyl group saves the hydroxyl group
from COMTenrymes without affectinglts ability
to activatereceptorthroughH-bonding.e.g.
OH
OH
I
HOH2C cH-cH2-t
cHr
Salbutamol(Albuterol) Yohimbine

OH
I
c H- c H2 - l
. cHr
Terbutallne Piperoxan
.Principles (Vol.ll)
Chemistry
of Medicinal 112 Drugs
Adrenergic

Clonidineis yet anothercx2-adrenoreceptor Mechanlsmof Actlon :

agonist which is used as a central antihyper-
tensive. lt may perhaps act on the baroreceptor
(blooctpressure)reflex pathway,on carcliovascular
centersih the medulla and also peripherally.lt
abolishes most symptoms of opiate withdrawal
ancl stilnulateshistamineH2 receptors.lt also acts Ammonium ion
as antianxiety agent that stimulates tx2-aclreno-
receptors and therefore decreasesnorepinephrine
R' - X- H
levels.
(I) Drugs that block the Interactlon of
-cHz-x-R'
noreplnephrlne whh receptor (Antagonlsts) ceptorcomplex
Alpha Adrenerglc Blockers : 31g.7.7
(a) F-Haloallrylamlnes: T se compouncls
resemble the nitrogen mustardTfiEineoplastic (b) Ergot dkdolds : Ergot was recognisedas
agents and may be representeclby the following cr-ackenergicagent in 19O6.The parent compound
generalformula: is Lysergicacid.'Ergocristine,ergocrylptine,ergo-
R I" -X comine ancl ergonovine which are the clerivatives
of lysergic acid are found to possessadrenergic
R
whereR=arylalkylgroup blocking action. A number of other amides cf
X= halogen lyser.gicacid have been prepared of which
The effectivenessis clependent upon the methylergonovineand methylsergideare employed
n a t ure of R. e.9 ., ph enox y benz am ine. clinically.
Dibenzamine[N, N, dibenzyl-N-(F-chloroethyl) (c) 'Imldazollnes: Followingare the examples
aminel was investigated by Nickerson ancl of clinicallyusefulagentsused in the management
Gocjdmanas an anti-leukemicnitrogen mustarcl.
of hypertension,i.e. Tolazoline.The encircled
Phenorybenzaminewas the outcome of molecular
portion resembles structurallywith norepinephrine
moclification of clibenzamineto remove the
z---------E----
toxicity. fE\!
i /\!
\"'g{. ) i
_N -cl-|, CH,CI
I
H.,C CH,
Tolazoline

cH.r
Phenoxybenzamine
NH
The groups attached to the nitrogen are
importantfor transportof the drug to the receptor
areaand binding to the receptor surface. PhentolamineHN
The p-haloalkylaminesthrough the formation o
of an ammonium ion react with a nucleophilic
group, present in the alpha receptor, forming a
stable and perhaps only slourly reversiblecovalent o
boncl,as shownin the Fig.7.7. Idazoxan
Principlesof MedicinalChemistry(Vol.ll) 113 Drugs
Adrenergic

(d) Other alpha receptor blocking agents

irtrclude,some benzodioxanesand dibenzazepines.
Prazosin,a quinazoline derivative is one of the
newerclinicallyavailablea-blockingagents.
H
o
tl
HlCO -C

H.rCO
NH, OH
Prazosin (8)Rauwolscine
p-Adrenerglc Blockerc :
Unlike cr-adrenergicblockers,the structural
cHlo requirementsfor p-adrenergicblockershave been
fairlywell definecl.
N SAR: (l ) PhenolicOH groupsare importantfor
ct-tro aclrenergicagonist activity. Removalof the 4-OH
NH' leaves intact only c.-agonist activity, (e.9.,
phenylephrine, methoxamine - both vaso-
constrictorsused in treating hypotension and
Tertrzosin f,,= nasalcongestion),whereas removal of the 3-OH
group abolishesboth a- anclp-agonist activity.
The 3-OH group can, however, be replaceclby a
Doxazosin R = SO2NHz (soterenol)or a OHCHz-(salbutamol)
group. 3-amino compounclscan be extremely
potent. Replacementof 4-OH group by any such
groups leaclsto an almost total loss of activi! ancl
cH rO compounclmay becomean antagonist.
(2) The two-carbonside-chainis essentialfor
N activity. The benzyliccarbon (next to the ring)
cHro must have (R)absoluteconfiguration.
A l l u z o sin
NH' (3) The alcoholicOH can be replacedonly by
ocHr an amino or OHCH2group
(4) Small(- H, - CHr) N-substituents procluce
cHro ' ones [-CH-(CH3)2, aryl] procluce

cHro Thereare two main classesof these agents :

NH, Abanocluil (a) Arylethanolamines
(b) Aryloxypropanolamines
(a) Arylethanolamlnes : lsoproterenol is a
H basicstructureto yield gooctp-aclrenergicblocking
N compouncls.

HO
I lH

lndolamin

t
 114 AdienergicDrugs
Prlnclplesot MedicinalChemistry(Vol.ll)

C..eri-\rr tno<\iFrcaiio k'e Y.r\a.<\e (\r) c-oN/erting the arornatic Portion to

basic structure,like. phenanthrene or anthracene was disadvan-
(i) Replacementof catechol hydroxyl groups tageous.
(DCr),
with chlorineto give dichloroisoproterenol a (vi) Other derivatives, in which the para-
classic p-blocking agent. lt is the first useful hyctroxylgroup on phenyl ring is replaceclby
p-blockerdiscoveredin 1948. SinceDCI is also a
m et hy ls ulph o n a m i d e w e r e a l s o p r e p a r e d ,
partial p-agonist and it cannot be used as a
e.g. Sotalol.
hypotensive agent. DCI turnecl out to be
carclnogenlc.

OH OH
ICH-C Hr CHT SO.' NH
ICH
! Sotalol
)ichloroisoproterenol

(iD Replacement,ofthe electron rich hyclroxyl In this series, if the methylsulphonamicle

gro-upswith an electron rich phenyl at 3, 4
positionsgives pronethalol,which is even better
p-blockerthan dichloroisoproterenol.
OH
ICH
Pronethalol
(iii) N-Substltutlon :
(a) N- - N-dis\rb3tit\rte,
inactiYe.
(b) Alpha-methylgroup decreasesactivi!.
(c) Activity is maintainedwhen phenylethyl,
hydroxyphenylethylor methoxyphenyl-
ethyl groups are adcled to amine pa.rtof
the rnolecule.
(d) Cyclic alkyl substituentsare better than
correspondingopen chain substituentsat
nitrogenatom of amine.
(e) Chain length may extend to a tota! of
4-atomswith or without a terminal phenyl
carbon.
(iv) Reductionof one ring to give either of two
tetralineanaloguesdid not affect activig.
group is replaceclby nitro, appreciableactivigl is
maintainecl.
(b) Aryloxypropanolamlnes:
(1) Pronethalol,an arylethanolamine, was
withdrawn ,from clinical testing becauseof reports
that it causedthvmic tumours in mice. However,
within two years of this report, Black and
co-workerscliscovered,a potent p-blocker propra-
nolol, a closestructuralrelativeof pronethalol.
cH-cH,-
c -o rn 1 : o u n d s are
a)ol
H,_NHCH(CH.r),
(logP = 3,65)
Propranolol
Propranololis the prototype of the group of
p -blocking agents known as aryloxypro-
panolamines.
A propranololmetaboliteof particularinterest
is 4-hydroxypropranolol,which is a potent
B-antagonist.
Principleeol MedicinalChemistry(Vol.ll) 115 AdrenergicDrugs

(d) Longer alkyl chains are less effective but

o-cH,-cH-cH,'
IOH
OH
propranoiol
4-hydroxy
(2) (a) Most clerivativesof this seriespossess
various substituteclphenyl rings rather than the
naphthyl ring. The catechol ring system can be
replaceclby a great varie$l of other ring systems
varying from phenylether (oxprenolol) ancl
sulphonamides(sotalol) to amicles (labetolol),
incloles(pindolol,benzpinclolol) anctnaphthalene
(propranolol).N-substituentsmust be bulky to
ensureaffinity to p-receptors; isopropyl is the
smallesteffective substituent.
(b) Substitutionof CH3, CI, OCH3 or NO2
groups on the phenyl ring was most favoureclat 2
and 3 positionsanclleastfavouredat 4 - position.
(c) Alkenyl and alkenyloxy groups in the
ortho positions on phenyl ring, provicleclgood
activigl.e.g. oxprenolol,alprenolol.
Thesecompoundscould be consiclerecl as ring
openeclanaloguesof propranolol.
isopropyl or t-butyl, which gives an optimal
basicityor nucleophiliciglto the amino group for
receptoraffinity are most preferred.
(3) A maior clinicalproblem with propranolol
was its high lipict solubility,which alloweclit to
penetrate nerve tissue and exert an unclesirable
cardiodepressant effect in aclclition to its
p-blocking.To avoicl this problem, use of polar
group (suchas methanesulphonamicle-NHSOzCH3)
was consiclerecl.The prototype of this series of
compoundswas practolol,which is devoid of the
clepressanteffect of propranolol. It was the flrst
carclioselectivep1-antagonist.
O-CH.-CH_CH,
OH
NHCOCHT Practokrl
(logP = 0.79)

o-
- oH CH;€I+OCHr
Metoprolol
Other selectivep;-blockersunderstuclyare :
Oxprenolol

o-cH"-cH-cH
-l
I

cH., OH
{H,-NH--{
cHr
OH
o-cH.-CH-CH,-NH-C
-l
OH
Alprenolol
Prlnclpleeof iledlclnal Chemlstry(Vol.ll) 116 AdtrmrylcDn4s

Thesecompoundsare characterisedchlefly by
p-substitutlonrather than o-substltutlon. HzN
Selectlvep2-Antagonlsts:
Butoxaminehas a selectivep2-antagonlstlc
action. lt blocksp2-receptorspresent ln smooth HO
muscleand in skeletalmuscle, - cHz
HrCQ

c H- CH Labetolol
I I
OH cHl
OH
I
cH2- cH
Butoxamlne
It ls an usefulresearchtool but lt does not. at
present,haveclinlcaluse. /cHzcH2
Other compounds whlchhve selectlve
p2-blocking actlon,are

CH-t
H.,C
C-arvedllol
C H - C H _N
tl Labetololand carvedllolarc the examplesof
oH cFt-1 non selectlvep-blockerswlth o | -receptor
antagonlstlcactlvlty.
Anothercompoundhavlng dlrect vasodllatlng
cH.rso.,NH effectsln additlon to p-blockagewhlch offers an
additional advantageof a reduced perlpheral
oH cHr resistancewith the orlglnalantlhypertenslve
actlon
ls:
Metalol
Non-selectlvep-Blockers r
Alongrlth alprenolol,propranolol, oxprenolol,
other new compoundssuch as nadolol,tlmolol
and labetolol,alsoexhlblt non-selectlvep-receptor N OH cHr
blockeractivity. H

where p-blockers have been resolved, the

p-blockingactlvit5lhas resldedwlth the S-enan-
tiomer.This has the sameabsoluteconfiguratlon
oH cH] as the naturallyoccurrlngagonlsts,noradrenallne
andadrenaline.
Cllnlcal Slgnlflcanccof p1-Blockcrsas Antl-
Nadolol hypertcnslveAgents r
It ls found that p1- receptorsare predominant
OH H cHr ln heart(alongwlthfuw p2-receptors). Stlmulatlon
N of p1-receptorstherefore,resultsIn an increaseIn
cHr heart rate and lncreasedforce of contractionof
heart muscles.Therefore,selectlvep1-blockers
galned a hlgh cllnlcal Importanceas antlhyper-
tensiveagents.
Hlghlyselectlvep1-antagonlst Slmilarly,p2-receptors are predomlnantln lungs
Blsoprolol particularly bronchlal muscles (alongwlth few
 of MedicinalChemistry(Vol.ll)
Principles 117 Adrenergic
Drugs

B1-receptors). Hence, selective p2-blockerswill Receptor Structure :

cause bronchial muscles constriction, a case con- The most effectivecompouncl,acting on alpha
trainclicateclin patients suffering from bronchial receptoris norepinephrine.
asthma ahd hence clinically useless,but can serve
as a research tool for a meclicinal chemist to
clevelop new, potent, selective p1-blockers or
HO
antihypertensive agents. Cardioselectivep-anta-
OH
gonists are clrugs that have much greater affini$
for the p1-receptors of the heart than for p2 Norepinephrine
receptors in other tissues. Such agents should
The more bulkierthe substituentson nitrogen,
have two important features : (a) The lack of an
alphareceptoractiviWdecreasese.g. lsoprenaline.
antagonist effect on the p2-receptor in bronchi.
This woulcl make p1-blockers,safe for use in
patients who have bronchial asthma. (b) The
absenceof blockageof the vascularp2-receptors cH - cH,- I\
(which mecliate vasodilation), which otherwise I
OH
leads to vasoconstriction resulting in increasecl
lsoprenaline
peripheral resistance,an undesirable effect in
antihypertensive activity of non-selective cr-Receptor :
pr-antagonist.Theoretically,one cannot obtain The cr-receptorcarries a negatively charged
complete cardioselectivity because of the group (probablya phosphate)which will then react
presenceof both p'- ancl Br-receptorsin cardiac with the positivelychargedammoniumnitrogen.
ancl lung tissues.Hence, on strict pharmacological Bulky substituentspresenton the nitrogen (as
grouncl, antihypertensiveagents of this category in the case of isoprenaline),would hinder the
could be expected to raise rather than lower the attack of positively charged cation on phosphate
arterial pressure by blocking the vasoclilation- anion. Hence, isoprenalinehas less affinigl for cr-
receptors.
mecliateclby vascularp2-receptor.They are anti-
hypertensive and act through the following
oostulateclmechanisms:
OH
('l) Inhibitionof renin release. I c
CH- C H r -
fH.,
I
(Z) Inhibitionof carcliacoutput (p1-btockage). I
I
6e
(3) Inhibition of sympathetic output by IP=O
centralaction.

(4) R estora tion of va s c ular r elax at ion

o o
response.

(5) Inhibition of the synaptic norepinephrine

release. tlg. 7.8 : c-receptor actlvatlon

a
Prlnclplee
of Medlclnal Ool. ll)
Chemlstry 11E Adrcmtglc Drugs

Table 7.7 : Usefrrlp-btocklngagcnts

2
-cHz-NHR
OH

Sr. No. Nanre x n Selecttvltyon reccptor

t. Pindolol lsopropyl nonselective

z. Bunitrolol 2-CN t - butyl nonselectlve

3. Nadolol t-butyl nonselective
)7 -
I
HO

3. Metoprolol +cHzcHzocH3 lsopropyl p1- receptor

4. Atenolol 4-CH2CONH2 isopropyl p1- receptor
5. Acebutolol 4-NHCOCaHT lsopropyl p1- receptor
6. Timolol

OH CH.,
\,

A new serlesof selectlvep1-blockercreplaclngN-alkyl groups(e.g.lrcpropyl, t-butyl) by araallgrl

groupswirsdevelopedwhlch blnd to the p1-receptorthroughan addltlonalH-bondlnglnteraction.

N /NH
OH N /N CHs
HgC OH

Epanolol Prlmldolol

HA'ztlx
OH

OH
Xamoterol
Principles
of Medicinal (Vol.ll)
Chemistry 1n Adrenergic
Drugs

Dual'actlng antlhypertenslve agents : from in vitro stucliesancl greater than Z5O : 1 in

Introduction of a known vasodilator moiegl
into the o-position of a B-blocker,which is known
to be sterically undemanding, has given the
p-blockervasodilatorprizidolol.
OH
NHC(CH1)-1
vivo. ICI 118551has no partialagonistactivity;it
has the same clegree of membrane stabilizing
activity as propranolol and is currently unclergoing
clinicalevaluationfor potentialuse in migraineand
essentialtremor.
OH
NHCH( CHr ) 2

N HNH2
. Prizidilol Me (c)
Isoxaprololwas 16 tipes more potent than Spirendolol (LI 32468) (cl) is another
labetololas a p-blockerand Fs more potent as B'-selectiveblockerin clinicaltrial. lt is effectivein
an cr-blocker.
Hr
controlling essentialtremor at closeswhich have
no effect bn heart rate.
OH
o NHC(CH3).3

NHC(Clt3)3
OH
Isoxaprolol b '(c)'
It was hypothesized that the carclioselectivity
MK-761(a), was equipotentwith timolol as a was the result of an interaction between the
p-blocker ancl 3.8-times more potent than oxygen or sulphuratom and a complementarysite
hydr"rlazine a5 a vasodilator, ancl was not a on the p-receptor.
p2-agonist. H

NHC(CHr)r

Epanolol OH
(a) Epanolol (lCI 141292), a carclioselective
Although it is not formally describedas a B- bloc k er w i t h partial agonist activity, is
combination, p-blocker-nitratemolecule, K 351 undergoingclinicalevaluation.
(b) clearly owes its vasodilator activity to the
presenceof the nitrate ester. OH H o
OH N
o Me Me

Imidolol
(b)
lmiclolol is reportecl to be p-blocker with
An extensionof the work led to the potent
p 2-selective blocker, tct 118551 (c). A c- blocking activity.
p2-selectivigratio of 173 : t has been reportecl ooo
 8.I INTRODUCTION
8.1 INTRODUCTION As the name indicatesthe principal pharmaco-
logical action of this classis to clepressthe central
GENERAL
ANAESTHETICS nervous system. These inclucle,
(a) Generalanaesthetics
SEDATIVES
ANDHYPNOTICS 127
(b) Hypnotic-Sedatives
(c) Tranquilizingagents
(d) Anticonvulsants
8.4 ANTICONVULSANT
DRUGS 138 (e) Central nervous system clepressantswith
skeletalmuscle relaxantproperties.
8.2 GENERALANAESTHETICS
General anaesthetic is a class of CNS
clepressantdrugs which produce partial or total
loss of the sense of pain with a controlled and
reversibledepression of the functional activigr of
cNs.-*
In orAET8perform more complicateclsurgical
operations,the surgeon neeclstime and needs a
patient whose muscles are relaxecl. General
anaestheticservesboth these obiectives.
Characteristics of general anaesthetlc :
(1) The agents in this class enjoy wicle
structural variation ancl hence strict structure-
activity relationshipcannot be frarnedout.
(2) These agents are non-specific in action
i.e., they clo not interact with specific receptors.
Hencethey arethoughtto be simplegeneralcellular
poisons.
(3) They are used at high concentrationand
h,eveaccessto all aieasof the boclv.

(121)
 of Medicinal
Principles $ol. ll)
Chemistry 12
Stagesof anacsthesla :
The concept of Blood - Brain - Barrierhas been
put forward to explain the unique and specialised
mechanism by which, brain excludes many
substances presented to it by circulation.
lmportantphysiologicalpropertiesgoverningentry
of compoundsin brain include : (i) the clegreeof
ionisation at physiological pH (non-ionisecl
compoundspenetratemore reaclily)(ii) molecular
size:abovemolecularmass400, there is noticeable
increase in penetration ancl also when cross
section of molecule, (seconcl- smallest van der
Waal'sdiameter)exceeds10 A or 1.O5mm and
(iii)lipophilicity.
Log Pe= 2.0 + 0.3 is an icteal,llpophilic
character
to clesigna neutral moleculeffiassirre p.n.-
tration into CNS. Uncler'physiologicallyhealthy
conclitions,polar moiecules only enter CNS via
specificuptake mechanisms.Hence to target polar
compounds in brain by passive cliffusion,one
should avoicl polar H-bonclinggroups ancl keep
molecularsizeto a minimum.
Overton-lUeyer Hypothesls of Anaesthetlc
Actlvity :
Anaesthesiarefers to the complete lacl<of
somatic sensation.Overton, at the turn of the
century, attempted to explain drug-inducecl
anaesthesia.He, and later H. H. Mever, statecl
that :
( I ) All neutral lipid-solublesubstanceshave
depressantproperties on neurons.
(2) Thrsactivity is most pronouncedin lipicl-
rich cells.
(3) The effect increases with increasing
partition coefficient, regarcllessof the
structureof the substance.
Although the absolute drug concentration
necessarvto achieve anaesthesiavaries greatly,
the clrug concentrationin the lipicl phase- that is,
in the cell membrane is within one order of
magnitucle, or 2O-5O mm, for all anaesthetic
agents.
In 1954. Mullins. in a modificationto the
Overton-Meyer hypothesis, proposecl that
besides the membrane concentration of the
anaesthetic,its volume, expressedas its volume
fraction (mole fraction x partial molar volume), is
important. This reasoning implies that the
anaestheticexpands the cell membrane, and that
t
CentralNervousSystemDepressants
anaesthesiaoccurswhen a critical expansionvalue
is reached at about O.3-O.5 o/oof the original
volume.The surfaceareaof the membranewill also
expanclby severalpercentagepoints.
ln general,lipophilic and unioniseclmolecules
pass most readily into the central nervous system.
In case of general anaestheticagents, as the
concentration is increased, penetration into the
clepth of
CNS increases,resulting into increa.secl
anaesthesia.For convenience,Guedel divicted
into four separatestagesin 1937 :
anaesthesia
Stage I Analgesla : LOnS ClOUS neS S lS
maintained,analgesiais procluced.Since higher
cortical centres are depressed,this sta.geis also
calleclas Corticalstage.
Stage ll Dellrium or stage of ex
Con-sciousness is lost. The further r
cortical inhibiQonleaclsto excitement ancl the
patient may shout anclstruggleviolently. He may
salivate,vomit or clevelopcough.
The first two stages are combinely termed as
incluctionperiocl.
Stage lll Surglcal anaesthesla Skeletal
muscles are relaxed and hence, most of the
operative proceduresare performed at this stage.
It is further subclivicledinto four planes repre-
senting progressiveincreasein clepth of anaes-
thesia and decreased respiration. Respiration
ceasesaltogetheras stage lV is enterecl.
Stage lV Resplratory Paralysisor Medullary
Paralysls : This is a toxic or overdose stage in
which there is a respiratoryand cardio.,rascu lar
collapseanclthe tissuesrapicllybecomeanoxic.
ln modern practice, anaestheticseither by
intravenousor rectal routes (basalanaestheticsor
fixed anaesthetics)are generally given to cause
loss of consciousnessbefore a voiatile anaesthetic
is given ancl hence transition from complete
consciousness(Stage I) to surgical anaesthesia
(Stagelll) is so rapiclthat none of the earlierstages
of anaesthesiacan be seen.
Preanaesthetlcmedlcatlons :
( I ) Generallya hypnotic is given on the night
before,to assurea gooclnight sleep.
(Z) One or two hours before surgery,atropine
(o,rhyoscine)is usually aclministerecl to prevent
excesssecretionof saliva or mucous which might
impede the work of anaesthetist.
 Prindiples
ol MedicinalChemistry(Vot.il) 18 CentralNervousSystemDepressants

Table 8.1
Classlflcatlon of volatlle anaesthetlc agents
Class Examples
1. Hvclrocarbon Cyclopropane,Ethylene
2. Halogenateclhydrocarbon Halothane,Ethvl chloricle
5. Ether Diethyl ether, Vinyl ether
4. Alcohol Trichloroethanol
5 . Ultrashortacting barbiturate Thiopentalsodium, Methohexitalsodium
6. Miscellaneous agents N itrous oxicle, Ketamine hyclrochloricle,propaniclicl
(3) Morphine (or Pethidine)is also given to (b) Ethylene : lt has no particular advantage
min imise fea r a n d a p p r e h e n s i o n . A l th o u g h over the other anaesthetic agents which are
anaesthesia is often induced with a basal currently in use. On the other hancl, its lack of
anaesthetic agent, it is often maintained with a potency ancl its highly inflammableand explosive
gaseousor volatile anaestheticwhich is aclmini- properties, preclucleits use in recent clinical
sterecl by various techniques.The simplest one Pracuces.
consistsof clropping the liquicl anaestheticon a (ll) Halogenated Hydrocarbons :
gauze or other absorbentmaterial supported over The replacementof hydrogen of low molecular
the patient's nose and mountecl by a framework, weight ethers and hydrocarbons
by halogen
forming a mask. But the vapours, often explosive results in an increasein its anaestheticpotencv
(ether) may spread into the surroundingarea.The with the proportional clecreaseirr its flammabilitli
new techniques (anaestheticmachine) allow e.g.
controlleclsupply of oxygen, carbon clioxide and
anaesthetic concentrations by means of flow-
meters.
(l) Hydrocarbons : T
I A I
I I I
In homologous series of alkanes,alkenesancl I
I ccll t
I U
alkynes, the. anaesthetic activity is directly I '5 >\ I
I qJ(J I cHClr
\
,

3
proportionalto the-chain length. But since toxici\r
also increasessimultaneously,only ethylene ancl \ cH,cl2 I
t
,

cyclopropane remain the anaesthetic agents of .t cH3cl .l t&

I I
clinicalvalue. I V
(a) Gyclopropane : lt is a clense,colourless
gas with sweetish odour and taste. 15-ZOo/o Y/Y
cyclopropane mixed with 8o-85o/oY/Y oxygen is But t his h a l o g e n s u b s t i t u t i o n i s a l s o
sufficient to achieve the stage of surgical accompaniedby an increasein toxicity which has
anaesthesia. C.Hz limited their useas anaesthetics.
(l ) Among the halogens"some sf the chlori-
natedanaloguesare usedclinicallyto some extent.
HzC CHz
e.g. chloroform, ethyl chloricle anc{ trichloro-
Since it is most plasma insolubleof anaes- ethvlene.
thetics,it producesrapiclbut smooth incluctionof
anaesthesia. lt enjoys the following aclvantages: ct-.tctl
('l) High potencyanclwide marginof safety. Chloroform
(2) Non-irritantand pleasantto use. cl
(3) Sincecatecholamine rele;6eis greaterwith
qyclopropane,blood pressureis maintaineclcluring
Gt3cHzcl cr-l =cHct
anaesthesia. Ethylchloricle Trichloroethylene
 of MedicinalChemistry(Vol.ll)
Principles 124 CentralNervousSystemDepressants

(2) Brominationof hydrocarbonsis also triecl inductionperioclmay be reducedby using a more

but none of the compounds is found clinically rapiclly acting agent-followectby the gradual
applicable. changeto ether. But sincethe bloocl-gas partition
(3) Aclctitionalqualifications(like clecreasecl coefficientis high, the perfusionof anaesthetic
toxicig, decreaseclflammabiligl,decreasedboiling from alveoli to blood ancl from blood to fattv and
point with an increasein the anaestheticpotency) muscle tissue is rapicl.This safeg factor contri-
are associateclwith the fluorinateclhyclrocarbons butecl towards ethers popularitSl.
a n cl e the r s e . g . Ha l o th a n e . Flur ox ene. (b) Ethervapours form an explosive mixture
Methoxytlurane, Enflurane, Isoflurane ancl with air or oxygen.
Sevoflurane. (c) Ether undergoes oxiclation rapiclly on
CFq- CHBTCI exposureto air, light or moisture to form peroxide
ancl acetallehvcle which can be inhibitecl bv
Halothana..-_*-*
copper.
CF 3 - C Hz - O -C H = C H z (cl) Premeclicationwith atropine is essential
Fluroxene since irritation by ether vapours causesexcessive
cH3o- cFz-cHclz bronchialsecretions.
(e) Carcliacstirnulationis observedwhen ether
Methoxyflurane
ts used as an anaestheticsince ether causesrelease
cHFzOCFzCHFCI of catecholaminesinto circulation.
Enflurane (0 Ether is usuallyaclrninisterecl in a nitrous
cHF2OCHCtCF3 oxide-oxygen-CO2 mixture. Generallya high
concentrationof ether (11-l5o/o)is required for
Isoflurane induction but once attained. can be maintained
FCH2OCH(CF3)2 with much lower concentrationof ether.
Sevoflurane (2) Dlvtnylether :
Halothane,a volatile and non-flammableliquicl, It resembleswith cliethyletherin its oclour,
propertiesand its action. lt is more unstablethan
is o n e o f t h e m o s t c o m m o n l y employecl
cliethyletherancl hence stored in amber glass
anaestheticagent (2 - 2.50/o) . Sinc
bottles.The inflammabilitvand high volatilitvmake
sensitive. it is storecl in brown vinylether unfit for the use in hot climates.Since
o/o I
stabiliseclby O.O1 thymol. incluctionwith vinvlether is very fast, it should
(llD Ethers : only be used for operations of short cluration,
In this series.an increasein the chain Iength which otherwise mav ciuse irreversible liver
results in an increaseclanaestheticactivi! with clamage.Hencevinylether is clearl_v oFveryllimited
the simultaneousincreasein toxici$. Hence only utility.
cliethyletherand clivinylether are founcl to be of (lV) Alcohols :
clinicalimportance. From long time alcoholsare known for their
c H3- c Hz - o-c H z -c H 3 ability to clepresscertain higher centres of the
central neryous system. The clepressantactivity is
Diethylether
retaineclonly upto 8 carbon atoms. None of the
CHt=6 11 -O- CH= CHz alcohols is used for maintenanceof anaesthesia
Divinvlether but some halogenatedalcohols e.g. tribromo-
(l) Dlethylether : ethanoland trichloroethanol are potent hypnotic
(a) Ether takes comparativelymore time to and are capableof producingbasalanaesthesia.
saturatethe alveoli (slowly saturatingagent) and cl3c- cHzoH
hence incluctionperiocl is long. The prolongecl Trichloroethanol
 of MedicinalChemistry(Vol.Il)
Principles 12s CentralNeryousSystemDepressants

(V) Ultrashort actlng barblturates :

For rapiclincluctionof anaesthesia,the sodium
salts of ultrashort acting barbituratesare usually
aclministereclintravenouslyor by retentionenema. N- CH.,
The advantagesassociateclwith these agents are :
(l) Smooth induction
H
(2) Fairmuscularrelaxation
(3) Absenceof salivarysecretions Hexobarbital

(4) Non-explosivenature
(5) Short ancl uncomplicateclrecovery. cH.,
I
The potent respiratory clepressionis the risk C= O
generallyassociateclwith their use and hence they
are usecl to procluce rapicl and pleasant
anaesthesia,which is then maintaineclwith the
vol.rtileanaesthetics.
Their high lipiclsolubilityand
rapicl clestruction of these clrugs by livqr,
contributeto their short-durationof action.
HO'
Examples: Alt-axalone

Hr C- CH, - C = C - C H
N- CH,
CH" = 611- CH ;
o N
Na H

Methohexitalsodium Bemegricle

I
CH,
I
C =O
cHl cH. cH' _C H
N- H
CH , = 6 g _C

Thiamylals odium
HO'

Ar6 Alfaxalone
(Vl) Mlscellaneous agents :
CHI CH' CH,_ CH
(a) Ketamlne hydrochlorlde : Generallyused
cHr- cH; as an induction anaestheticprior to the use of
o other anaestheticclue to its rapiclonset and short
clurationof action on parenteraladministrationand
may be of value in short surgicalprocedureswhich
Thiopentalsoclium
do not requireskeletalmusclerelaxatilcn.
 of MedicinalChemistry(Vol.ll)
Principles 127
ancl thus inhibits the essential conformational
changesof membraneprotein involveclin ionic
conductance.The membrane protein itself, may
alsobe the site of action.Theseproteinscomprise
the apolar amino acicl rpsicluesembecldeclin the
lipid bilayer of the . nerve membrane. The
anaestheticagents mopifo the properties of the
lipid bilayer in which these proteins function ancl
thus inactivate these proteins which are essential
for proper functioningof CNS.
llctabollsm of volatlle anaesthetlcs :
A small amount of the anaestheticundergoes
the metabolism.
(a) Hydrocarbonsare mainly convertedto
--l CF3CH2OH
CF3CHCIBT + CF3CHO+ Cl- + Br
Halothaner
CF3COOH+Cl-+Br
(b) Halogenated hyclrocarbons unclergo
Jehalogenationby microsomalenzymes.
(c) Ethermetabolismoccursin two phases.In
:he first phase, ether is converted to an alcohol
cH3cH2-o-cHz-cH3
Diethylether
+ CH3CHO
CH3CHZOH
ethanol acetaldehvcle
anclaldehyclewhich are furthermetabolisecltoCO2
in seconclphase^
Classlflcatlon :
Besicleson chemicalbasis,generalanaesthetic
may also be classifiedon the basisof their physical
state, like.
(a) Volatlle anaesthetlcs : e.9., Ether,chloro-
form, trichloroethylene,halothane, fluroxene,
methoryflurane,vinylether,anclethylchloricle.
(b) Craseousanaesthetlcs : Nitrousoxide ancl
cyclopropane.
(c) Non-volatlle anaesthetlcs : Ultra short
ketamineanclpropaniclicl.
actingbarbiturates,
CentralNervousSystemDepressants
8.3 SEDATIVES
AND HYPNOTICS
lcleally,a seclativehypnotic should induce
sleep that is similarin sleep pattern to the natural
sleep,
A seclativeclrug decreasesactivity and excite-
ment of the patient ancl calms the anxiety by
producingmild clepressionof CNSwithout causing
drowsinessor sleep.
hypnotic clrug produces drowsiness,
compelling the patient to sleep by depressingthe
CNS, particufarly the reticu.lar activity which
characteriseswakefulness.
Pharmacologically, seclative-hypnotic ancl
generalanaestheticagents are usually re.garcled
as
agents causingonly increasingclepthsof the CNS
clepression.
Sincethere is a lack of structuralspecificityin
both these classes,these agents appear to be
non-specificin their action.
The various sedative-hypnotic agents are
employed as,
(1) Antianxietyagentsin the emotionalstrain
and chronic tension state
(zl Anticonvulsantagents
( 3) Muscle relaxants
(4) Generalanaesthetics
(s)Potentiationof analgesicclrugs
(6) Acljuvantsto anaesthesia
(7) ln hypertension
Th-e'pr ;.,sed administrationof these agents
is not recommenclecl becauseit may result
i n to
(1) Alteration in the pattern of naturally
occurringsleep.
(Z) Increasingtoleranceancl physicalclepen-
clenceto the clrug.
(3) Many hypnotics produce a hangover
effect.
(4) Sincedeath can be causedby respiratory
collaose if usecl in higher concentration,
sedative-hypnotics are trequently used
agentsin attempting suicicles.
 of MedicinalChemistry(Vol.ll)
Principles
Classiflcation :
Though, jt is saicl that, the sedative-hypnotic
drugsare not characterizecl
by common structural
Featuresi.e. non-specificclrugs,two important
propertiescompel them to sharecertaincommon
structuralfeatures.
(1) The presence of hydrophilic groups is
necessaryfor their transport from gastrointestinal
tract to aqueous bocly fluicls while their pene-
tration into CNS necessitates the clrug to be
sufficiently lipophilic. These objectives can be
fulfillecl by the non-ionic surfactant chara-
cteristics.
(Z) They shoulcl posseE\peh *trlructu ral
features which would normally resist their rapid
metabolism. ln these agents, generally polar
gr ou p s lik e , CONHCONHCO ( b a r b i tu r a te s ) ,
- CONH2 (amic{esj.OH (atcoholi, OCONH1 (carba-
mates),are attacheclto a non-polarmoie$, usually
all<yl.aryl or a haloalkylgroups.
Arbitrarily, the seclative-hypnoticsmay be
classifieclas,
(1) Barbiturates
(Z) Benzodiazepines
(3) Acyclic hypnotic containing nitrogen
(4) Cyclic nitrogen containinghypnoticse.g.,
pipericlineclionesancl quinazolinones.
(s)Alcohols ancl alclehvdes
(6) Acewlene denva ves
(7) Miscellaneousagents
(a) Bromides
(b ) Aciclsand esters
Antihistaminesanclanticholinergics
(d ) Sulfones
(e) Plant extracts
(f) Enclogenoussubstances
(l) Barbiturates:
The first agent from this class. i.e. barbital
(5, 5-ctiethylbarbituricacid) was introduced in
1903 by Fischerand Von Mebring followed by the
introductionof phenobarbitalin 1912. Since both
these agents turnecl out to be powerful hypnotic
drugs, over 25OO barbiturates were synthesisecl
anclevaluated,of which very few were proveclof
ln CentralNervousSystemDepressants
clinicalutility. Tt ,und in this series
is Barbituric ac trioxohexahydro-
pyrimicline which is c{evofc{of CNS c{epressant
activity but the presenceof alkyl or aryl groupsat
position 5 conters sedative-hypnotic and
sometimesother activities.
o
H
Structure-actlvttyrelatlonshlp :
- In 1951, Sandberg postulated that, a good
hypnotic barblturicacid clefivativemust have
.(a) The acicfitlt value within certain limits to
give a proper ratio of ionised (clissociatecl) and
unionisecl (unclissociatecl)forms which is
important to cross bloocl-brain-barrier.
It takes approximately 4O-6O o/odissociation
to enable a barbiturateto cross BBB ancl exerts an
effecton CNS.A determinationof the pKa can thus
be predictive of CNS activig.
tb) A lipid-water solubility (partition coeff-
cient) between certain limits.
(a) Acltlt9:
On the basisof acictigvalues,barbituratesare
ctivicledinto two classes.
Hypnotlc Class :
(i) 5, S-disubstitutedbarbituricacicls.
(ii) 5, 5-disubstituteci thiobarbituricacicls.
(iii) 1, 5, 5-trisubstitutedbarbituricacids.
Inactlve Class :
(1) I-substitutedbarbituricacids.
(z)5-substitutedbarbituricacids.
( 3 ) 1, 3- clisubstituteclbarbituricacids.
(4) 1, S-clisubstitutecl barbituricacicls.
(s)1, 3, 5, S-tetrasubstitutedbarbituricacids
are inactivesince they are not acidic.They
upon metabolism, produce 1, 5, 5-
trisubstituteclbarbituricacicls,which are
aciclic.
 Principlesol MedicinalChemistry(Vol.ll) 1A CentralNervousSystemDepressants

(b) Llpl<l-WaterSolublllty : The greaterthe branching,more potent will be

the drug e.g. pentobarbitalis more potent than
Once the acictityvalue criteriais satisfiect,
the amobarbital.
lipicl-watersolubility or partition coefficientis
calculatedto find out whether the compound is
active or not. The following structuralskeletonis ,o
essentialfor hypnotic activig. tl
cH.rcH)cH"cH.
cHlcHr.
(

H
(1) The sum of the carbon atoms of both
substituentsat carbon 5 should be between 6 and
1Oin orclerto attain optimal hypnotic activity.This
sum is also an inclexof clurationof action.
(2) Within the same series,the branchedchain
isomer has greater lipicl solubili\r and hypnotic
activity but has shorter duration action.
I
I JUm Vatue Duratlon of actlon
(l) 7-9 Rapiclonset ancl shortestcluration
(z)5-7
Intermediateclurationof action
(3 ) 4 Slowest onset ancl longest duration
| (Two ethyl groups or an ethyl and a
L phenyl)
Branchecl.cvclic or unsaturated chains at 5
position generally reduce the cluration of action
due to increasedease of metabolic conversion to a
more polar, inactivemetabolite.
General scheme for synthesis of Barblturate :
H
Pentobarbital
o
CHsCHCH'CH
czH
H
Amobarbital
(3) However, the -stereoisomerspossess
approximatelysame potencies.
(4) Within the same seriesthe unsaturation
(i.e. allyl, alkenyl, cycloalkenylanalogues)may
result in greater potency than the saturated
analogueswith the samenumberof carbonatoms.
(5) Aliqyclicor aromaticsubstituteclanalogues
are more potent than analogueswith aliphatic
substituentswith the same number of carbon
atoms.
(6) Introductionof a halogen atom into the 5-
all< I substituent increasesDotencv.

R-X -X
cooc"Hs
NaOCrH, NaOC.'H.

Diethvlmalonate Ivlonoalkyl
diethyl Dialkyldiethyl
malonate malonate

R
o
tl NaOC,H, Urea
-C /,c\NH
\

R'
ll I I
67c-.*..c1:.o glc-."rc\o-*o*
H H
).)-olalKvl barblttrrrcactd Sodium5,5-dialkyl
barbiturate
Principlesof MedicinalChemistry(Vol.ll) 1g) CentralNervousSystemD€prosserts

Table 8.2
Berblturate Classlflcatlon

Name Substltuents llcdetlvc dose Hypnotlc dose

R,I R5 R5 (tg) (-g)
l. Long actlng Barblturates :
Barbital H CzHs -CzHs 300
Phenobarbital H --*t:-- ' -.-CzHs -Q Hs ls - 30 loo
Mephobarbital CHr CzHs - -Q Hs 30- loo 100
2. Intermedlate actlng Barblturates :
Amobarbital H CzHs -cH2cHzcH(cHJa zo M 100
Butabarbital H CzHs 15 30 100

Probarbit;rl H CzHs - cH - (cH3)2 150- 400

3. Short actlng Barblturates
Cvclobarbital H CzHs t o o , 300

Heptabarbital CzHs 100 zo0 - 400

Pentobarbital CzHs -cH -cHzcHzcH3 100

cHr
Secobarbital -cHzcH= cHz -cH-cHzcHzcH3 100
cHr
4. Ultra-short actlng Barblturates
Hexobarbitone CHr cHr 400- soo

Thiopentone CzHs -CFK,HZCH2CH3 C2o>qygenis

I
CHa replacedby
suiphur
 Principles
of Medicinal
Chemistry
(Vot.il) 131 CentralNervousSystemDepressants

(7) Introc'luctiono f a polar substituent(OH.

NH2, COOH,CO, RNH, SO3H)into the aromatic
group at C-5 resultsin decreasecl lipiclsotubility
?t, o
cHrcH'cH'CH ll
and potency.
(8) Alkytation at I or 3 position may result c:Hs
tn
compounclshaving shorter onset and clurationof (

actionsinceN-methyl group reclucesaciclifuvalue. H

(9) Replacementof oxygen by sulphur Thiopentat
at
Z-carbon, shortens the onset ancl duration of
actiondue to increasecl lipid sotubility.
OO) Introcluctionof more sulphur atoms (at
CH,CH -I
C-4 ancl C-6) clecreasesthe hypnotic activity.
Classlflcatlon : (H

Depending upon the cluration of action \o

barbituratesare divicleclinto four classeslike
(l) Long actingbarbiturates (6 hoursor more)
(2) Intermecliateacting (3-6 hours)
(3) Short acting (lessthan 3 hours)
(4) Uttra-shortacting (t.V.)
Metabollsm :
A few barbiturates (which alreacly possess and clurationof action, may be clinicallyemptoyed
enough polar groups) with low lipicl water partition
coefficientsare largely excreted unchanged in
urine. While barbiturateswith non-polar structure
(lipophiliccharacter)are metabolisedresulting
into
the introduction-ot more polar groups in the
structurewhich may be excieteclifr the urine in free
form or as conjugatesof glucuronicacicl.
Liver remains as the principal site of meta-
bolism. The metabolic changes that may occur
with non-polar barbiturateinclucle.
(l ) Oxiclationof radicalspresentat C5 to yielcl
hyclro>qy,keto or carbo><vclerivatives.
(2) Opening of the barbituratering by hyclro_
lytic cleavage.
(3) N-clealkylation(N-clemethylation) N-
substituteclbarbiturates.
(4) De-sulfurisationof 2-thiobarbiturates
is a
common metabolicprocesse.g. thiopental cliazepineswhich are quickly
when metabolised,resultsinto a pento_ excretecl,can be used as hypnotics
barbitalmolecule.
H
pentobarbital
All these metabolic clranges result in an
increasein poiar characteristicsof the barbiturate
molecule.
Therapeutlc Uses :
Barbiturates,clepenclingupon their porency
as
( 1) Non-analgesicseclative- hypnotic
clrug.
(2) Anticonvulsantagent.
(3) Generalanaesthetic(basalanaesthetics).
(4) ln psychiatric treatments, as cliagnostic
ancltherapeuticaicls.
(2) Benzodlazeplnes:
Ai'e*Er*vqesearch had been carrieclout on
the benzodiazepoxicleclisplayeclpsychotropic
activity, in experimental animals. Over ZOOO
compounclsbelonging to this series have been
synthesiseclancl pharmacologicalscreening of
these compounds has been carrieciout in the
search of better tranquillzer, muscle relaxant,
anticonvulsantor a seclativehypnotic clrug.
All benzocliazepines exhibit hypnotic action to
more or less extent with varylng degree of
metabolism in liver. Hence only those benzo-
metabolisecland
in clinical
practices.
 Principles
of Medicinal (Vol.ll)
Chemistry 1A CentralNervousSystemDepressants

:
Structure-Activlty-R.elatlonshlp (2) The chemical nature of substituentsat
The basic l, 4-benzocliazepinestructurel5 as positionsI to 3 does not affectthe activity.
shown below : (3) N(4) shoulclusuallybe substituteclwith a
group with low electronclensity.
(4) Position 7, if substituteclwith electron
withclrawinggroups, resultsinto an enhancement
c= i(
5
R4
of activity, while substitutionelsewherein this
aromaticring resultsin decreasein activigr.Same
holds true, for I! substitutionin phenyl ring on C5.
r6 adclitrun to their antianxiety action, the
5-aryl-1, 4-benzodiazepine
( 1) All CNS - clepress"utbenzocliazepines benzocliazeplnes which are exclusivelyuseclas
are
rsuallv substituted with a 5-aryl or 5-cyclo- hypnoticsare summarisedin the followingtable.
rexenvl group
Table 8.3
Cllnlcelly used benzodLrzcplnes
---_

L-4-be!roqi44ep!q9
-S:efY!:
Name Rl R2 R,3 R,7 R!
Chlordesmethylcliazepam H :o H cl cl
Fosazepam o
t
(cHz)P(CHr)z =o H CI H
Nitrazepam H =o H Noz H
Norcliazepam H =o H cl H
Nimetazepam CH: :o H Noz H
Flunitrazepam CH: =o H Noz
Flurazepam (CHz)zN(CzH5)2 :o H cl F
SAS643 (cHz)z
oH =o OH cl F
Quazepam cHzcF3 =S H cl F
Lorazepam H
:o OH cl cl
Temazepam cHr =o OH cl H
Potassiumchlorazepam
H
Z a OH cooK cl H
zboK
Estazolam
H cl H

Triazolam
H cl cl

Clonazepam =o H Noz cl

\
Principles
of Medicinal
Chemistry
Ool.ll)
There are new lmiclazole-benzocliazepines
which are, water solubleancleasilyinjectable.They
haVe hypnotic-seclativewith markecl amnestic
(i.e., memory loss)property.They may be used in
dent istry, e n d o s c o p ie s a n d i n c l u c ti o n to
anaesthetics.
C H "- C H ,
It is an anti-anxie$ benzocliazepinerelated
compound completely clevoid of anti-convulsant
and seclativeproperties.
HN-N
It is a powerful diazepam and barbiturate
antagonist.
Mode of action of benzodlazeplnes :
(1) ln central nervous svstem, benzo-
diazepinesdo not equally affect the activity at all
levels and hence cannot be classifiedas general
clepressantof CNS.
Table E.4 --*a=\
Benzodlazeplnesversus barblturates
Benzodlazeplnes
Act on limbic system, thus reclucealertness 1.
and wakefulness.
z . They clo not causetrue anaesthesia. Z.
3. Sleep inducectby benzocliazepinesresembles 3.
much with naturalsleep.
4. In overdoses. less chances to cause 4 .
unconscrousnessand resplratory clepression
ancl hence relativelv more safe.
5 . Theyget slowly eliminatedfrom the body. 5.
6. Long-termuseis rarelyinclicatecl.
1g| CentralNeryousSystemDepressants
(Z) The midbrain reticularactivating system,
which is responsiblefor the maintenanceof a
wakefulness,is depresseclby benzodiazepines.
(3) The limbic system incorporatesa balanced
complex of excitatoryanclinhibitory components.
The antianxiety activity of benzodiazepinesmay
be attributed to the depressant action of these
clrugs on the mechanismswhich evol<eanxiety
anclaggression.
(4) In convulsions, these clrugs neither
elevate the thresholcl for convulsions nor
suppress the repeated stimulation. They just
prevent the spreaclof the seizures.
(5) Justlike the actionof gammaamino bugrric
acid, benzodiazepinescause either presynapticor
(rarely) postsynaptic inhibition in polysynaptic
neuronal pathways in CNS, affecting the turnover
of various neurotransmittersin the brain. This nray
result in the interFerencein the transmission
processes.Since benzodiazepinesare founclto act
indirectly, they are not GABA-mimetic in true
sen5e.
Cllnlcal Uses :
( 1 ) As antianxiety agents.
(z)As sedative or to potentiate the action oF
a hypnoticdrug.
( 3 ) Muscle relaxantand anticonvulsantagent.
(4) Psychostimulantagent.
(s)Preanaestheticmedication.
(6) During withdrawal of alcohol in chronic
alcoholics.
Barblturates
Act by depressingthe corticalresponse.
They can causetrue anaesthesia.
Likely to proclucehangoverancl psychomotor
rmpatrment.
Overclosesmay result into a cleath.
They get eliminated more readilv than
benzodiazepines.
6. Long-termuseis rarelyindicatecl.
 of MedicinalChemistry(Vol.ll)
Principles 1g CentralNervousSystemDepressants

Both the amide and urea moieties seen in (a) Urethanes :

barbituratesare reproduced in numerousacyclic
CNSseclatives(e.g., carbamates,amides,uriecles,
etc.). They may contain saturatecl,unsaturated, gCONH,
halogenatecl,epoxicleor alicycliccarbonskeletons.
Non-barbiturate Seclative-Hypnotlcs:
C= CI {
There are many clrugs,though structurallynot
relateclto barbiturates.can procluceseclationancl
hypnosis.The time of onset, duration of action It is generally employecl for the prompt
ancl hypnosis, and untoward effects may be the treatmentof simple insomnia.Prolongeduse may
probable points of clifference>=_ , result into toleranceand physicaldependenceand
_-
(3) Acyclic hypnotlcs containing Nltrogen : henceis not advisable.
Besicles,therapeuticefficacyancl relative safeg of (b) Urelde*:
some agents, this class cloes not offer any
advantage over other hypnotic classes. The Acylationof urea yielcisureides.Many of the
clinicallyused agentsare listed below : ureidesare founclto be useful hypnotics.

Syntheslsof : l, 4 - Benzodlazepine -4-oxldes

NHz CIOC NHz NH,OH

ZnCl.,
+
CI CO CI

CH'C I
NHCOCH-.,CI
\
RNH.,
CH.
/'
Rearrangement *-o
C *-o CI CI C= NO H

| . 4 Benzodiazepine-4-oxide
 of MedicinalChemistry(Vol.ll)
Principles 135 CentralNervousSystemDepressants

Route for synthesls : It is useclprimarily as centrally acting muscle

relaxant ancl antianxiety clrug. In larger closes
(8OOmg), it is sometimesused as a hypnotic.It is
less toxic but exhibits some clegreeof acldictionas
R-CH,-cooH
that of barbiturates.
(d) Amlcles :
Alkyl malonicacid stitutedaceticacid
The following agents from this class are
marketed as tranquilizersand muscle relaxants,
having good sedativeproperties.
R-.CH,- COCI

ll H cHlcH r c H . - c _ c _ c o N H ,
o
Oxanamide
Examplesof this classare :

-cH - coNHcoNH2
cH3cHzcH Lr - lr L1n\
cH3 czH5 valnoctamrcle
Capuricle
CzHs
(cH3)z
cH- cH - coNHcoNHz
cH2= cHCHz-c- coNHz
Br I
Bromvalurea CzHs
Diethylallyl acetamide
(c2Hs)2
- c -CONHCONH?
I
Br
H. CQ
Carbromal
Bromvalureaand carbromalare in clinicaluse HlCC) coNHCH,CON(C,H5).'
from long time clue to their short acting,. milcl
hypnotic action. They are consiclereclto be
relativelysafeclrugs. Trimethobenz-glycine
Sinceboth of these agentscan releasebromide Diethyl allyl acetamicle is a more potent
ion in vivo, their prolonged use may lead to acute hypnotic than the corresponcling saturatecl
br omicle to xic a t i o n a n c l h e n c e i s n o t analogue.
recommended. (4) Cycllc hypnotlcs contalnlng Nltrogen :
(c) Carbamates ! After the successof barbituratesin sedative-
cH,'ocoNH, hypnotic therapy, many heterocyclic ring
I structuresbearing a close structural relationship
cHrcH'cH.'
with barbiturateswere svnthesisedand screened
cH,ocoNH2 for CNS clepressantactivity. The clinicallyintro-
cluceclagentsfrom this classare,
Meprobamate
Pflnciples
of Medlcinal pol. ll)
Chemistry 136 CentralNervousSystemDepressr

(a) Plperlctlnedlones : (b) Qulnazolinones :

When comparecl with barbiturates, agents 2 - Methyl - 3 - aryl - 4 - (3H) -quinazolinors
from this class are less actirre but better toleratecl preserveo4ypyrimiclinestructure oF barbiturata
seclative-hypnotics. The following agentsfrom quinazolineclassare iur
clinicalpractices.

czHt
czH:
N
N
H
Hrc
Dihyclroprylone
Methaqualone
Methaqualone lacks analgesic, Iocal anaes-
thetic and spasmolyticactivity. Though similartc
H:C
barbituratesin its hypnotic effects, it is also a
CzHs potent rantitussiveagent. The undesirableeffects
N include delusions,hallucinations,disorientatio
H with confusionand convulsions.
Methyprylone Ethinazoneanclmecloqualoneare other quina-
zoline type drugs which exert a potent analgesic
ancl antitussive activigr in adclition to hypnotic
activity.
coHs
c:Hs
N C:H:
H N

Glutethimide
Methypqllone undergoesmetabolic alterations
in the body ancl changes to Ethypicone, which
also possesseshypnotic activity. Ethinazone

H:C CrHs
CzHs
N
H
Ethypicone
Methyprylone cloes not exhibit analgesic,
tranquilizingor musclerelaxantactivities.Similarto
barbiturates,it causesdepenclence.
Glutethimictedoes not offer any advantage
over barbiturates.More potent than any other
non-barbiturate hypnotics, other properties
remainsameas that of methypryllone.
N
Mecloqualone
(5) Alcohols ancl aldehydes :
(a) Since branching of the alkyl chain in
alcohols,affordsa greater resistanceto metlbolic
inactivation,resulting in increaseclactivigl, all
clinicallyuseful alcoholsare tertiary alcohols.The
presenceof an electron-withdrawihggroup or
unsaturation characterized by electron densitlr
Prlncipleool MedlclnalChemlrtry(Vol.ll) 197 CentralNervousSystemDepressants

near the alcohol group seems to potentiate the To overcome these problems, a number of
activity further. clerivativeswere preparecl;the importantamongst
Clinicaliyusefulagentsfrom this classare, them, are,
cHr
I
cH3-c -czHs ct3c-cH{oH)z (cHr1,
NcHzco9
Chloralbetain
OH CH: CH:
Amylene hydrate I I
cH3-c - cHz-cH-o-cHcct3
cHa I
OH OH
cl3c-c - cHr Chloraloclol
I
OH c[(cHzocH(oH)ccr3)]4
Petrichloral
Chlorobutanol
CH = CHCI (b) Aldehydes:
I Paralclehycle,
introclucecl in 1882,is one of the
Cz Hs - C- C= CH oldest ancl safest hypnotic clrug. lts unpleasant,
I taste, pungent oclour ancl mucous membrane
OH irritatingpropertieslimiteclits wiclespreaduse.
Ethchlorvynol
CHa
I
CzHs-C-C=CH

OH
Methylpent5rnol

Paraldehyde
(6) Acctylene dcrlvatlves :
_i_
A few analoguesethinamate,hexapropymate
Chloral hydrate anclcarfimalecan be groupeclunclerthis class.
--.aE, _
C.Lloralhydratc dcrlvatlvcs :
Despite a safe and reliable hypnotic agent, CH, - C= CH
:rloral hydrate possesses the following
:isadvantages: OCONH"
(i) Poor analgesicpropergr.
(ii) Quite irritating to the mucous-meffi5rane Hexapropymate
and skin, and may causenausea,vomiting
and diarrhoea.
il) In high dose, may cause marked
CH.C= C _.CONH"
respiratoryrdepression.
.iv) Has an unpleasanttaste and odour.
v) Causesphysical depenclence. Carfirnate
Principles
of Medicinal (Vol.I)
Chemistry 138 CentralNervousSystemDepress

(7) Mlscellaneous agents :

(a) Bromldes : Though they were used as
anticonvulsantsand seclatives,clue to their
extremely low rate oF excretion, they tend to
accumulate resultin g into int ox ic at ion e. g. CH.,
Potassiumbromicle. N - Cll.cH,N
(b) Acictsand esterc :
Examples, CH..

CH,CHNH,
-l
COOH ocHl

[]rilamine
L-Tryptophan
".-(d)Sulfones : The agents from this cla
N induce toxic effects at therapeutic doses a
o hence no longer are used as sedative-hypn
tl drugs.
c,Hsoc
(e) Plant etrracts : A number of plant extra
are reported to possess seclative-hypn
activit5r.Examples : Raclixvalerianae,Rauwo
serpentina,Avana sativaand Glandulaelupuli.
(f) Enclogenous substances : lt has be
postulateclthat, the sleep inducing substancesr
Etomiclate
present in the cerebrospinalfluicls,which a
(c) Antlhlstamlne and Antlchollnerglcs
responsiblefor occurrenceand nature of the slee
Examples,
Although the clraracterisationof these substan
has not yet been completed, the.y are thought
possesspepticle-lil<estructure, nrore precisel
CH.. nonapepticlestructure.
/
Such sleep inducing factorswere isolateclfro
C - OCH,CH,N the cerebrospinalfluicls of goat, clogs ancl r
cH.' brains ancl efforts to ictentifu and character
such factorsare still on the way.
8.4 ANTTCONVULSANTDR.UGS
Doxylamine Epilepsy is one of such diseases whe
selectively acting drugs are still lacking. T
prevalenceof epilepsy is between 3 to 6 per 10
population.
The term epilepsy is cleriveclfrom the Grs
CH., worcl epilambenein which means 'to seize' ,
convulsions.A convulsionis a violent involunt
C H OC H .CH" N /

spasmocliccontraction of the skeletal muso

\
CH., lature.
Epilepsyis a collectiveclesi$nationfor a gr{
of chronic CNS clisorclershaving in common d
occurrence of brief and self limitecl, suclden al
Diphenhydramine transitoryseizuresof abnormal motor, senso
Principles
of MedicinalChemistryPol. ll) 't39
autonomic or psychic origin resulting into a
'epeateclneuronalclischarge.
All forms of epilepsy have their origin in the
rrain. Epilepsy results when many neurons in
union,unc{era high excited stage, clelivermassive
Cischarges abolishinga finely organisedpattern of
:he integrativeactivity oFthe brain.
John Jacksonproposeclthat these seizuresare
:aused by occasional,suclclen,excessive,rapid
and local dischargesof grey matter and _once
nitiatecl bv the abnormal focus, the seizures
?.ftackthe neighbouringnormal brain resultinginto
eeneralisecl convulsions.
This abnormalfocus may originate as a result
cf locafbiochemicalchanges,ischemraor the loss
cFvulnerablecell inhibitory systems.
The normal inhibitory mechanismsgenerally
'?strict the sDreaclof convulsive activitv to the
-e;ghbouringnormalcells.Hencea seizurefocusin
-..n may remain normal over long periocl of time
;.-d may not cause signs ancl symptoms of
However, certain physiological changes
-ilepsy.
r,av trigger the focusanclthus facilitatethe spread
:r abnormalelectricalactivitvto normaltissue.
Suchtactorsinclucle:
( 1) Changes in blooc{ glucose concentration
z) Blooclgas tension
(3) PlasmapH
(4) Total osmotic pressure and elegtrolyte
composition of extracellularfluids.
s) Fatigue
ol Emotionalstress
Nutritionalcleficiency.
S Tra u ma , in f e c t io n , m e n i n g i ti s , b r a i n
tumours, cerebrovascularclisease, or
metabolicabnormalities.Epilepticseizures
of unidentifieclcauseare known a-sprimary
or idiopathic epilepsy whilLe-,/epileptic
attacks of known causes are called as
seconclaryor symptomaticepilepsy.
Seizures,in fact, are nothing but electrical
:rr .:sionsoFthe brain.Once initiatecl,a-seizureis
CentralNervousSystemDepressants
maintainedby re-entryof excitatoryimpulsesin a
closeclfeecl-backfashion which may not include
the original seizurefocus. CompleteclepletionoF
n e u r o tr a n s m i tter, met abolic f act ors (like
accumulationof CO2 ancladenosine,clepletionof
02 and high energl phosphateintermecliates) may
contribute to self control of intensitv ancl cluration
or serzures.
ln summaqr,epilepsyis a CNSmalfunctioning,
which leads either to generaliseclhyperactivitSl
(involving essentiallyall parts of the brain) or to
hyperactivityof only a portionof:the brain.
Types of Epllepsy :
Vitamin 86 is the precursorin the formationof
coenzyme pyricloxal - 5 - phosphate which is
responsiblefor the decarboxylationof glutamic
aciclto form GABA and since hyclrazineclerivatives
can inactivate the coenzyme, pyricloxal - 5 -
phosphate via hydrazone Formation,these facts
confirm the funclamentalrole of GABA in the arrest
of convulsions.
lAl Generallzedepllepsy :
Once initiatecl, it spreads quickly into the
entrreor at leastthe greaterpart oFthe brain.
(i) Tonfc-cronlc selzures (grancl mall t lt
has a close resemblancewith electricallyinducecl
convulsionswhere the massstimulationof cortical
neuronsoccurs.As the name indicates,initialiy
there is a generali4gs!tonic activity followecl by a
clonic phase. lt resuitldue to a potent cerebral
excitationand is also l<nownas major seizures.Its
onset is pre-intimateclto the patient by a warming
sensationthat is l<nownas aura. Patient may
become cyanotic. Heart rate ancl bloocl pressure
increaseancl clilation of pupils also occur. These
signs are characteristics of sympathetic nervous
system stimulation. The total attacl<lasts for
severalminutes. After the attack, sleeps prevails
due to neuronalstore-exhaustion.
(II) Absence or mlnor selzures (petlt mal) :
It is reported to occur mainly in young children
between the age of C to 14. Seizuresfrequently'
clisappear spontaneously after adolescence
Prlnclplesof MedicinalChemistry(Vol.ll) tn
Seizuresare usuallyof brief durations(in seconds)
accompaniedby a momentaryloss of conscious-
nessand originatedue to synchronizationof both,
excitatoryand lnhibitory neuronswithin the brain
stem and rnesialreticularactivating system.
An Myoclonle selzures ; The attack is
characterizedby the jerky muscularmovements of
head, limbs or body as such. The duration of
attack remains near about 1 second and it
reappear at about 5 secondsintervalsfor a period
of a minute. The etiologl of atiack is not clear and
is supposedto be dueTb'tniq,damage.
(lv) Infantlle spasms ; The attack, sometirngs
begins with a cry and is often associatedwith
momentory unconsciousness.The structural or
functional brain abnormalities or pyridoxine
deficienqyare some recognizedcausesresponsible
for infantilespasms.
IBI Parttalor focal epllepsy :
In this type, the initial neuronaldischarge exert their anticonvulsantaction by clecreasing
originatesfrom a specific,limited corticalareae.g.
(r) Complex paftlal selzures (psychomotor
or temporal lobe selzures): lt usuallyoriginates
in the mesial anterior temparal lobe and is
characterizecl by hallucinations,fear, hate or other generationof seizures.Various anticonvul
emotional and behavioural abnormalities.
Symptomsare extremely complex and varied and
may someumes be confused with psychotic causesnon-specificdepressionof CNS functi
disorder.
(ll) Motor epllepsy ; Only one entire sicle of
the bocty is affected. Consciousnessis usually not
lost. In severe cases, motor epilepsy is
transformed into grand mal followed by paralysis en4ymesessentialfor brain respiration.
of the hyperactive side of the bocly. Motor
epilepsyis mainlywithnessedin the childhoodand
is due to more limited corticalabnormalities.
(lll) Sensoryepllepsy.. This is similar to motor
epilepsy except the fact that it arises in the
sensory cortex. Simultaneous attack of both,
motor and sensoryepilepsy in the patients,is also during the last two decades,most of the att
reported.
(Iv) Aklnetlc selzures : Superficially no
convulsionsare seen. Patient may suclclenlyfall
d o wn on the gro un d wit hout los s of
consclousness.
CentralNervous51
Sfafus eplleptlcus (acute repetltlvc
selzures) ; lt is the condition in which one attack
follows another without patients regaining
consciousness.The attack may be of grand mal,
petit mat or partial seizures.lf it remainsuntreated
it may be Fatal.Statusepilepticusoriginatesclueto
failure of the patient to follow therapeuticregirren
prescribed for him. Diazepam, clonazepam
thiopentone or lignocaine may be administere
intravenously to control this condition. lf the
treatment fails, general anaesthesiamay
required.
Mechanlsmof actlon of antlconvulsantdrugs :
(1 ) Many carbonic 'ric anhydra:
(Acetiazolamicle)are found to pos
vulsant or anti-epileptic activity. Carboni
anhydraseplays a role in promoting the eliminati
of excess carbon dioxide from the brainand bl
circulation.Sinceexcesscarbon dioxide c{epre
nerve functioning, these drugs are throught
cerebralrespiration.
(2) It has been postulated that excess
discharge of neurotransmitter is the cause
drugs (like phenobarbital, diphenylhydantt
diphenylhydantoi
increase the levels of serotonin in brain w
and thus controls the releaseof neurotransmi
(3) The anticonvulsant activity o f b
turates is attributed to their ability to
conformational rearrangements of oxida
(4) Gamma-aminobutyric acid level in brai
also important to prevent the spread of
seizures.Many anticonvulsantdrugs are rep
to operateby increasingGABA levels in brain.
Since GABA hypofunction is thought t
one of the major aetiologicalfactors in epi
has been focussedon the development of
ergic anticonvulsants.The diScoveryand cli
usefulness of sodium valproate gave
necessaryimpetus. The future strateg/ wo
to develop anticonvulsantswith GABA mi
Princlples
of Medicinal (Vol.il)
Chemistry 141 CentralNervousSystemDepressants

rnd antiglutamate (e.9.,dizocilpine)actionwithout progabide,vigabatrin)or antiglutamates(e.g.

terious side-effects.
Oasslflcatlon of antlconvulsant drugs :
The first seriousattempt to treat epilepsywas excessive stimulation of the brain neurons,
by Sir CharlesLocockwho, in 1857, gave large
doses of bromides under the erroneousidea that
the diseasewas due to masturbation,in order to
produce an aphrodisiaceffect. In virtue of their
effiectson the motor cortex, bromideswere used
in the treatmentof epilepsy.Sedationis induced
by decreasing the central reflex responses.The
initabilityof the motor cortex is also diminished. still going on.
Mental efficienqyis retarded.Bromismcomprisesa
chronic syndrome showing mental depression,
deftclent memory, general stupidity, muscular
weakness,rash, psychosis,conjunctivitis,ataxia,
etc. and is slrmptomaticof a chronicintoxication.
From 1857 to 1912,notmuch advancewas
made in the treatment of epilepsy. With the
introduction of barbiturates,a number of other
chemical substanceshave been synthesisedto
combat this disease.The various structurally
diversified antiepileptic agents can be broaclly
categorisedas
(a) Drugs which were introduced before
196O: These are closely related in structure to
phenobarbital.Examples include hydantoins,
deoxybarbiturates,oxazolidinedionesand succi-
nimides.
(b) Drugs which were introduced from 196O
to 1981 .. Examples include benzodiazepines,
iminostilbenesand valproic acid, and
(c) DruSswhidt were introducedafter l98l :
Theseagentsare either GABA-nergiqagonists{e.g.
Table 8.5 : C,ommonstructrrral features o@4!lu(ul3ant
lomotrigine).
Since epilepsy primarily results through
anticonvulsantdrug is principally, a CNS
depressantdrug. Many anticonvulsantshave
sedative-hypnoticeffects and some may cause
mental disturbancesand hence searchfor a more
ideal, newer structural types of potential
antiepilepticagent, which should possessa broad
spectrum of efficacy and minimal side-effiects,is
TherapeutlcAspects :
The various structurally diversified anti-
epilepticdrugscan be broacllydivided into
(l) Barbiturates
(2) Hydantoins
(3) Oxazolidinediones
(4) Succinimides
(5) Phenacemide
(6) Benzodiazepines, and
(7) Sodiumvalproate.
If the seizuresare not controlledby a single
drug treatment,multiple drug therapy is generilty
usecl,since more than one type of seizuresmay
occur in the patient.
The additional drug is usually chosen from
differentchemicalclass.
Though plasma concentration of anticon-
vulsant drug is usually related to its anticon-
vulsant activity, it may sometimeslead to wrong
interpretation,since many antiepilepticdrugs are
highly bound to plasma proteins and the
concentrationof free drug is only a small fraction
of the total plasmaconcentrationof a drug.
agents

I
Ureidestructure
nu Clrcs R' Class
o
ll Barbiturates Succinimides

Hydantoins NH" Phenacemide

-NIf l*
I
-o Oxazolidinedione Glutarimides
I
t
\
 of MedicinalChemistry(Vol.ll)
Principles CentralNervousSystemDepress

(3) Nz and N3 substitutions,in some ca

(1) Antlconvulsant Barbiturates :
also resulteclin an increaseclactivity.
The clinicallv effective anticonvulsantbarbi- (4) 5, 5 - clibenzyl barbituric acid, caus
turatesare o convulsions.
Metabollc stuclles :
(l ) About 40-600/oof the total phenobarbit
aclministerecl is bouncl to plasma proteins.
maior metaboliteparahydroryphenylderivative
obtained through oxidative hydroxylation by
hepaticmicrosomalenzymes.
'l
Barbiturates
(l ) Phenobarbltone
Rr = H, R2= C2H5;Rt = CoHs
orr ,H

(2) Mephobarbltoile=a-- \fC N

C :O
Rr = CHr,Rz= CzHs;Xr= CoHs / r,
C, H N.
(3) Metharbltal '{
H
Rr = CH:, po = C2H5;Rr = CzHs Phenobarbital
Amongst barbiturates,phenobarbitoneis the ,H
first introducedand most wiclely used antiepileptic HO -N
clrug. Though the above mentioneclbarbiturates
(long acting class) exhibit a high clegree of C C: O
effectiveness in grand mal seizures, pheno- :N
C?
barbitone is relatively non-selective. Others H
barbiturateslike methyl phenobarbitonealso lir
possessesslight anticonvulsantaction.
p- Hyclroxyphenyl clerivatlve
Structure'Activlty Relatlonshlp : (2) Mephobarbital ancl primiclone (cleoxy
(1) Optimum activi! is observedwhen one of barbiturate),both get metabolised in vivo, t(
the substituents at C5 is phenyl. phenobarbitalancl are active antiepilepticdrug:
(2) The 5, 5 - cliphenyl clerivativehas less only due to the fact that they serve simply as i
activity than phenobarbitone. sourceof in vivo phenobarbital.
Table 8.6
Drugs usecl cllnlcally In the control of epllepsy
Typeof epilepsy Drugs
of choice Lesseffective
drugs
(A) Generalized
epilepsy
:
1 . Grand
Mal Carbamazepin Primidone
Phenytoin
Phenobarbilone Methoin
z. PetitMal(Absences) Nitrazepam Valproate Acetazolamide
Sodium
Clonazepam
3, Myoclonic
Seizures Nitrazepam
Phenobarbitone Clonazepam Primidone
Sodium
Valoroate
lnfantile
S pasms Nitrazepam Bu
Vitamin
Clonazepam
(B) Partial
epilepsy
:
1. Psychomotor Phenytoin Methsuximide
Carbamazepine Primidone
Phenacemide
Methoin
Principlesol MedicinalChemistryOol. ll) 143 '
CentralNervousSystemDepressants

(2) Hydantolns :
coH H
N The concept that antiepileptics need not
impair consciousnessis emerged with the
N discovery of the most extensively usecl anti-
czH epileptic agent phenytoin in 1938. It is a non-
seclativestructuralrelativeof phenobarbital.Since
Mephobarbital then, many hyclantoinswere synthesisedancl
were evaluateclfor their antiepilepticactivig. The
hydantoinsare most effective against granclmal
while they remainineffectiveagainstpetit mal. The
clinicallyused antiepileptichyclantoinsare,

Primidone!I NH
I
I
I
I
I
R.3

Hydantoin
(l ) Phenylethylhyclantoin
Phenylethylmalondiamide Rr=H; pu=C2H5; \=C<Hs
While metharbital undergoes N - clemethv-
lationto give
(not useclclinicallynow)
(Z) Phenytoin
_N /H
\ & =H; &=QHs; \=QHt
C C =Q
(

\
(3) Mephenytoin
CH: r) = cHr; Rs= CzHs; = C6H5
\
,_a.:Er}.___
Metharbital
(4) Ethotoin
Rr=C zHs;&=H; R=CoHs

Toxlclty :
(1) Sedation ancl drowsiness are the most
common effects with the beginning of therapy
while tolerancedevelopsduring chronictreatment.
(2) Irritation and hyperactiviglin chilclrenancl
confusionin older aged peopleare observedwith
phenobarbitone.
(3) Folate deficiency, hypocalcaemia and
coagulationclefects in the new-born are other
toxic reactions.
Structure-Actlvlty Relatlonshlp :
(1) A S-phenylor other aromaticsubstituent
is essentialfor the activity.
(2) Alkyl substituents at position 5 may
contribute to sedation, a property absent in
phenytoin.
(3) Among other hyclantoins,like spirohydan-
toins, thiohyclantoins,clithiohyclantoinsand | , 3-
disubstituteclhyclantoins,some exhibit activity
against chemically incluced convulsions while
Principlesof MedicinalChemistry(Vol.ll) 14 CentralNervousSYstemDePressa

remain ineffective against electroshock inclucecl

convulsions.
Metabollc studles I
o
Metabolism is catalyseclby hepatic microsomal ll
N- CH, -o - P- - O Na
enzymes. l*
ONa
FosPhenYtoin
HO
Fosphenytoin is a phosphonoxy est
NH attacheclto the C3 position of the five-membe
nng'
N Synthesls I
H
Hyclroxy acids when condensed with ure
produce hyclantoins.
Phenvtoin p-Hyctroxyphenylderivative

HO NH-,
t-
I
CO
I
NHRI
-+
NH
NH
+ HrO
c,Fls
I
Ethotoin Rr

HYdantoins
Other hydantolns :
Other less important antiepileptichydantoh
inclucle
NH
C: Hs
/C H t
N

CH,
N
I
Mephenytoin p-Hydroxy phenylethyl hyclantoin CH.,
Mocle of actlon : 1-methyl mePhenYtoin
Epileptic seizures cause an accumulationof
Na+ ions within the cerebral neurons, which
H
initiates enhanced synaptic transmissionfollowing
C H l C H ,C H
ra p icl, r e p e t i t i v e p r e s y n a p ti c s ti m u l a ti o n'
Phenytoin clecreasesthe intracellular Na+ ion S
concentration by activating the biochemical
CHlCH = CH.'
process that normally extrudes Na+ ions from
neurons. 3-Allyl-5-isobutyl-2 thio-hyclantoin
 of MedicinalChemistry(Vol.ll)
Principles 145 CentralNervousSystemDepressants

(3) Oxazolldlnedlones:
CH- cHz
Like other antiepileptic drugs, the oxazolidine
-2, 4-diones were originally cleveloped as
hypnoticsor analgesicsbut were introduced into
anticonvufsanttherapy between 1946 to 1948.
Thesecompounds are isostericallyrelated to the Malidione
hydantoin,clifferingonly in that an oxygen atom is
replacecl by NH group. Trimethaclione,para-
methadione,and allylmethyloxazolidinedione are
the clinically used drugs from this class. The
oxazolidinediones are effiectivein the treatmentof
petit mal seizuresbut iFuseclalone, are ineftective
Dimiclione
againstother \pes of epilepsy.
Both are active against petit mal epilepsy.
While,

\9

5, S-Diphenyloxazolicline-2, 4-dione
Oxazolidinediones It is active againstgrand mal epilepsy.
(1) Trimethaclione (2) The N-alkyl substituent cloes not affect
the activigl since all clinicallyuseclagentsfrom this
Rr = C Hg ; &= C Hr :,JR= CHr class, unclergoN-clealkylationin metabolism.e.g.
The anticonvulsantactivit5l of trimethadione is
clue mainly to its N-demethylated metabolite,
(Z) Paramethadione dimethadione.

Rr = CHr ; I ! = CHr ;R = CzHs

)
'**-

(3) Allylmethyloxazolidinedione
(Malidione)
Trimethacl| (,t tt-

Rr = -CHzCH = CHz; ilu = -CH3 ; R=H N-demethvlation

5

Stnrcture-Acttvtty Relatlonshlp :
( 1) The nature of the substituentson C5 is
important e.g., lower alkyl substituentstend
towarcls anti petitmal activi$r while aryl substi-
tuents towards anti grandmal activi$r e. 9. ,
Dimethaclione
Principlesol MedicinalChemistry(Vol.ll) 146 CentralNervousSystemDepressants

Similarly paramethaclionealso undergoes N- Synthesls:

clemethylationin vivo to yielcl 5-ethyl-5-methyl A glycolic ester when condensedwith urea in
oxazolidine-2, 4-dione, which is responsiblefor the presenceof a base,yielclsoxazolidine-2,4-
observed anticonvulsant action of para- clionemolecule.
methaclione.
NHr
I
co
I
NHt

Paramethadione

--=c----:
N -demethylation

Oxazolicline-2,4-clione
(4) Succlnlmldcs :
Though less potent, succinimides have
enjoyed more successover oxazolidinecliones
5-Ethyl-5-methyloxazolidine-2,4-clione
since they possessless significantside-effects.
Theseclrugsare mocleratelyeffectiveagainst petit
Paramethaclione is similar to trimethaclionebut mal seizuresbut rernain ineffective against grancl
less effective ancl less toxic. mal. The first clrug from this series,Phensuximicle,
Mode of actlon : introclucedin 1953 is the weakest and now rarely
usecl.lt is followeclby Methsuximide(1958) and
The petit mal epilepsy involves low frequenqy
ethosuximide( 196O).
dischargesin the thalamus ancl cerebral cortex
Structure-Actlvlty Relatlonshlp :
which are indqcecl through reticular activating
system.
R"
Oxazolidineclionesare effective only against I
petit mat condition.
This effectivenessis clue to two folcl action of
these agents.
(1) they increasethe threshold (of excita-
bility) for production of petit mal seizuresof the Succinimicles
thalamiccentresand thus prevent the spread of (l) Phensuximide
electricalactivity to the thalamus; R = H; R'= CH3
R= C-6H5;
(2) they decreasesynaptic transmissionby
increasingthe duration of the refractorylperiod in (2) Methsuximicle
the neuronsthrough which repetitive discharges P =Q H5; R=CHe; R: CH3
occur;
(3) Ethosuximicle
(3) a slight inhibitoryaction on the resting
respirationof the braincells is an additionaleffect. R = CzHs;R = C H : ; R '= H
 of MedicinalChemistry(Vol.ll)
Principles 147
(a) Methsuximide ancl phensuximide have
phenyl substituents which make them active
againstelectricallyinduced convulsion.
(b) N-methylationdecreasesactivig against
electroshockseizuresand impart more activity
againstchemicallyincluceclconvulsions.
(c) cr-Methylalkoxyphenyl
succinimidesand
all<oxyben4ylsuccin imicleswere active anticonvul-
sants. The length of the alkoxy group here
determinesthe activity.
Toxlclty :
The most commonly occurring sicle-effects
with these clrugsare
(l) Gastro-intestinal complaints like nausea,
vomiting anclanorexia.
(2) CNSeffects include clrowsiness,euphoria,
lethargyancl heaclache.
(3) Others inclucle restlessness,agitation,
anxietv ancl skin reactions.
(4) Certain degree of tolerance to above
effectsmay clevelopin some patients.
(5) Phenacemlde:
Acetylureas is a group of compounds
structurally related with barbiturates ancl
hydantoin. Phenacemide is an open chain
analogueof the hydantoin.Introducedin 1951, it
possesses high anticonvulsant activity,
associateclwith serious toxicitv which limits its
u5e.
.\
cullt NH
o for compounds not interfering with tolate
R R'
Acetylurea
(1) Phenacemide
R=H: R=H
(Z) Phenylethylaceglurea
R= H ; R: C z H s
Not only these compounds possessa goocl
anticonvulsantaction but also possess senous
toxic effects.
CentralNervousSystemDepressants
Structure-Actlvlty Relationshlp :
(l ) Among aliphaticacetylureas, the highest
anticonvulsantactivity is found in those clerived
from branchedchain aciclsof about seven carbon
atoms.
(2) With a furtherincreasein molecularweight,
the anticonvulsantactivi$ graclually terminates
and hypnotic effect predominates.
(3) Phenacemide is most active agent
amongstthe aromaticacetylurea.
(4) Any substitution on the nitrogen of
phenacemide does not increase further the
anticonvulsantactivi\l.
(5) Activity clecreaseswith aromatic substi-
tution of phenacemiclewith a graclualincreasein
hypnotic activity.
(6) Diphenylaceglurea is inactive.
Mode of actlon :
The acellureas inhibit the metabolism of
other antiepilepticdrugs and hence effectivewhen
given in combination with other antiepileptic
drugs.
-N
Lamotrigine
Chronic treatment with phenytoin, pheno-
barbitoneanclprimidone has been known for some
timsto clisturb folate metabolism, resulting in
megaloblastic emia in some patients. A search
metabolismby Wellcomelaboratories(UK)resulted
in the phenyltriazineseriesfrom which lamotrigine
was dev el o p e d . I t s t a b i l i z e s p r e s y n a p t i c
membranesby blockingvoltage-dependentNa+
channels, thereby preventing the release of
ex c it at or y n e u r o t r a n s m i t t e r s , p a r t i c u l a r l y
glutamate and aspartate.
(6) Benzodlazeplnes:
Benzocliazepineswere cliscovered by Leo
Sternbachin 1956 at Roche laboratories.The
benzodiazepinesstarted their career primarily as
 1/A CenbalNervousSystsmDepressants
Principlerof MedicinalChemistry(Vol'll)

sedative-antianxiety drugs but established Mode of actlon :

themselvesalso as effective antiepilepticdrugs in somehow increase the
BenzodiazePines
recentYears. effectiveness of GABA, an inhibitory neurotrans-
ChlordiazePoxide was the first clinicallYused mitter bY,
agentfrom this class,followed
(1960)antiePilePtic (1) Makingeasy the functioning of varietYof
by oxazePam, nitrazePam' diazepam and GABA mediatedsynaPticsystems.
clonazepam. (2) Increasing the affinity of GABA for
H recepil sites in brain membranes'
N Metabollc studles :
I
(1) Clonazeparnis principally metabolisedto
otN inactive 7-amino derivative'
(2) Diazepammetabolisesto the N-dimethyl
analogue and oxazepam, both are biologically
active. -\-

TOxlclty:
( 1) NitrazePam: R:H (1) Drowslnessand fatigue are among the
(2) ClonazePam :R=Cl mo$t cornmonqymptoms'
(2) Muscular incoordination' behavioural
disturbancesand increasedsalivary and bronchial
secretions constitute less frequent side-effects.
(7) Sodlum Valproete (Valprolc acld) :
Valproatewas first synthesizedby B' S' Baron
in 188i ancl was initially used as an organic
solvent.
It is the latest drug'
antiepileptic it
Chemically'
is n-diProPYlacetic acid.
Diazepam
Stmcturc-Actlvlty Relatlonshlp :
(1) Theelectronwithdrawingatom or grouPat
position 7 increasesthe anti - ePilePticactivity ValProicacid
while electrondonating substituentsat 7, 8or9 Among other relatives of valproic acid' 3' 3' +
positionsdecrease it. trimethylp-ntanoic acid is also as active as valproic
acid. In t-hisseries, [i.e. dialkylalkanoic acid having
(2) A phenyl grouP at position5 is necessary
are less than 14 carbon atomsl
for activl$r. But only halogen substituents
(1) The anticonvulsant activi$l increases with
allowedin the ortho Position.
at ortho increased chain length-
(3) The electron withdrawing groups
increase the (2) Introduction of a double bond decreases
or diorttio positions at s-phenyl
activity while any substituent on meta or para the activi$r
position at S-phenyl decreasesthe activit5r. (3) lntroduction of a secondary or tertiary
grouP or replacement of carboxYl bY
(4) Methylsubstitutionat position1 confirms hydroxyl
hydro4ytgrouPhas no effect.
high activitY.
Principles
of MedicinalChemistryryol.ll) 149 CentralNervousSystemDepressants

Mocle of action :
vatDrotcaad rnnrDrt's: N_N
(1) CABA cleactivating
enzymes.
cH3coNH so2NH2
It blocl<s succinic semialclehycledehydro-
genase,the enzyme oxiclisingthe semialdehycle
metabolite.As this metaboliteaccumulates GABA- Acetazolamicle
T activig is decreaseclby enct-procluctinhibiiion
anclthe GABA concentrationincreases.
(Z) Re-uptal<eby glial cells anclnerve enclings
and thus increasesthe synaptic concentrationsof
so-'NH2
GABA.
Toxicity :
It is one of the potent antiepileptic clrug Ethoxzolamicle
havine minimal seclationancl other CNS sicle
effects. GIT clisturbancesare mo-st comrnonly
observecl.
NHrSO; N
Toleranceto its anticonvulsanteffects is vet
S
not reportecl.
o
\

o
/

(8) lmlnostilbenes r
Carbamazepine is introclucecl(1960s)in clinical Sulthiame
practices. It is structurally relatecl to tricyclic
anticlepressants.It is l<nownto increaseavailable
adenosinewhich is a natural anticonvulsantor
convulsionmodulator.
cHr so)NH2

s02NH2
5
N Disamide
ICONH, -Their,-anticonvulsant
action is due to their
--E-.
clirect inhibitibh of brain carbonic anhvclrase
Carbamazepine enzymes:
ln majority of the cases, toxicitli is relatively ln - aclcl
ition, sult hiame inhibit s oxygen
minor and may incluclemilcl clrowsiness,sl<inrash,
consumptionby the brain.
and gastric irritation.
Carbamazepineis metaboliseclto lO, 11- (lO) GABA-nerglc agonlsts :
epoxiclewhich also has anticonvulsantactivitv. There seem to be numerous GABA-nergic
(9) Carbonic anhydrase Inhlbitors pathwaysin the CNS.CABA is foundin the highest
(sulphonamides): concentrationin the substantianigra. It is also
Acetazolamide,ethoxzolamicle, founcl in hypothalamus ancl occurs in lorv
sulthiameand
clisamidewere shown to possessanti-convulsant concentrationin practicallyall brain strucruresas
property. well as in the spinalcorcl.
Principles
of Medicinal (Vol.ll)
Chemistry 150 CentralNervousSystemDepressants

GABA metabollsm r

GABA-T
- cH.,- cH"- coo Vit 86
GABA

succrnlcsemlaldenvoe coz
GAD
Vit 86
ooc-cH"-cH"-coo
Succinate

o-c-cH.,-cH"-coo
coo
cr-ketoslutarate L-Glutamate

GAD : Glutamicacicldecarboxylase.Cofactoris vitamin 86. GAD founclonly in mammalianCNSanclin

the retina :
GABA-T: G.ABA-transaminase. SSADH: Succinicsemialdehydeclehydrogenase.
GABA can be deactivated ancl recycleclby transaminationreaction with d-ketoglutarate to yield
lutamate.
GABA-receptor was thoroughly investigated GABA mimetic THIP (tetrahydroisoxazolo-
in the early 1980s.The GABA-A receptoris a high pyridinol),a non-adclictivepain-relievingagent, is
affinity binding site with fairly constant density. reported to be equivalent to morphine. The
The GABA-B receptor has a low binding affinity correlation may be enkephalinergicneurons,
ancl shows great variation in receptor density in involved in pain pathways,seem to be regulatecl
various brain areas.GABA-receptoris regulatectby by GABA-ergicneurons.
a thermostable protein callecl GABA-moclulin, Huntington'schorea,a neuromotordisorder
havinga molecularweight of 15O,OOO. Thisprotein involvesdefectivecentralGABA-metabolism.lt is
is an inhibitorof i.ireCa++dependentand both C- hereclitarydiseasethat manifestsin involuntary
AMP clependentand C-AMP- inclependentprotein movementswhich disapp_ear onl_vcluringsleepand
l<inases.lts removal increasesprotein phospho- leaclsto mentaldeteriorationin adults"lt arisesdue
rylation in the synapses by 20 folcl ancl the to deficiency of glutamic acid decarboxylase
number of receptors (or their transmitter recog- (GAD).
nition ability) increases.The receptor assembly
seems to be composed of GABA-receptor,the
protein kinase with attached GABA-modulin, the
ionophoremediatedCl- ion transport.The GABA-
modulin binding site is apparentlythe same as
benzodiazepine binclingsite.
The existence of peripheral GABA-receptors
has been shown. Sincethey are locatedat outer
mitochonclrial
membrane,they may be involvedin
the modulationof intermecliary
metabolism,
GABA is involved in feeding, sleep, hormonal
secretion,CVS functionsancl in analgesiathat is Brotizolam Midazolam
not mecliateclby opiate-sensitive neurons. The (sedative-hypnotic)
 of Medicinal
Principles (Vol.ll)
Chemistry 151 SystemDepressants
CentralNervous

cooo

PLP PMP NADP NADPH

-coo Succinic acid
Succinic
Glutamic
acid GABA
semialdehyde
L-Glu _KG
tlc. E.l : Blosvnthesls ancl metabollsm of GABA
Becauseof vinyl substituentin vigabatrin(l) of loweringthe pKa of the amino group. Thiswould
lipophilicity increasesanct (2) vinyl, being an tncreasethe concentrationof non-zwitterion form
electron withclrawin.qsubstituent, has the effect which is more lipophilicthan zwitterion.
Table E.7
Structure of compounds that act at GABA - erglc synapses

OH
o-N I
o o C CH
H,N Hl N \.oo"
oe oe H^R/ C
GABA M u s c im o l 2-H ydroxy
GA B A

H
I
C
lll
NH
H1 H.R/ L cooe
I
4-MethylGABA is xsj4
nopropion
-3-Hydrazi CH'

GABA
Acetylenic

OH
COOH
H,N-O cH.,
--coo-..
Amtno oxvace c aclo
HHP Isoguvacine

Hr N COOH
OH

COOH

Gabapentin 4, 5-Dihydroxvisophthalic
acid
Picrotoxin
Principles
of Medicinal
Chemistry
Uol. ll)
New and potentlal antlconvulsants :
(a) Vigabatrin (gamma-vinyl GABA) is an
irreversibleinhibitor of the enzyme amino-
transferaseand interfereswith the catabolismof
GABA.
(b) Lamo trigin e is be liev ed t o ex er t
antiepilepticaction by inhibiting the releaseof
excitatory neurotransmitterslike glutamic ancl
asparticacids.
(c) Denzimol is an antiepilepticagent. An
involvement of purinergic ancl benzodiazepine
mechanismsis suggested.
(d) Stripentolis a ethylenealcoholderivative.
It acts by inhibition of synaptosomal GABA
uptake and inhibition of metabolic transformation
of GABA.
(e) Eterobarb has anticonvulsant action
probably due to its metabolic conversion into
phenobarbitone.
Other examples include zonisamicle,topira-
mate, iodaxaprine and oxacarbazepine.Unlike
carbamazepine,oxacarbazepinedoes not undergo
oxiclativemetabolism to toxic carbamazepine-1 O,
I I -epoxiclemetabolite.
Valdice behavesas a prodrug like valpromicle, the target enzyme (GABA-AT) to a reactive
while cli-isoprc,pylacetamiclediffers from
Valproicacid Vigabatrin
CH,CH,CHTl CHTCH,CHTl
cHcooc.H.
CHlCH'CH''
Valclice Valpromicle
154 CentralNervousSystemDepressants
valpromidein being more stable^The amiclelinkage
in the former is protectecl fiom hyclrolysisby two
methyl groups at p-position.The methyl groups
prevent attack of amidases through steric
hinclrance.
Vlgabatrln :
Symptomaticepilepsy can result from specific
physiologicalphenomenonsuch as brain tumours,
syphilis,cerebralarteriosclerosis, multiple sclerosis,
Buerger's clisease, Pick's clisease,Alzheimer's
clisease, sunstroke or headstroke, acute
intoxication,lead pclisoning,heacttrauma,vitamin
p6cleficienry,hypoglycaemiaancllabour.
The cohcentrationof GABA is regulateclby
two pyridoxal -5 -phosphate (PLP) dependent
enzymes, L-glutamic acid decarboxylase (GAD)
which converts glutamate to GABA ancl GABA-
aminotransterase(GABA-AT) which degrades
GABA to succinic semialclehycle (SS).Although
succinicsemialclehycle is toxic to cells there is no
builcl up of this metabolite becauseit is efficiently
oxicfisecfto succinic acid by the enzyme succinic
semialdehycle dehydrogenase (SSADH).
Vigabatrinis an unreactivecompound that is
converted by the normal catalytic mechanismof
compoundwhich attachesto same enryme.
N
IcoNHr
NHz
Oxcarbazepine
CH,
Di-isopropylacetam
ide
Princlples Chemistryflol. ll)
of Mediclnal 153 CentralNervousSystemDepressants

Table 8.8
Drugs that work by elther facllltatlng (e.9. benzodlazeplne agonlsts, barblturates), or inhlbltlng
GABA (e.g. plcrotoxln, blcuculllne, PTZ)erglc transmisslon

{I1 GABA AGONISTS (||) GABAhrurnCOXrSrS

N-CHj
e o
HrN H
H:N
o
GABA Muscimol

o\,/o
Picrotoxinin
Bicuculline

Baclofen

flr) BENZODIAZEPINELIGANDS: (tv) BEhIZODIAZEPINT,

ANTAGONISTS

coocH2cH3

CI cH.r

cF.,
c L2t 8872 ROl5-l?88
Diazepam i nhibitor
GABA-modulin
Principles
of Medicinal
Chemistry
(Vot.[) 154 CentralNervousSystemDepress

(v) p-cAnBorrNEs

o
o H3C- H.,C
tl
C- ocH.l
il
H.rCO

H.rCO
Ethvl-p-carbolinc--3
-carboxylate DMCM

(a) Depressants:
o
CH ,
O NH N = C(CHr ) :
I tl
cHrct-t,cl-t'cH H.iC.OOC
I
c-c.--- H
CH.CH;
N
(
I
H HrCu
Pcntobarhrtal
Etazolate E to r n i d a tc

(b) Convulsants:

R
o-
B i c y c l o p h o sp hea\te
te r s
RO5-3663

Pcrrtylene
tetrazole
(wz) H,C

Anis a ti n
 of .illcdlclnalChcmlclry(Vol.ll) 155 Ccntll llcwour Sy.demOcprsrsailc

Teblc E.9
Structures of andogues of glutamate

(r) Antagonbts of glutamlc acld

COOH HOOC- CH - CHz- CHz- CHz- CH2- PO3H2

cooH D-2-amino-5-phosphonovalerate
dicarboxylicacid
Cis-2,3-piperidine

cH2- so.lH
cl
HOOC- CH- CHz- CHz- co-

aminomethylsulphonate
T-D-glutamyl
NHz
Lamotrigine
(b) Agonlsts of glutemlc acld :

cooH HOOCH

Hzc-C
I
cHr
OH
KainicAcid Acid
Ibotenic

HOOCHCH2q
N-O HOOC-CHr-CH2-CoOH

N-Methyl-D-Asparttlc
NHz
Acid
Quisqualic
Principles
of MedicinalGhemistry(Vol.ll) 156 CentralNervousSystemDepressan

Table 8,10
Comparison of oral antlconvulsant drugs

Optimumserum
Anticonvulsant
drug pmol/,
concentrations (hours)
Half-life Commonor important
(p g / ml) aoverse
effects

Carbamazepine 25 - 50 (6 -12) 25- 50initially Drowsiness,

dizziness,
ataxia,
diplopia
(Te g re to l) 10- 30longterm rasnes, l euc0penra,
neartbl o c k
hyponatremia

(Frisium)
Clobazam 18 Drowslness,
dizziness,
confusion,
ataxia

Clonazepam '2 0 -6 0 Drowsiness, ataxia.behaviou

v
(Rivotril) disturbance,
bronchial
hypersecretio
in
infants

uXItmide
Ethos 300- 7C0(40-1
00) 30- 70 Nausea,
vomiting,
tiredness,
dizzine
(Zaro
nrtitn mood
disturbances,
leucopenia,
rashes

yt0tn
Phen 40 - 80(10-
20) 10- 60 Drowsiness,impaired rnemory and
(Epa
ntutin) attention,
ataxia,
blurred
vision,
diplop
gumhyperplasia,
hirsutism,
acne,facia
coarsening,
rashes,sensory
neuropat
liverdamaqe,
osteomalacia

Phenobarbitone 80 - 180( 15- 40) 70- 120 D row si ness,

memoryi mpai rme
behavioural
disorders,
hyperactivit

Primidone 4- 11 As for phenobarbitone,

occasion
(Mysoline) pronounced
at start

mvalproate ?6n - 700(50

- 100) 6 - 15 Drowsiness,
confusion,
tremor,
insomn
m) nausea, gain,
weight alopecia,
bleedin
tendency, pancreatili
hepatotoxicity,

Vigabatrin(Sabril) Somnolence, fatigue, confusio

dizziness, gain
weight
Prlnclpbr ol tledlclnelGhemlfi (Vol.ll) 168 Canfal NeryourSystomD€pt€stanb

NZN-N
il
NHz

Ruflnamlde co2H

pH2oso2NH2
Tigabine

Toplramate Tlgqblnels GABA agonlst. Chemlcallylt ls

but - ]
R H - N - [4, Ml -(3-methylthlen-2-yl)
OH
enyll nlpecotlcacld HCl.lt ls a potent lnhibitorof
t-clHe GABA uptake Into synaptosomalmembrane
neuronsand gllal cells. lt thus augmentsand
Stlrlpentol proloqgsthe slmaptlcInhlbltoryeffectof GABA
ooa
 9.1 INTRODUCTION
INTRODUCTION 159 Local airaestheticagents are the clrugswhich
are applied (as close to the site of action as
SITESOF ACTIONOF LOCALANAESTHETICS possible) to achieve a selective analgesia or
anaesthesiaof relatively restricteclareas of the
bocly. To be useful clinically, the action should
93 NERVETISSUES always be reversible.The sensitivity of a nerve
fiberto a localanaestheticis inverselyrelatedto its
9.4 MODEOF ACTION diameteranclsincepain fibresin general,aresmaller
in cliameterthan many other $pes of sensory
fibres ancl most motor fibres, they are anaesthe-
95 CLASSIFTCATtON sizecl by concentrationsof local anaesthetics
which causeneither muscleparalysisnor abolition
RELATIONS+IIP
STRUCTURE-ACTIVITY 163 of the senseof touch.
Thesedrugs are mainly used tor the temporary
relief iiT hc€€ii&eg!-pain
and itching due to minor
burns,insect bites, allergic responses,in clentistry
anclminor surgicalproceclures. A local anaesthetic
in contact with a nerve trunk can prevent the
initiationand the transmissionin both sensoryand
motor neryes.
9.2 SITESOF ACTION OF TOCAL
ANAESTHETICS
(l) Topical anaesthesia: lt is used to relieve
pain or itching at mucous surfaces,damageclskin
surfaces,wounds or burns. Local anaesthetic
agent is ineffectiveif it is appliectclirectlyto the
unbrol<en skin.
(2) Infiltration anaesthesla : In minor opera-
tions,a localanaestheticis injecteclat one or more

( 1se)
Principlesol MedicinalChemistry(Vol.tt) 160 LocalAnaesthetic

Peridurat
SpinalBlock ;Blak Epineurium

Nodeof Ranvier
>. Inliltration
anaesthesia
z::-_-_-l
Motor
Endoneurium ncrve
Perineurium
NerveBlock myctinsheath axoplasma
-t:-,-
Topicalanaesthesia
!
Sensory
nerve
fig. 9. I : The sites of actlon of local anaesthetlc agents

sites in ancl around the area which is to be arrangeclstrands of collagenousfibers calleclas

anaesthesiz-ect.The finer nerve enclings in such
area are affected by this methocl.
(3) Nerve block : A relativelyhigher concen-
tration of local anaestheticis injecteclas close as
possibleto the main nerve trunl<suppliecl,the area
in which anaesthesia
is requireclcluringsurgery.
(4) Splnal anaesthesla : In this case,a local
anaestheticis injectecl into the subarachnoicl
space to blocl<the roots of those nerves supplied
to the site of operation.
(5) Perlclural block : A local anaesttreticis
injecteclinto the pericluralspace and comes into
contactwith the dura and the region outside the
cluramatter anclthus coversand anaesthetizes the
roots of.the spinal nerves.lt is useclin obstetrics,
cluring thoracic ancl abdominal surgery and to
relievethe postoperativepain.
9.3 NER,VETISSUES
The outer layer of connective tissue, which
wraps the sensory and motor nerve outside the
spinal cord, is known as epineurium.In this, a
nerve is itself enclosedin a membraneof dense,
concentric layers of connective tissue, called as
perineurium.Within the perineuriumthe incliviclual
nerve fibers (axon) are embeclcledin longituclinally
enqoneunum.
Epineu
rium
Axon
Perineurium
Endoneuriunr
ilg.9.2
E.lch axon has its own cell membrane
(axolemma)tightly surrounclecl by (not in all axons)
a myelin sheath. The myelin is not continuous
along the fiber.The interruptionsare calledas the
nodes of Ranvier.The axolemma servesas a barrier
between the cytoplasm of the axon (axoplasm)
ancl the endoneurium.The compositionof the
membraneis highly lipoiclalwith some protein.
9.4 MODES OT ACTION
(l) Socllum channels : The nerve membrane,
is composeclof lipictsas well as proteins equal (or
sometimesexceeding)to the quantity of lipicls.lt
possessesselective perrneabilityto ions and
molecules.To understancl the impulsegeneration
ancl ion fluxes phenomenon, the concept of
'Socliumchannels'is put forward.lt is supposed
to be a protein (possiblya lipoprotein),that is
Principles (Vol.ll)
Chemistry
of Medicinal
Prote Aqueous
Pore
Interior
Ilg. 9.3
embedded in the matrix of the axonal membrane
and has an aqueous pore extencling Fom interior
of the matrix to the outer surface of nerve
membrane.The concept is proposeclto describea
mechanismfor the controlleclinflux of cations,
which is achieved by the opening and closing of
the aqueous pore of the soclium channel by
constructionof the channel at trivosites. One gate
is at the external encl of the pore ancl the seconcl
gaie is at the internalend of the pore (wlthin the
membrane).They are known as M and H-gates.
The Na+ channelis a six-segrnentedprotein, of
which four segments span the axon membrane.
Thereare two gates.The M-gate in the mictclle,and
the H-gate at the inner opening. Both gates must
be open to allow passage of the ion. In a
depolarizeclmembrane,the M-gate is closed. The
ion-selectivefilter is O.3 - O.5 nm in cliameterancl
consistsof an ionized acidic group that attracts
cationsbut repels anions. Both tetroclotoxinand
saxitoxin slide into the open ion slit with their
guanicliumgroup ancl block it with.the rest of the
molecule,binclingto the eclgesof the channel.
Outs i d e
M-gate
lnside
H-gate
(a)
El g. 9. 4: O pen (a) and closed (b) forms of sodlum lon'channel
161 l-ocalAnaesthetics
Sincethe socliumchannel is the sole route for
the influx of sodium ions during nerve depolari-
sation, the simplest way to exert local anaesthetic
action is to block these sodium channels thus
preventing nerve clepolarisation and impulse
propagation. Many iocal anaestheticagents have
been shown to interactwith these channels.
Local anaestheticsplug both the Na+ and K+
channels and can act either from the outside or
from the inside of the neuron. lonized speciescan
a c t o n l y fr om t he out side. Non-ionized
compounds that can penetrate the membraneare
capableof blockingfrom insicle.
Some local anaestheticby perturbing the lipid
structure,triggers a fluiclizationof the lipicl bilayer,
allowing a conformationalchange in its protein
constituentsthat results in closing and general
clistortionof the ion-channel.
Tetrodotoxlnis found in the liver and ovaries
of the puffer fishes ancl in the eggs oF some
amphibians,while saxitoxin is proclucedby marine
clinoflagellatesof the genera, Gonyaulax and
Gymmodinium. Both are Na+ channel blocking
neurotoxlns.
Both toxins seem to be high Na+ channel
specificby virtue of their guanidiumgroups,since
guanidium,ions can pass through Na+ channels
ancl interactwith the open ion-channel.
(2) The association of local anaesthetic
molecules within the membrane may affect
selectivepermeabilig characteristicof the nerve
Outsrde
M-gate
ln s r d e H- gar e
o)
 of MedicinalChemistry(Vol.ll)
Principles 162 LocalAnaesthetics

membraneby increasingthe clegreeof disorderof

the lipids that constitutethe nerve membrane.
(3) Interactlon wlth calclum : Calciumexists Outergate(C)
in the membranein a bound state.lt is the release
of this bound calciumwhich initiatesthe action Lipoprotein
potential and ion permeability changes. Local
anaestheticagents displace the bound calcium
from these sitesancl form more stablebonclswith
calcium,therebyinhibitingionicfluxes.
(4) Some localanaestheticagentsincreasethe
thresholdpotential (a voltage essentialto charr5,;
the localizeclpotential to the action potential), Innergate(A)
therebythe nerve cannotelicit the action potential
anclimpulseis not propogatecl.
Action
flg. 9.6 : Sodlum channcl
potential Less accepted hypothesls :
40
(l) According to Nachmansohn,due to
gtructuralresemblanceof procaine with acell-
chollne (6cetylcholine antagonist), local
anaestheticsmight owe their effectivenessto an
Threshold interaction with acetylcholinereceptors in the
potential nervefiberc.
-1 0 (2) Similarlysincehistamineis presentin at
Resting least some peripheral nerves ancl many local
Potential
anaestheticsantagonisethe actions oF histamine,
tlg. 9.5 it is also proposeclthat their effectivenessis due
(5) Refractlve periotl : Immecliatelyafter an to their antihistamineaction.
impulsepropogation,the axon remainscompletely All the local anaestheticsin current clinicaluse
unexcitable (absolute refractory). Some drugs
have their sitesof actionwithin, or on the intemal
extendor prolongthis refractoryperiod. surface of the plasma membrane but there is a
(6) Conductlonveloclty : This is the velocig group of substances that prevent excitation
at which an impulse is conclucteclalong the nerve. (action potential) by an action on the external
Some drugs may alter this concluctionvelocig. lf surfaceof the nerve membrane e.g., tetrodotoxin
conductionvelocigr is retarcled,it may result into ancl saxitoxin.
recluceclimpulse concluction.
ln summary, local anaestheticsclo not affect .5 CLASSITICATION
the resting pgtential of nerve but they prevent the (A) Esters :
clevelopment of the action potential; in other (i) Aminoalkylestersof p-aminobenzoic acid.
worcls,they stabilizethe nerve membrane,mal<ing
it less excitable. (ii) Alkylestersof amino benzoicacicl.
Anaestheticsthat are only effective in the (iii) Estersof benzoicacid.
cationicform (like cinchocaineand lignocaine)have (B) Amldes :
their postulatedreceptorslocated in the vicinigr of
the gates, perhaps in the soclium channelsthem- (i) Aminoacylamicles
selves(A and C), while anaesthetics which exist in (ii) Aminoalkylamicles
only uncharged form (benzocaine), cannot (C) Urethanes
occupy, the sodium channelreceptorsbut c4use
an expansion of the membrane (anclthus narrow (D) Amlnoketones
the channel,B) by increasingthe movementsof (E) Amlnoethers
the lipid moleculesor by altering the conformation
(t) Mlscellaneousagents.
of the lipoproteinmoieg.
 of MedicinalChemistry(Vol.ll)
Prlnciples 1d| LocalAnaesthetics

Similarly, Takman has proposecl another The structure of most of the useful local
classificationof local anaesthetic
agents,basedon anaesthetics containhydrophilicancl hydrophobic
their sitesof action.Accorclinglylocal anaesthetic groups that are usually separateclby an
agentsare classifiedas : intermediate alkylchain.
(l) Thoseacting at the externalsurface(gate)
The hyctrophilicgroup is usually a tertiary
of the sodium ion-channel.
amine,but it may also be a secondaryamine.The
(2) Thoseacting at the internalsurface(gate)
hydrophobicgroup is usuallyan aromaticresiclue.
of the sodium ion-channel. In almost all the cases,the linkage between the
(3) Those acting by an aromaticgroup and the al$l chain is either of the
dtemicalparameters. ester or amicletype and nature of this bond is a
(4) Those acting by a combination of a determinantof certainpharmacologicalproperties
receptor (gate) and receptor indepencl^ntmecha- of theseagents.
nism.
oll
srnucruRE-Acnvrry
RErATroNsHrp
"gCThe prototype agent from this category is an Aryl- c -X-aminoalkyl chain
alkaloid,cocaine.Besidesbeing a centrallyacting (l) Ester llnkage
reuptakeinhibitor of norepinephrine(psycho- X
tomimetic), cocaine has been used as a local
anaestheticfor almost a hunclredyears, on the
Aryl- NH - t aminoalkylchain
recommendationof Sigmund Freucl.Analogues (ll) Amlde llnkage (X = O)
with more favourable properties have been Since nerve membranesconsist primarily of
synthesized.Some of these analogues,lil<e lipids, increasingthe hydrophobiccharacteristics
benzocaine, are useful only topically. The (lipictsolubility)of a'seriesof compounclsshould
protoglpe of injectable local anaesthetics, result in facilitateclpenetrationof these clrugsin '
procaine(novocaine)was introduced in 19O9.lts the nerve membranei.e., the potency of local
relativelyshort durationof actionand low potency anaesthetic compounds shoulcl be directly
can be increased by co-aclministrationwith proportional to partition coefficient. Unfortu-
epinephrine.The synthesisof Iiclocainein 1946 nately toxicigl also increasesconcurrently.But
was a maior breakthrough.lt is an amide insteaclof since the in vivo system is much more compli-
an ester. lt is more potent than esters,less toxic catecl,any effortto increasea given degreeof lipicl
and a more versatile clrug. Liclqcaineis also used solubility, cloes not assure a potent local
intravenouslyas an antiarrhythmicagent.-ln that anaestheticactivity ancl nor cloesa high clegreeof
t application,it must pass through the liver, the pot_gllcyassure its clinicalutilig clue to simul-
principaldrug metabolizingorgan in which it loses taneous iln-ftase in toxicig.
an N-ethyl group to become a convulsantand
Structure-Actlvlty Relatlonshlp for local
emetic. To minimize this, tocainidewhose cr-
anaesthetlcscontalnlng an ester llnkage :
methyl group prevents degradation,ancl which
lacksthe vulnerableN-ethyl group, was prepared. oIt
- The enzymatic hydrolysis of ester group Aryl- c -X - Aminoalglside- chain
motivatedSwedishinvestigatorsto searchfor less (a) Aryl group :
readily hydrolyzable anaesthetics. Isosteric
replacementof alkoxy oxygen of COORgroup by ( 1 ) A n aryl raclicaI attachecl clirectly to the
NH [-CONHR]or CH2 [COCH2RIwas suggestecl. carbonyl group, results into a conjugation
Apart from usual greater hyctrolyticstability of which in tu rn enhances local anaesthetic
amides,additionalsterichinclranceat amiclelinl<age activity.
makesthe -NHCOgroup lesssusceptibleto hydro- (2) Similarlyalicyclicand aryl aliphaticcarborylic
lysis.Dibucaine(reversedester)was developedas
acidestersare alsoactivelocalanaesthetics.
antipyreticbut found to be local anaesthetic.
Principlesof MedicinalChemistry(Vol.ll) 164 LocalAnaesthetics

(3) ln aryl vinyl radicals(Ar - CH : CH -), the
mesomericeffect of the aryl radical does not
extenclto the carbonylgroup ancl hence such
compouncls are not effectiveclinically)
(4) The aryl substituentswhich increasethe
electron density of the carbonyl oxygen,
enhancesactivity e.g., all<oxy,amino, and
alkylaminogroups at ortho or paraposition.
(b) Brldge 'X' :
Here the 'X' may be carbon,nitrogen,oxygen
or sulphur.The nature of 'X' affects cluratir:nof
action ancl relativetoxicity.
(c) Aminoalkyl group :
(l) The amino group-rs<{errllCleredas the
hyclrophilic part of the molecule. The activity
decreasesand irritation property increasesin the
following order :
7" < Z" < 3" amine
(2) The alkyl position only influencesthe lipicl
so lu b ility.
(3) In general, the aminoall<ygroup is not
necessaryfor local anaestheticactivity but it is
useclto form water-solublesalts.e g., benzocaine
(X = O; aminoalkyl: CzHs)
.{f Structure-ActlvltyRelationship for local
anaesthetlcs contalnlng an amicle linkage :
X (liclocaine).
group
Aryl - NH - C - Aminoall<yl
(a) Aryl group : The all<ylsubstitution(parti-
cularly CHr), at ortho or para position, enhances agentsare chieflyglucuronicles.
Classification of Local Anaesthetlcs :
(A) Esters :
(t) Amlnoalkyl esters of p-amino benzoic acid :
the activi!. It provides steric hindranceto the
hyclrolysisof the amiclelinkageand contributes to
the lipiclsolubilityof molecule.
(b) Substltuent 'X': In general,X may be
carbon(isogramine), oxygen (liclocaine), or nitrogen
(phenacaine).
(c) Amlnoalkyl group : The nature and its
relativecontributionto activi ls same as ln the
compoundscontainingan ester linkage.
Mctabollsm :
Local anaestheticagents undergo oxidative,
recluctive. hydrolytic and synthetic reactions in
the bocty. Nearly all clinically useful local
anaestheticagents have the following general
s t r uc t ur e:
Esteror
Archnatic Aminoallgrl
-Amicle-
Group Group
Linl<age
The important points of attack, are
(l) Dealkylatlon of the amlnoalkyl group :
Thus,3' aminesare convertedto 2' amines.
(2) Hydrolysls of the estel or amlde
linkage : The hyclrolysisis catalysed by different
enzymesfor different local anaestheticagents e.g.,
pseudocholinesterasesin plasma (procaine) ,
enzymes of encloplasmic,reticulum of Iiver
(3) Hyclroxylationof the aromaticring moiegr.
(4) Conjugation products of local anaesthetic
o
ll
c - o- Rs - R(,

HN
R1

Name
Procaine H H H -cHzc{z- - N (C2Hs)2
Chloroprocaine cl H H - cHzcHz- - N (CzHs)z
Propoxycaine rO H H - cHzcHz- - N (CzHs)z
Benoxinate H BuO H -cHzcHz- - N (C2Hs)2
Tetracaine H H - cHzcHz- - N (CHi)z
Butacaine H H - cHzcHzcHz- -N(n-CaHe)2
 (Vol.ll) 165 LocalAnaesthetlcs
ChemistrY
of Medicinal
Principles

(ll) Alkyl esterc of amino benzoic acld :

/\ COOR;

Na me R3

NHz
Orthocaine

Benzocaine
NHz (cHz)3cH3
lnry!rye
(lii) Estersof benzoic acld :

cooRi

Name

cHl
lsobucaine
Cocaine
CH:

Hexvlcaine -CHCH'NH
Meprylcaine
cHr

CH-,CH2CH2-N
cH ' C H2CH2N CyclomethY- -o
I Riperocaine
caine Hrc
H,c
Principlesof MedicinalChemistry(Vol.ll) 166 LocalAnaesthedcs

(B) Amldes : (D{ Aminoketones :

(i) Aminoacylamicles(i.e.compounclswith
a- NHCO- linl<age
Rz: CH3Fxceptin prilocainewhere Rz=H
R- O C OC H ,C H -,
o
tl
N H -C -R
(i) Falicaine:
R= C:Hz (ii) D y c l o n e 'R =C a H s
(E) Aminoethers :
Name R
l. Liclocaine ,_CHz_ N( C2 H5z C H 'C H ,C H .C H I
Z. Prilocaine cH.
l"
-cH -NHCHZCH2CH3
3. Eticlocaine C:H: OCH-''CH,'N(CH.),'
-cH(c,H5)----N
Dimethisoquin
(r) Miscellaneous Agents :
4. Mepivacaine
NH
N
I
I Hr

5. Bupivacaine
Phenacaine

I C H ,OH
CH- .,CH,CH,CHI

Bupivacainervas developed by modificationof

the side-chainof lignocaine.
(ii) Aminoall<vlamicles(i.e. compounds with Benzvlalcohol
CONH- linl<age)

ocrH,r cH.r(cH.')ro -
o(cHr).r

coNH(cH,),'N(CrH5)l Pramoxine

Qinchocaineor Dibucaine
(C) Urethanes :
(Compouncls with a-NHCOOlinkage) CH' CH= CH'

NH - COO H,
Eugenol
clsc-c(cH3)r-oH
NH-COO-C H -CH..' - N Chlorobutanol
Diperoclonor Diperocaine
aao
 IO.1 INTRODUCTION
10.1 INTRODUCTION
The antipsychotic agents, now more
commonly calleclas the "neuroleptics"are one of
1O.2 NEUROLEPTICS the most importantand widely used classof drugs
which developeclafter the secondworld war.
10.3 MECHANISM
OF ACTION
A psychotropic,psychoactiveor phenotropic
clrug is one that inhibits, sharpens or alters
10.4 THERAPEUTICAPPLICATIONS
behavioural, mood and emotional responses.
Psychiatricillnesses can be clivicled into the
10.5 ANTI-DEPRESSANTS
neurosesand the psychoses.A neurotic patient
usuallyretainssufficientinsight to realisethat he is
10.6 MONOAMINE INHIBITORS
OXIDASE ill while the psychoticpatientlives in a world of his
own, believes that only his own actions are
10.7 TRICYCLICANTI.DEPRESSANTS completely rational and is a victim of his
hallucinationsand delusions.
10.8 ANXIOLYTIC
DRUGS
The antipsychotic agents have the capacit5lto
seclate or tranquilize the blunt emotional
expressions,aggressiveancl impulsive behaviour,
leaving the higher intellectualfunctionsrelatively
unaffected. Hence they are also known as major
tranquilizers.
Variouspsychiatricillnessesinclude :
(l) Neurotlc dlsorders :
(a) Schlzophrenla : The full panoply of
symptoms was first described by ProfessorEmil
Kraepelinat HeidelbergUniversig in 1899 Schizo,
phrenia is a neurologicalas well as psychological
clisorder.It is known in general by fundamental

(167)
Principlesof MedicinalChemistryflol. ll)
secondaryto the change in mood and activi!.
Most of these disorderstend to be recurrentand
onset can often be related to stressfulevents.
Depressive illnessesvary greatlyin symptomsand
severi$. The terms mania and severe clepression
denote opposite ends of affectivespectrum.
The affectivedisordersinclucle:
manicepisode
bipolar affectivedisorder
clepressiveepisodes-mild, moderate ancl
severe
recurrent clepressivedisorder
persistentmood (affective)disorcler
other mood (affective)disorclers.
A large proportion of population is affected by
depressivedisordersat some stage of their lives.
Mood disorders are verv often chronic and
recurrent Depressed persons often become of
suicidal nature. They may attempt suicicleeven
using overclosesof their prescribed anti-clepre-
ssantdrugs.
(1) Major depressionis a unipolar(one-phase)
affective (emotional) disorder. The completely
differentmanicdepressiveclisorderis calleclbipolar
affectivedisorder.
(2) The depressed patient has feeling of
helplessness,hopelessnessancl worthlessness,
and often thinks of suicide. Thus clepressioncan
be fatal. The depresseclperson may be socially
withdrawn with retarcled activi$, speech and
thinkingor there may be restlessness and anxiety.
Patientsmay come to their cloctors becauseof
insomnia,appetite ancl weight loss and impaired
sexualperformance.
(3) The same symptoms appear in the
depressivephasethat usuallybegins the onset of
manic depressivedisorder. If a doctor prescribes
an anti-depressantin such a case,it could trigger a
manicepisocle.
(4',)Not so rarely, depression
C may occur witith
delusions.rs. Hallucinatoryvoices may accusethem,
or they may have morbid visions. Such delusions
and hallucinationsmay suggestschizophrenia.But
prescription of an antipsychotic drug exposes
such patients to risks of incurable movement
disordersas side-effects.Currentlyavailableanti-
depressantagents take 2-3 weeks to become
effective. This is because neurotransmitter
receptorst4ke that long time to adapt to the drug
and increasetheir sensitivigl.
169 PsychotropicDrugs
(lll) Anxlety dlsorders :
Eachof us has experiencedanxie$ and fear.
Apprehension,fright, nervousness,panic, etc. are
some of the few words which are used to describe
anxie\r. The terms, anxiegl and fear are often
used interchangeably.Thus anxieg describesan
unpleasant state of mental or psychological
tension often accompanieclby physicalor physio-
logicalsymptoms in which one feels helplessand
exhausted.
Panicdisorder can be low-level ancl constant.
Symptoms are anxiet5l, nervousness,fatigue,
headachesancl insomnia.Physicalsymptoms can
include heart pounding, abnormalheart rhythms,
chest pains, trembling, sweating, nausea,
cliarrhoea,clizziness, faintnessanclrapiclbreathing.
The symptoms resemblethe body's normal flight
or fight reaction to arousal by danger. Chronic
anxieg and panic attacks thus may be causeclby
abnormal aclrenergicactivi! in the central and
peripheralnervoussystems.
Many psychiatristshave linked phobic dis-
orders to panic disorders. Examples are
agoraphobia(fearof open spaces),claustrophobia
(fearof cramped spaces)and social phobia (feeling
of embarrassmentwhen among people). Doctors
treat panic disorder with heterocyclicantidepre-
ssants or MAO-I plus alprazolam.In adclition,
benzodiazepineminor tranquilizers can help
patientsto face phobic situationwith lessanxie!.
The diagnosticand statisticalmanual of mental
disorclersdivides anxiety disordersinto eight sub-
$rpes :
(D panic disorclerwith or without agora-
phobia,
(iD agoraphobia without history of panic
disorder.
(iii) socialphobia,
(iv) simpiephobia,
(v) obsessivecompulsive disorcler,
(vi) generalizeclanxietll disorder,
(vii) post traumatic stressdisorder,
(viii) other anxiety disorder.
The two anxiety clisordersmost common in
prevalenceare panic and genBralisedanxiety. In
generalizedanxiety disorders, the anxiety is
persistentand the patient complainsof feeling on
edge whole time. Typicalsymptomsof generalized
anxietydisorderincludemotor tension(trembling),
palpitations,tachycarclia,nausea,and emotional
overresponsiveness (e.g., irritability, difficulty in
 :rinciplesof MedlclnalChemistry(Vol.ll) 170
concentrating,insomnia).While the panic dis-
orclersconsist of recurrent spontaneoussuclden
episodesof fear and apprehensionwhich are not
restricted to any particular situation or set of
circumstances.Hence, these attacks are unpre-
dictable.Symptomsincludesuddenonsetof palpi-
tations, chest pain, choking sensations,dizziness
ancl depersonalization.There is often a secondary
fear of dying, losing control or becoming insane.
Virtually all clepressedpatients suffer from
anxiegl, although the reverse may not be true.
Anxieg has an arousalfunction,whereasdepre-
ssron inhibits. In most clepressions,these two
states exist together, albeit with contradictory
functionsand in oppositedirections.
Cardiovascular,respiratory, neurological,
, gastrointestinal,u nnary etc. are some of the
i systemswhich are affected by anxiety. A number
of diseasescan also generateanxiety.
'. Anxieg symptoms may be caused by many
:fneclicines.Similarlydiscontinuationof a variety of
ricrugs (e.g. anxiolytics) may cause prominent
':,anxietY.
The psychotropic drugs can be clivided into
three major categoriesclepenclingon their clinical
usefulness,namely
(1) The neuroleptics,
(2) The anti-depressantsancl
(3) The anxiolytics.
(l) The neuroleptlcs :
(Antlpsychotlcs or mafor tranqulllzers) :
These clrugs are used in the treatment of
psychoses. Clinically, these agents counteract
hallucinationsand delusions, alleviate psycho-
motor excitementancl facilitatethe social acljust-
ment of the patient, by reducing dopaminergic
rctivig in the CNS.
(2) The antl-depressants (Thymoleptlcs):
Theseinclucle
(a) MonoamineOxidaseInhibitors
(b) Tricyclic Anti-depressants
(c) LithiumSalts.
They increase the availabilitSlof catechol-
amines and indoleaminesat the appropnate
receptorsites of the brain.
(3) Ihc anxlolytlcs :
(antlanxletyagents or mlnor tranqulllzers)
Thesemainlyinclude:
(a) Benzodiazepinsand
(b) Propanediol carbamates e.g. meprobamate
PsychoEopic
Drugs
These agents reduce the turnover of
norepinephrine and serotonin and facilitate
y-aminobutyricacid activity.
10.2 NEUROTEPTICS
The drugs from this category, are used
primarily for the treatmentof schizophreniaand
mania though many of them have anxiolytic
actionstoo.
Classlflcatlon:
The antipsychotic agents are best classifiedin
terms of their chemicalstructures:
II I Phenothiazines (Chlorpromazine)
II II I{auwolfiaalkaloicls(Reserpine)
lilrl Butlrrophenones(Haloperidol)
IlVl Miscellaneousdrugs
[|l Phenothlazlnes:
During second world war, a number of
phenothiazinederivatives were prepared in the
laboratoriesof the Frenchpharmaceuticalmanu-
POULENC' in Paris.Among these,
facturer.'RHONE
were seriesof lO-(Z - climethylaminoalkyl)pheno-
thiazineswhich on pharmacological screeningwere
found to possess strong anti-histaminic
properties. The 1O - (2-dimethyl amino)
propylphenothiazine(Promethazine) was studied
extensively. Among its diverse pharmacologic
properties are seclative,anti-histaminic,antiemetic
ancl potentiating effect on the sedative action of
barbiturates.
With the synthesis of chlonpromazine,by
Charpentierin 195O,a very large number of
phenothiazinederivatives possessingdiversified
pharmacological activities like skeletal muscle
relaxant, tranquilizers,seclative-hypnotic,potent
ant ihis t am i n i c , a n t i s e r o t o n i n , a n t i e m e t i c ,
analgesic,anthelmintic,u rrnaryantiseptic have
been developed. Furtherdeparturefrom the basic
phenothiazinering structure resulted into the
developmentof new triryclicring compounds.
Promethazinewas prepared as a potent anti-
histaminicagent. It causedpronouncedsedation.
Similar CNS-depression was encounteredin yet
another anti-histaminicanti-cholinergicdrug, di-
phenhydramine,in which the etheral oxygen
isostericallytakes the placeof one CH2group. An
attempt to separateCNS-clepressant.activity from
anti-histaminicactivigl, chain length increasewas
suggested in promethazine.The resulting
 ol Medicinal
Principles flol. ll)
Chemictry 1n Psychotropic
Drugs

compound promazine was further modifiecl by Il Trlcycllc system

traditional chlorine (e.g., chlorpromazine)to (a) Most of these compounclshave either a
stabilize aromatic phenothiazinesystem against six-memberecl centralring e.g., Phenothiazine class
premature oxidative detoxification. Thus an
(6-6-6\
antipsychoticdrug, chlorpromazinewas bomed.
OR
ChlorpromazineHCI is the first major tranqui-
(b) s ev e n - m e m b e r e c l c e n t r a l r i n g
lizer of the phenothiazinegroup of compounds.lt
is usecl in the treatment of anxie$1,tension, e.g.,lmipramineclass(6-7-6).
agitation and in lesseningmotor activi! in both
psychoneuroticsand psychotic patients. The
antiemetic effects of chlorpromazinemake it
valuablein the treatment of nauseaand vomiting
associatedwith carcinomatosis,uraemia, acute N'
infections, nitrogen mustard therapy, racliation I(c
H:).,- N (C H r),
sicknessanclvomiting cluringpregnanqy.
I rl rpnrmine
, Structure-Actlvlty Relatlonshlp :
(c) Compoundshaving larger central ring are
usually devoid of significant antipsychotic
activigr.
(ci) Compounclswith a five-memberedcentral
N R" nng e.9., Carbazole,also lack antipsychoticactivity
IR ancl procluceonly anti-depressanteffiects.
t0

Phenoth
laT.lncs

Thesesubstancesare chemically constituted

by a lipophiliclinearlyfusedtricyclic system having
a hydrophilicbasicamino allqylsiclechain.
(CH').r
- N(CH.r)z
The sitesof moclificationsthus inclucle:
Carbazole
lll Tricyclicsystem
(e) Analogsof triqycliccompoundsthat lacka
Ull The basicaminoalkylsiclechain.
central ring, are (with some exceptions)generally
Relativeto ring A, ring B plays a lessspecific clevoiclof antipsychoticactivi!.
role in binclingof tricyclic neurolepticto receptor
sites.The apparentnecessi$lof a tricyclicring for
neurolepticactivity perhapsstems from a require-
ment that ring B be fixecl in such a way that it can-
not assume certain conformations that may
prohibiteffectivebinclingto the receptors.The ring CH(CH,').
-_
substituentslike chloro or trifluoromethylincrease
the lipophilicity of the molecule. Moving the o
substituentsto other positions of the ring may Pinroz-ide
create steric factors unfavourable for drug-
receptorinteractions. It is clearlyderived from benperidol.
Principlesof MedicinalChemistry(Vol.ll) 172 Psychotropic
Drugs

(a) Phenothlazlne derlvatlves : (c) If oxygen is introcluceclinto the 1 position

of the 3-aminopropyl sicle chain, it results into
The activity of these compounds is cleter- potent anti-clepressant like actionse.g..
mineclby:
(i) The natureof siclechainat C-lO.
(iD The amino group of the siclechain.
(iii) The substituentson the aromaticnucleus. LI
N
(t) Modlflcatlons of the dkyl slde chaln : I
CO ( CH, )-, N tC .l l ,) .
(l ) Maximum potenqy is retaineclwhen there
Chlolacizinc
is a three carbonspacingbetweenthe basicamino
group ancl the nitrogen of the phenothiazine (cl) Introcluction of a CH: substituent at
nucleusbecauseit permits the maximum resem- position Z or position 3 of the sicle chain
blanceof phenothiazineconformationwith that of apparentlyhas little influenceon activi!.
most preferredconformationalform of dopamine. (e) Brictgingof positicn 3 of the side chainto
Thehomologueof chlorpromazine in which the ring position I of the phenothiazinenucleus,reduces
and amino nitrogen is separatedby four methylene the neurolepticactivigr,e.g.,
units cloesnot proclucedesired effects.
(2) Substitution.on the propylene chain of
1O-(3-aminopropyl)phenothiazinesmay also
influence antipsychotic potency.

\tC F l , t'

(ll) Modlflcatlons of the baslc amlno group :

(a) Maximum neurolepticpotency is.retained
hz 3
cH2cH'cH2
- N(CH.r),, in compounds having a 3" amino group. ln
compoundswith Zo or I o amino group, activity is
either reclucecl or abolishecl.
for example (b) In general, alkylationof the basic amino
(a) Introduction of methyl group at position group with groups larger than methyl, decreases
1, clecreasesantipsychoticactivity ancl may result neuroleptic activity.
in imipramine-likeactivity. (c) ln pharmacologicalscreenrng,porency ls
founcl to be decreased by replacement of
(b) lf position 1 of the side chain is incor-
climethylamino group of chlorpromazinewith
porated into a cyclopropane ring, potent pyrroliclinyl, morpholinyl or t hiomorpholinyl
imipramine-likeactions are noted in pharmaco- groups.
logicalscreening. (cl) Activity is retaineclor increaseclif the
amino group is incorporateclin qyclic.systemslike
pipericlylor piperazine,e.9., Mesoriclazine,ancl
Carphenazine.
The piperazinecompoundsare more potent
N CI
than aliphaticcompoundsancl have relativelyless
I aclrenoceptorblocking activity while pipericline
,-C\ /.cHrN(CH1)2 group is intermediatein potency and possesses
H, CH
more antimuscarinicactivity than chlorpromazine.
Principlesof MedicinalChemistryflol. ll) 178 PsychotropicDrugs

G) Piperazinephenothiazinesmay be esteri-
fied with long chain fatty acids to produce slowly
absorbed, longacting,lipophilicprodrugs.e.g.,
cocH2cHl

Hr)r- -cH2cH2oH

N CF.,
Carphenazine
(e) Bridgeclpipericlineclerivativesthough are (, H :), - C H .,C H ,'OC O(C H .)N C
bulky, still retain a high clegree of neuroleptic
activigl.
Fluphenuz.ine
decanoate
(0 Introduction of hydroxyl, methyl, hydro-
xyethyl groups at position 4 of piperidine and Prolongecldurationis due to its slow release
piperazinemoieties results in increasein potency from an oily clepot.
e.9.,
(h) Significant activity is retaineclwhen N-4
S
piperazinesubstituentsare as largeras phenylethyl
or p-aminophenylethyl.
N (i) ln the series of 4, 4-disubstituteclpiperi-
ctinyl propylphenothiazines, azaspirane and
CH:),
chlorspiraneare clinically effective antipsychotics.
Briclged
piperidinc
dclivarive

CH: ) r-
H " ) ,-
Azaspirtrne

N CI cl
N

(_ H:). - - CH. CH :) t -

Prochlorperazine Chlorspiritnc
 of Medicinal
Principles flol. ll)
Chemistry 174 Psychotropic
Drugs

Table to.l : Phenothlazlnes

l0
N
I
Rl

e = R' = H)
( R,
Ph e n o th ia zin
Gcnerlc Name Rl
(A) Propyl dldkylemlno sldc chaln
(i) Promazinehydrochloride - (cH2)3N(CHJz. HCI
(ii) Chlorpromazine - (cHz)sN(CH3)2
(iii) Triflupromazine - (cH2)3N(CHr)z
(B) Alkyl plpcrldyl slde chaln : ntta
(i) Thioridazine
-(cH ,;;
Hrct
(iD Mesoridazine o <- scH3
-(cH,);

(C) Propyt plpcrazlnc sldc chaln :

(i) Prochlorperazine - ( c H . ') r - N N-CH

(ii) Trifluperazine

(iii) Thioethylperazine - scHzcH3

(iv) Butaperazine cH3

-co(cHz)3

(v) Perphenazine
-(cFl2).r- N-cTCH,oH

(vi) Fluphenazine
- ( CH, ' ) r - N N-CH.CH.OH

(vii) Acetophenazine
- ( CH' ) r - N N-CH,CH.OH

(viii) C-arphenazine
-(cH,).r-
- cHzcH3
Principles
of MedicinalChemistry$ol. ll) 175 Psychotropic
Drugs

The most wictely usecl Z-substituentsare Cl Cllnlcally used agents :

chlorpromazine, prochlorperazine, perphenazine); Reserplnetype alkalolds
CF:(trifluprom.vine, trifluperazine,fluphenazine);
SCHr(thioriclazine).
Replacementof a terminal N, N-diethvlamino
group by pipericlino exploits the clecreasing R
.alencyangle at the 3o-nitrogenof the latter so
rhat accessof the basic group to anionic sites
rnightbe improved.
flll) Phenothlazlne Rlng Substftutlon : H]COC oR'
The potency of antipsychotic phenothiazines tl
s mainly influenceclby both, the location and the
o ocHr
rature of substitutionon the tricyclic nucleus.
(a) With some exceptions, substitution at Generlc Name
rcsition Z is optimal For neurolepticpotency. In
general,potenqyincreasesin the Followingorder of Reserpine
:osition of ring substitution :
l< 4 < 3 < Z
(b) 2 -Su b sti t u t io n o f t h e p h e n o th i a z i n e
-ucleusincreasesthe neurolepticpotency in the oct-lr
ollowing orcler:
oH< H<CN<CH3 <Cl<CF3 z. Rescinnamine ocH3
(c) ln general, disubstitutionancl trisubsti- OCH
-.rtion of neurolepticallyactive Z-substituted o
tl
:,irenothiazines have little effect or are harmfulto -C-CH:CH ocHr
:otency.
(cl) Oxidation of the sulphur at S-positionin
l'rtipsychotic phenothiazinesdecreases neuro- Deserpicline
eptic activi!.
ill Rauwolfia alkalolcls :
Reserpineand its analogs hacl been wiclely
-sed in the treatment of serious mental and
clisorclerswhich are characterizeclby
-notional
aryingclegreeof CNS excitement. Reserpineis [ll] Butyrophenones !
i,lw mainly of historicalinterest in psychiatryancl Butyrophenoneswere clevelopeclby P. A .
s generally not usecl for this purpose. Toclay, Jansen,a Belgianscientistfrom pethidinefentanyl
,=erpine and related compounclsare used mainly glpe analgesics.
s anti-hypertensives. Their antipsychoticactions A number of compouncls from a series of
;re due to their ability to inclucethe releaseof fluorobu$rophenones was founcl to be effective
rrogenicaminesfrom storagesites. in the treatment of major psychoses.Haloperidol
The Rauwolfiaalkaloiclsare classifiedinto four stanclsas a prototype of this series.
l--aJps :
(i) Reserpinetype alkaloicls
(ii) Yohimbaneisomers o
ll
(iii) Ring E heteroqyclics C- (cH.)rNR

(iv)Aimalinegrpealkaloids
Principles
ol MedicinalChemistry(Vol.ll) 176 Fsychotropic
Drugs

(a) Haloperldol : (f) Paraperldltle:

C ON ( C H 1 ) .

NR= NR=

CI

The most potent neurolepticsin this seriesare

Other clinicallyused agentsfrom this category 4-aminobutlrrophenones in which
are (l) The aryl group is optimally a 4-fluoro-
(b) Splroperldol : phenyl,
(2) The briclge between the benzoyl and
amino group is an unbranchedpropylene
and
(3) NR is a 4-substituteclpiperidinylor tetra-
NR= hyclropyrictyl.
N Createst potency is notecl in tertiary amines,
I H- but a few seconclaryamines are also active.
The SARof this categoryz is cletermineclby :
(1) The nature ancl position of aryl substi-
(c) Benperldol : tuents.
(2) Variationof carbonylfunctionalig.
(3) Alterationof the propylenebriclgeand
(4) Changesinvolving the basicamino group.
In all types of antipsychoticcompouncls(e.g.,
phenothiazines,reserpine,bugrophenones) the
NR= aromatic center shoulcl be separateclfrom neuro-
leptic nitrogen by 4 atoms for optimum anti,
psychotic activig.
o
(d) Droperlclol :

NR=

o
(e) Trlfluperldol :

H a l o p cr r d r l l
NR
CIt,
It binclswith D2 clerpaminergic
receptor due to
structure similarity with antipsychoticpheno-
tnlaztne.
 Prlnclplesof Medlclnal
Chemlstry
flol. lt) 1V
Psychotroplc
Drugs

havlng conslderableanfl_
OH

cl

Haloperidol

(a)
Structureslmilarltywlth reserplnealkalolds.

C SO,'N(CH.r)z
tl
611- (CH2)z
_ _ CH,

(b) Thlothlxene

Centbutinole;n=3;R=F
Its a new neurolepflcand anti-hypertenslve. X
It ls a hybrid skeletoncomprisingof reserplne
CHCH2CH2_R
and buglrophenoneleads.
(c)
Other bugrrophenoneslike terfenadtneand where:
oxatomide have anti_histaminicactivlty wlthout (i) Clopenthlxol:
sedativeactions.Theyare used in the treatment
of
searcnaland perennlalallergicrhinltis.
- cH2cH2oH
Rlng andogs of phenothlazlnes:
Theseagentsare derived by isosterlcreplace_ (ii) Flupenthlxol
is stmllar ln structure wlth
ment of one or more atoms,/groupsIn the structure fluphenazlne:
of the effectiveantipsychoticphenothlazlnes.
(l) Chlorprothlxene:
X = CF.,;
i N _ CH,CH2OH
It is an isostereof chlorpromazinein whlch the \,--l
nitrogen is replaced by a methylene group.
0ii) Tefluthlxol:
Refeasedin 1961,lt ls effiectivein the treatment
of
schizophrenlaand ln psychotic and several
neuroticconclitions. X = CF.r;6F;R

S
(iv) Plflutixol:

c cl
tl
cHcH2cH2
X = CF..,;
6F;R = - |r | cH2CH2oH
- N(CH.r)2
Prlnclplesof iledlglnal Chemlrtry(Vol.ll) 178 Plychotroplc Drug!

ocH3
HsCz- N
tl
cH(CH,,)2N(CHj)"
(d) Dimeprozan
(b)Sulpedde : & - -H; & =-SOzNHz
Ralo,riPrlde:Rr=-OCl-lr; &=-Br
Benzamldederlvatlves (e.g., sulplrlde) were
developed thro'rgh the modlflcatlon of the
structure of procalnamlde.Thls led to metoclo-
pramlde, a drug havlng antlspasmodlcand antl-
dopamlnlc effect In the perlpheql as well as
showlng rcme antlpsychotlcactlvlty.
N
I
cH.]
Cloplpaz.rn

N
I
cH3
(c) Ondansetron
Ondansetronhas anxlolytlc - antlpsychotlc
actlvlty, besideslts use to control .nauseaand
cH.r- vomitting of cancerchemotherapy.
Loxaplne
Thecentralrlng was o<pandedto 7-membered
heterocyclicstructure motivated by posslbllity
that antlpsychoticand anti-depressantwill be
presentIn one drug. Loxaplnehas a central rlng
having the unique oxazeplnestructure.lt ls used -N
cH(cH2).r
in the treatment of acute and chronic
schizophrenla.
MlscelLeneousenflpsychotlc drugs :
Various compounds whlch are dlstinctly
different from the phenothlazinesand thelr rlng (d) Pimozlde
analogsand ftom the f,uorobuglrophenones, have Pimozlde,fluspireleneand penfluridolare the
been successfullyused ln the treatmentof major outcome of structuralmodlflqatlons on buglro-
psychoses. Followlng are examples of such phenones.
clinicallyusedagents.

,C4CH
H(CH2h
- N
Hlc

(a) Mallndone hydrochloride (e)Flusplrelene

Principbsof MedicinalChemistryOol. !l) 179 PsychotropicDrugs

Butaclamolis a potent dopaminergicblocking

agent and is an effectiveantipsyclroticagent.

c l{ 1
/-Dcplcnyl

OH
(c H r )rc I
cH-cH,Cl{'cH,.,_
I
OH
B u t a c l a n ro l
Similarlythe neuropepticle,neurotensin(NT),a BMY-I 4802(atypical
anripsychoric)
co-transmitterin clopaminergicneurons,may have Fluoxetineexhibits relatively selective inh[bi-"-
an antipsychotic effect through modulation of
tion of serotonin reuptake. lt has its own sicle-
dopaminerelease.
effects of occassionalnausea, nervousnessand
F insomnia.But its selectivity leaves it without the
OH side-effectof clry mouth, constipation,biurred
vision, orthostatichypotensionor abnormalheart
- N
cll(cH.')r rhythms. lndeed patient may not be able to
commit suicidewith an overdose.
F
( c) Pentluridol
IO.3 MECHANISMOf ACTION OF ANTI-
(0 Apomorphine
PSYCHOTIC
OR.NEUR,OLEPTIC
DR,UGS
(1 ) I n 1 9 58,Carlssonsuggested that dopa-
FrC mine. besidesa precursor of noraclrenalineand
CH,CH,NHCH] aclrenaline,might also functioninclepenclently
as a
neurotransmitter.

Fluoxetine

Acetylcholine Dopamrne
D o p a mi ne Acetylcholine
Dopamine Acetylcholine
Normalp erson
person
Psychotic
ilg, l0,l (schizophrenia)
(b)
Principlesof MedicinalChemistry(Vol.ll)
(2) The highest concentrationsof clopamine
have been found in the thalamus, the hypo-
thalamusand some of the basalganglia.
Dopaminenot utilizeclin receptorreactions,is
degracledto homovanillicaciclin the brain,
HrCO
HO
H or n o v u n i l l a
i cc icl
(3) Dopamine usually has a depressantaction,
particularlyon cells that have been excited by
glutamate.
(4) In the control of emotional responses,the
hypothalamus is closely associated with the
re.ticularancl the limbic systems, the latter,
incorporates a balanceclcomplex of excitatory
(ACh)anclinhibitory(clopamine)components.
(5) There is an eviclencewhich suggests that
schizophreniais associateclwith the presence of
greaterthan normal amountsof clopamine(inhibi-
tory component) at central synapses in the
striatum anclother brain regions where it resultsin
overfiring of neurons. Since Parkinson'scliseaseis
associateclwith a deficiency of clopamine,
neuroleptictherlpy may evoke Parkinsonismlike
symptoms.
Thereare five iclentifiedclopaminepathwaysin
the brain, each accounting for an effect of
neuroleptics.The mesolimbic pathway is most
H,').,- N
CH,
8-chloro-
2,3,4,4-tetrahydro H I
-3-methyl-5-phenyl-
|H Domperidone
-3-benzazepine-7
-ol
180 Psychotropic
Drugs
probably involvecl in the antipsychoticefficacy of
neuroleptics. The nigrostriatal pathway is
implicated in extrapyramiclalside-effects.The
mesocorticalpathway is probably involved in
seclativeaction ancl hypothalamic-hypophyseal
ancl incertohypothalamicpathways are respon-
sible tor the neuroendocrinesicle-effects caused
by neuroleptics.
(6) The antipsychoticdrugs e.g., chlorpro-
mazine acts by
(a) Increasingmetabolicrate of clopamine.
(b) Blocking dopamine (D2) receptorsand
reserpinelike clrugs which cause depletion of
clopaminergicneurons.This resultsin an increasein
concentrationof excitatory component (ACh) ancl
clecreasing the concentration of inhibitory
component(clopamine). There is an evidenceof a
direct quantitative correlation between the
antipsychoticactivity of various neurolepticdrugs
and their ability to block H-clopaminein rat
neostriatalslices. All the antipsychoticdrugs
increasethe turnover of dopamine in the brain.
Some of these clrugs also have a seclative
effect, becauseof their cr-aclrenolyticancl anti-
histaminergicproperties.
(7) Antipsychoticclrugsshift the balance(a),
in favour of ACh (c), this clifferenc.ebetween the
concentration of dopamine ancl ACh, leads to
an increasein extrapyramiclaleffects (posture and
the involuntaryaspectsof movement). Hence all
antipsychotic drugs are always associatedwith a
varylngdegree of extrapyramiclaleffects.
,----------it---
,
I
!,cl
l'
_Y--',\ N i c
Clozap
C
azrptne
Hybridof -benzodi
t\
(dotted
andphenothiazine portion)
Principlesof MedicinalChemistry(Vol.ll)
Cirlorpromazine
tie. 10.2 : Slmllari between conformations of chlornromazine ancl clonamine
Extrapyramiclalsymptoms take their name
from cone-shapeclstructures, callecl pyramicls,
that extencl from the meclulla oblongata to the
spinal cord. The pyramiclslie along the course oF
impulse transmissionsthat govern voluntary
movement. Involuntaryr movementsare controlled
along another pathway involving the corpus
striatum. Becausemovement clisordersarise in a
pathway outside that of the pyramicls, they are
termed as extrapyramiclal.Clozapine appears to
work in mesolimbicancl mesocorticaltissues.but
not in striatal tissues,thus avoiclingprocluctionot
extrapyramidal symptoms" Unfortunately, clinical
use of clozapine was subsequentlycurtailed by
incidence oF blood clyscrasias,and especially
agranulocytosis, a potentially lethal non-
neurologicaldisorder.The agent most similar to
clozapineis fluperlapine.
(8) The superimposability of the contor-
mations of clopamine ancl chlorpromazine blocks
the dopaminereceptors.lt furtherexplainswhy an
effective antipsychotic phenothiazine derivative
should possess three carbons in the side chain,
separatingthe two nitrogen atoms.
10.4 THERAPEUTICAPPTICATIONS
(1) Antiemeticagents
(z)Potentiation of actions of, analgesic and
seclativeagents.
(3) In treatment of moclerate and severe
mental and emotional disturbances.
181 Psychotropic
Drugs
OH
HO
Doparnt
ne
Refapseoccurs in about 3O-4Ao/o of patients
within a year of corhmencing treatment. illnesses
in patients on maintenanceclrug therapy are often
precipitatecl by acute stress (e.g., traumatic life
events) or chronic stressassociatedwith patient's
lite-sgrle. Lite events ancl factors related to
excessivelevels of stress at home, particularlyof
an emotionaland interpersonaltype is responsible.
In actual practice of medicine, therefore,besides
drug therapy,socialand psychologicaltreatments
are alsoemployeclForbetterresults.
IO.5 ANTI-DEPRESSANTS
Depressionis an intensenormal responsebut
usually of relatively brief clurationto loss and
disappointment. lt is a prominent feature of
severalmood d isorclers(affectiveclisorders).
It was proposedthat clepressionis causeclby
climinisheclformation of norepinephrine ancl
serotonin.Theseneurotransmitters are essentialto
provide motor drive to limbic system to increase
the sense of wellbeing, goocl appetite and
psychomotor balance.
Affective clisordersare characterizeclby mania
and depressioni.e., two extremesof mood. Mania
is characterizeclby elevation, hyperactivity ancl
uncontrollable thought and speech. While
depressionis characterizect by feelingsof intense
saclnessor worry, agitation, self-depreciation,
physicalchanges(insomnia,anorexiaand loss ot
clriveanclenthusiasm) and mentalslowing.
Principlesof MedicinalChemistryflol. ll) 184 PsychofopicDrugs

Although manic-clepressiveclisorder is a Classlffcation of Antl-depressent Drugs

different mental illness from schizophrenia,the (1) Monoamlne oxldase lnhlbltors :
manic phase of this disorclercan be mistakenfor Phenelzine,
schizophrenia.One clifference is that mania Isocarboxazicle,
appears abruptly, whereas schizophrenic Tranylcypromine,
symptoms develop unsuspecteclover a long Dextroamphetamine
periocl. There is also frenzieclphysical activity. (2) Trlcycllc Antl-depressants:
Patientscan becorne irritable and violent in the (l) lmlnodlbenzyl derlvatlves : lmipramine,
manic phaseanclthere may be clelusionsof great Desipramine,Chlorimipramine and Trimi-
wealth,power,geniusor beinga famousperson. prarnrne.
Manic-clepressiveclisorder is treatecl with (ll) Dlbenzocycloheptanederlvatlves :
lithium salts ancl the minimum effective dose of A m it ript yline, prot ript ylene,
anti-clepressant. Lithium seemsto act by inhibiting Nortryptylene
phosphatidylinositol4, S-diphosphate,a second (lll) Dlbenzoxeplnederlvatlve : Doxepin.
messenger in many neurotransmittersystems. (3) Second generatlon clrugs :
Overuse of anti-depressantscan cause rapid (|) Blcycllcs:Viloxamine,Zimeldine.
cycling between mania ancl clepressionevery 3 (ll) Trlcycllcs : Dibenzepine, A moxapine,
months. lmprindole.
Llthlum : ln manicclisorders,
lithiumion, long (lll)Tetracycllcs: Mamprotiline,Mianserin,
known as an uricosuric agent, was founcl to (4) Otherc:
control the manic phase of manic depressive Trizodone,Nomifensine,Bupropion,Fluvo-
clisorclers.
Both lithium and neurolepticshave been xamrne.
founclto be effective in prevention as well as in (5) Benzodlazeplnes: Alurazolam.
the managementof manic episocles.Neuroleptics (6) Electro-ConvulslveTherapy.
proclucea faster responsethan lithium salts but (71 Mlscellaneous :
cause more sicle-effects(e.9., confusion,over- (i) p-aclrenoreceptoragonists, e.g. Salbu-
seclationslurringof speechand ataxia).Lithium is tamol, Clenbuterol.
effective also for patients with bipolar disorclers (ii) ThyrotropinReleasingHormone.
whether depressiveor manic Carbamazepine is I0.6 MONOAMINE OXIDASEINHIBITORS
now emerlfing as an alternative prophylactic in According to the current concept, nore-
both bipolaranclunipolardisorclers. pinephrine is synthesizeclwithin the nerve cells
Lithium carbonatedecreasesthe releaseof ancl stored in intraneuronalgranulesat pre-syna-
norepinephrinefrom the pre-synapticterminals ptic nerve endings from which, it is releasedby
ancl enhancesits reuptake, actions opposite those nerve impulses into the synaptic cleft where it
of the tricyclic anti-depressants. In addition, it interacts with the post-synaptic receptors. The
released norepinephrine is inactivateclmainly
decreasesthe severi$l of the swings between
through :
mania ancl clepressionthat occur in the bipolar (l) its reuptakeby the neuron,
clisorcler.Lithium (l) acceleratescatecholamine (2) its conversionto normetanephrine(meta-
reuptake(2) stimulatesNE turnoverancl(3) inhibits
bolite) by the enzyme, catechol-o-methyl-
NE-release.Lithium salts inhibit phosphati- transferase.
dylinositol synthesisand may therefore interfere
with Ca++mediatedintercellularcommunication.
Affective disordersresult due to changesin
normal metabolismof neurotransmittersby means cH - cHl - NHo
of substances(like Monoamineoxidases;COMT I
en4/mes)that promote or preventthe production OH
of the catecholamine.
Normetanephrine
Principles
of.Medicinal (Vot.ll)
Chemistry 1&l Psychotropic
Drugs

Sitc ol lrtrnrcsttlfilgc [:l l c c ttrcr c l l

Metaholitcs N'lctaholitcs
+I
I
I Intlitgritrtullr'
DOPA+ Dopanrine Pool I
NE
M'()Stne

. ro.3
Norepinephrinereleasedintraneuronaliy,either
spontaneouslyor by interferencewith the binding
mechanismsby reserpinelike c'lrugs,appearsto be
inactivatecl by mono amine oxiclase enzymes
(MAO). The MAO is a family of enymes located
primarilyin the outer membranesof mitochondria.
Theseenzymesinactivatebiogenicaminessuch as
norepinephrine, clopamine,serotonin,tryptarnine
ancl glramine by conversion to alclehyclesancl by
subsequent oxiclation or recluction to an acicl or
alcohol. (Oxiclativedearnination)e.g.,
CH.-_C H )- NH,
I continuedfor atleast6 months after recovery.
OH
' N o r e p i n e p h r in e
MAO
CH-CHO + NH.,
I levels in the brain and prevents the fall in amine
OH
Aldehydemetahclitc
In general,the major metabolicpathway for
the catecholaminesin peripheral tissues is by
COMT,while the major route of metabolismin the
brain,is by MAO enrymes.
Among many compounds exhibiting MAO
inhibition,incluclingcocaine, mescaline. chlor-
p r omazine, ha rmalin e, an d p-chlormercuri-
benzoate, only hydrazines ancl aralkylamine
compounclshave therapeuticsignificance.
M onoam i n e o x i d a s e i n h i b i t o r s c a n b e
clramaticallyeffective especially where anxietli,
panic and hypersomniaare prominent.They are
usually reserveclfor treatment of depression in
patients who fail to responclto electroconvulsive
therapy and/or tricyclic drugs becauseof their
potential for toxic interactionswith certain foocl
and drugs.
The response to anti-clepressantsis usually
clelayecl,with a time-lag of upto 3-4 weeks,
although the seclativeancl anxiolyticpropertiesof
some drugs may provide partial relief of insomnia
ancl anxietlr immediately. In severe depressive
episodes,anti-depressantmedicationshould be
The events leaclingto the cliscoveryof anti-
depressantactivity of MAO inhibitors occurred
simultaneouslywith, but indepenclentlyof, those
leading to the clevelopmentof imipramine, a
tricycfic anti-clepressant. In 1952, Zeller ancl co-
workers, cluring clinical stuclies of iproniazid
(a structuralanalog of isoniazid)as an antituber-
culosisagent tounclthat it elevatesbiogenicamine
levels incluceclby reserpine.Brodie and Shore in
1957 showed that iproniazicl, especially in
conjunctionwith reserpinecoulclcauseexcitement
in animals.Basedon theseobservations,Klineand
co-workerstested iproniazid in depresseclpatients
with favourableresults.
CO NHNHCH( CH. ) ,

lproniazid
Principles
of Mbdicinal (Vol.ll)
Chemistry 1u
Becauseof serious sicle-effectsof iproniazid,
subsequentlyvarious substituteclhyclrazinesancl
hyclrazicleswere preparecl ancl testecl For their
cligical utility. All MAOs act by increasingthe
ava.ila-ble concentration of neurotransmitters NE
ancl 5-HT. The clinically usefulagents are listeclin
Table10.2
Sfructure-Activity Relatlonshlp :
(t) Hydrazlne derlvatlves
C H "C H . NHNH.
Phenelzinc
(a) Although hyclrazine(NH2NHz)lackssigni-
ficant MAC) inhibitor properties,alkyl substi-
tutions may conferstrong activity. Among a series
of alkyl substitutecl hyclrazines, maximum
effectivenessis observecl with ethyl hydrazine.
Increasingthe size of the allqylgroup beyonclethyl
clecreasesthe activig. Similarlyisopropylhyclrazine
is more effectivethan n-propylhydrazine.
(b) In general, cycloalkyl substituteclhydra-
zinesare about equipotentwith the corresponcling
n-alkyl hydrazines.
(c) A hydrogen atom on the hydrazine
nitrogen bearing the alkyl group is essentialfor
MAO inhibitory action. Unsymmetricalclialkyl
substituted hyclrazines(RlRzNNHz)are clevoid of
significantactivity. Symmetricalclialkylsubstitutecl
hyclrazinesRtNHNHR2are generally less effective
than the correspondingmonoalkyl clerivatives.
Certain clisubstituteclhydrazines are cleaved
metabolicallyto releasea highly active monoalkyl
derivatives.
(cl) Hydroxyalkylhydrazinesare usually less
effective MAO inhibitors than the corresponding
alkylhydrazines.However, etherification of free
hyclroxyl group may increase the activity
considerablyancl sulfur and imino analogswere
about half as active.asthe ethers.
(e) Aromatic ring substituents with polar
groups generallydecreasethe activi$.
Psychotropic
Drugs
(2) Hyclrazlclederlvatlves :
o
tl
CH, NHNH- C
CHr
Isocarboxazid
(a) Unsubstituted hyclrazicles,(RCONHNHz)
clo not significantly inhibit MAO.
(b) Monosubstitutecl hydrazides (RCONH-
NHR1), however, may enhancethe MAO inhibito4l
activity.
(c) In compounclshaving generalformula,
(CHr)z
RCONRzNHCH
the main functionoFalkyl group appearsto be that
metabolicallyto release
of a carrier;it is hyclrolysecl
the MAO inhibitory substituted hydrazineat the
target organ. All hydraziclesare highly hepatotoxic,
anclare no longeravailable.
(3) Non-hydrazlnelnhlbltors of MAO enzymes:
A large variegl of chemicals like alcohols.
amiclines,guanidines,isothioureas,xanthinesand
amphetaminesinhibit MAO in vitro. These
compounds,however,are essentiallydevoid of in
vivo MAO inhibitoryactivity.
H,C NH,
H .,C - N - C H 3
(S)(+) - Amit'lamine
This compounclis a non-hepatotoxic,compe-
titive reversibleMAO-A inhibitor.
Principlesof MediclnalChemistry(Vol.ll) 1S PsychotropicDrugs

Table lO.2 : Cllnlcally useful MAO lnhlbftors

Compound Chemlcal Narne Structure
l. Iproniazid 1-isonicotinoyl-2-isopropyl- hydrazine
coNHNHCH(CH.)"

Phenelzine 2- Phenylethyl-hyclrazine CH"_CH,-NHNH"

3. Pheniprazine 1-Methyl-2-phenylethyl-hycl
razine cHr-CH-NHNH,

4. Tranylcypromine Trans-2-phenylcyclo-propylam
i ne
HC
H2

5. Parglline N-Methyl-N-Z-propynylbenzylamine CHz-N-CHr-C=CH

o
6 . lsocarboxazid 1-Benzyl-?-(5-methyl-3- tl
CH.'- NHNH- C
isoxazolylcarbonyl)hydrazine

o
il
coNHNHC2H4C
Nialamide N-Benzyl-p-(isonicotinoylhydrazino)-
propionamide
HrC - H
o
il
c

Moclobemide 9Hr QH,

I
,-C=CH 9H, -CH-N-CH, -C=CH

Clorgyline
Deprenyl
Principles
of MedicinalChemistry(Vol.ll) 186 PsychotropicDrugc

Other compounds of interest are (cl) Cyclopropylamlnes : e.g.,

(a) Harmala alkalolds :

,/H
-C-C \*",

Hr CO H,
N
I Cypromine
H cH-,
Harmrne It is a powerful MAO inhibitor, both, in vivo
anclin vitro.
Tranylcypromineis dehydrogenatedby MAO
to an imine which then adds to an essentialthiol
group of the apoenzyme ancl thereby cleprives
HrCO N MAO of further activity. Molecular modifications
I include : nucl€ar substitution, widening of
CLI
H cyclopropane ring, chan.gingacetvlenic bond to
Harrnrline cloublebonclor small rings.
Therapeutlc usefulness of MAO Inhlbftors :
Harmine and Harmaline,both possessconsi- MAO-inhibitorsinhibit MAO enryme system
derab\eMAO inhibitoryactivi!. anc\ cause an increase in the concentration of
(b) lndoleallqrlamlnes : endogenous epinephrine, norepinephrine and
serotonin (5 HT) in storage sites throughout the
Both c-methyltryptamine (a) and a-ethyl- nervoussystem.The increasein the concentration
tryptamine(b) inhibitMAO in guineapig liver. of monoaminesin the CNSis the basisfor the anti-
clepressantactivity of these agents. Nafazodone
inhibits serotonin reuptake generally but blocks
R activigl of a serotonin receptor subrype; 5HTz.
I High activigr of 5-HT2 receptor has been linkedi
cHr- cH - NH,,
with suiciclenature.
N
These drugs are used in the treatment of
H psychoticpatientswith milcl to severeclepression.
The treatment results into an increaseclsense of
(a)R= C H , ( b )R = 6 . , 9 , well being, increased clesire and abiligr to
communicate, elevation of mood, increased
Disubstitutionat 0-position of amino ethvl physical activity and mental alertness and
sicte chain decreases the activi while substi- improvementin appetite
tution of the inclolenucleushas vatiable effectson Drugs that Inhlbft the reuptake of monoannlnes
MAO inhibition. at the synapse !
(c) Propargylamine derlvatlves : Sincethey clo not inhibit rnonoamineoxidase_s.
e.9., these clrugs rarely produce stimulation or
excitement but may produce phenothiazinelike
mild sedation.They are effective in the treatment
of emotional ancl psychiatric disorclersin which
depression is a major symptom. Mianserin,
CH.'- N - C H ' - C: CH clanitracenand iprincloleare suchweak Monoamine
uptake inhibitors that their anti-depressant
Prrgyline activi! must be based on other mechanisms,
perhapson antagonismto serotoninor histamine
or decreasein norepinephrine-dependent adehy-'
It is a powerfulinhibitorof MAO enzymes. late cyclasein the forebrain.
Principles
of Medicinal pol. ll)
Chemistry 187 Psychotropic
Drugs

IO.7 TRICYCLICANTI,DEPRESSANTS Structure-Actlvlty Relatlonshlp :

It is a classof compouncls,structurallyrelated (1) The maximum anti-depressantactivity
to phenothiazineclass of antipsychotic agents,
the prototype of which is imipramine. results on separationof the basic amino group
from the tricyclic nucleus by a propylene briclge.
Significant activity is, however, retainecl by the
ethylene congener. But compounds with chain
length exceecling propylene are relatively in-
effective and produce toxic effects. Branchingof
l c H r ) 1- N ( C Hr ) 1 the side chain does not affect the activity e.g. The
Imipramine activity of trimipramineis basicallysimilarto that of
Following the discovery of the therapeutic rmrpramtne.
value of phenothiazinederivativesin treatment of
psychiatric clisorclers,many structural analogs
were testecl.Among theseiminodibenryl(clibenza-
zepine) analogs (1951) were also synthesizecl.
During clinical evaluationof a number of such
compounds,in 1957, investigatorsfouncl them
effectivein some depressivestatesancl relatively
ineffectivein generalagitateclpatients. C H ? C H C H .,
'l
The anti-clepressant
activity of relatecltricyclic cH..
compounds depenclson
Trirniprarnine
(l) The natureof tricyclic system
(2) The natureot siclechain
(Z) Nuclear Substftutlons:
(3) The natureof the basicamino group.
(a) Variecl effects have been observed with
Most compounclshave 7 to 8 membered
nuclear substitutionof aminopropyl clihyctro-
centralring. Some potent anti-depressants
have a
Zo amino group and in some casesa side chainof clibenzazepines e.9.,
two carbon atoms.
(l) Dlbenzazeplne-dlerlvatlves
:
Imipramine(a) is the prototype (introcluceclin
I 958) of anti-depressantclihyclroclibenzazepines
although its action may clerived, at least in part,
from a metaboliteclesipramine(b),

(1) 3-chloro derivative r Less active than

rmlprarTltne.
(Z) 1O-(CH3)2
derivativeis equipotent.
(3) Z, 8-(CH3)2clerivativeis ineffective.
(b) Nucleardisubstitutiongenerally decreases
(a)R = C H. ( b ) R = H the activity.
 of MedicinalChemistry(Vol.ll)
Principles
(c) Anti-clepressant activity of amlno
alkylatecl iminostilbenes parallels that of
corresponcling derivatives.
clibenzazepine
CH.,
(cl) Several piperazinopropylclerivatives are
founcl to be ineffective.
(cH:)r- -tt
(e) lmlpramlne analogs :
I
(1) X = NH -+ Equipotentto imipramine
(2 ) X= S- + Eq u i p o t e n t
(3) X = O -+ Significantanti-histaminic
(2) Dlbenzocycloheptane dedvatlves :
(a )R = C H . ( b) R = H
Amitriptyline(a) is the prototypeof this class.
It is equipotent to imipramine. lts metabolite,
Nortripldine (b) is about Z to 5 times more potent
than the parent compound.
188 PsychotropicDrugs
Structure-Actlvlty Relatlonshlp :
(a) A 3-Cl substitution on amitriptyline
enhances the potency while a 3-CH3 group
diminishesthe CNSdepression.
(b) Double boncl between I O and | 1
positions,increasesthe activity.
(c) ln the higherring homologue,the clibenzo-
cyclo octaneis more effective.
(cl) Severalnovel bridgeclring ether derivatives
of amitriptyline are founcl to Possess very
powerfuI anti-clepressantactivift.
o
I
c
I
C
(e) Several amitriptyline analogs with the
following structure are clinically effective anti-
clepressants.
The alkenelinkageintroducesthe possibili! of
cis-transisomerism into the structure where, in
some instances,one form is more active than the
other.
(i) X= O +D o x e p i n e
(ii) X = S -+ Prothiaclene
(iii) X = SO + Potentanti-histaminic.
Prlnclplee
ol Medlclnal pol. ll)
Chemlstry 1@ Psychotroplc
Drugs

(3) Slx membcred centrd rlng antl-dcprcssants A conflguratlonof three carbon slde chaln
The effectlveanti-depressantdrugs ftom thls favouringthe closenessof the termlnalbaslcgroup
categoryare, to the benzenerlng lmparts neuroleptlcactlvlty
whlle the conffguratlonleadlngtc
of terminalbaslcgroup on a ben:
antl-depressantactlvlgl.Forexample,maprotiline
an antl-depressantagent,hasa longerslde chain
lR - (CH2)3NHCH3]enabllngthe overlapplngof basic
nltrogenon a benzenerlng whlle a neuroleptic
C H C H ,C H-, N ( CH1). agentbenzoctamlne (R= CHzNHCH3) cannot have
Melltracene suchoverlapplngand ls devold of antl-depressant
action.

cH,cH'cH,,
- N(CH1)r
Dimethacrlne
DlbenzoIb, el blcycld 12,2, 2l-
octadlene derlvatlvcs
Neuroleptlc benzodlazcplneleads r
Dlbenzodlazeplne
cH2cH2GH2NHCH3
Maprotlllne derlvatlves:X = NH;
Slnce the slte of action and actlvl$l spectra Y- H
depend on the partlculartype of sterlc confl-
guratlon whlch the trlqyclic rlng systemadopted, dozaplne:X = NH;
minor modlflcatlons in structure produced Y=c|
dlffierentactlvlty - neuroleptlcor antl-depressant. Dlbenzothlazeplne
Followlngsterlcparameters are ficundto govemthe X = S;
dertvattves:
shapeof the trlqyclicsystem. I
(a) The angle whlch the planes of the two
cHr Y=H
lateralaromatlcrlngs makewhen prolectedtowards Other drugs l
one another.lt ls known as the angle of bendlng (l) 9-edrcnoccptorAgonlsts r
(a). Thusthe neurolepticagentsllke phenothlazlne Salbutemol : lt has got antldepressant
or thloxanthenehaves = 25oand are relatlvelyflat actlvlty. lt Increasesturnover of 5-HT and
mole c u l e s . Whlle dlbenzazeplne and noreplnephrlnebut do not affect dopamlne
dibenzoglcloheptadiene(o, = 55o to 65o)possess metabollsm
antl-depressantactlvity and are relatlvely bent (2) Sympathomlmetlc Stlmulants r e.g.
molecules. Dextroamphetamlne,plpradrol and methyl
(b) The angle of annellatlon (0): tt ls the phenlndate are occaslonally used as antl-
angle at whlch the two lateralaromatlcrlngs are depressants.
attachedto the central rlng. lt ls lO" for neuro- (3) Second generatlon drugs Trlcycllcs :
leptics(e. g; phenothtazlne and thloxanthene)and Dlbenzeneand Amoxaplne are effectlve antl-
4O" for dlbenzazeplne. depressants.They act by blocklng dopamlne
(c) Thc anglc of torslon (y) r lt deflnes receptors.Amoxaplne has both the antldepre-
twlstlng of the planesof the two lateralaromatlc ssant and neuroleptlcpropertles.They have low
rlngs relativeto eachother. lt ls O" for neuroleptics antichollnerglc,less sedatlveeffect but hre more
and ls upto 20" for a central 7- memberedrlng constlpatlveand causemore sexual dlsturbances
containingtrlqycllcagents. thanamltqrptlllne.
Prlnciples
of Mediclnal flol. ll)
Chemlstry 1gt PsychotroplcDruge

Tertracycllcs: (b) Nomlfenslne : lt blocksreuptakeof both

l. Maprotlllne : lt has selectiveactlon on
catecholamines. lt has markedanxlolytlcproper-
ties and is well toleratedon heart.
2. Mlanserln : lt Is adrenoreceptor anta-
gonist and leaclsto increaseln neurotransmltters
outflow thus potentiatingthe effectof norepine-
phrine.lt has pre-synapticblockingaction ancl
also anti-histaminlc propert5l.lt has low antlcho-
linergiceffectsand hasno cardiotoxicigr.
N
norepinephrine and dopamlneand has no effect
on 5-HT.lt haslow antlchollnerglc
and cardlacslde
effect.
It was wlthdrawnIn 1986as hemolytlcanemla
was reportedln numberof cases.
(c) Buproplon: lt works throughdopamlne
relateclmechanlsms.lt lacks sedative, antl-
muscarinicand vascularside-effect.Overdosesof
it causesconvulsions.so lts marketlnghas been
halted.
(d) CnHs

T
R
R= (l) (CHtzN(CH3)z
+ Thlazeslm
Blcycllcs I Mlansenn( I ,
(a) Vlloxazlne : lt inhibits caiecholamine (ii)(cHt3N(cHJz
reuptake and blocks muscarinicreceptors. lt
causesless seclationand has no cardlactoxicity. (iiD (cH.,).r
- - CH.
Efficaqyis like other conventionaldrugs.
(b) Zlmeldlne : lt is specificin blocklng5-HT
Ail are potent antl-depressants.
reuptake. lt is more effective in serotonergic
clepression. (e)
(c) Iluvoxamlne : lt has mlnimum effect on
noradrenergicprocessesand has no antlchollnerglc
effects.Common side-effectls nausea.
cH -cH -
OH
F.c H2
(CH2)aOCH3
Cyprolldol
ryHCH3

N - OCH2CH2NHz

Fluvoxamine
(4) Mlscellaneous agents :
(a) Trazodone : Structurally slmllar with
fluorobut5lrophenonesrtrazodone ls an effective
antidepressant.lt blockspresynapticuptake of 5 -
HT. lt has low sedatlon, antlchollnerglcand
aclrenergicside effiects.lt is the most novel drug
usedin the treatmentof depressionand anxlety.
F H
Paroxetlne Sertraline
Sertraline
(g) Cocaine,the local anaesthetictropane
alkaloidof cocaleaves,is a potent noreplnephrlne
reuptake lnhlbltor, but has no antl-depressant
activity.Slmllarlytriqyclicsllke mlanserin(l) and

- cHzcH2cH
N
I
(CH2)r- N(CHr)2
Trazodone lprindole (2)
Principles
of Medicinal (Vol.ll)
Chemistry 19'l
iprindole (2) are both excellentclinicallyuseclanti-
depressantsbut clo not block norepinephrineor
serotonin reuptake. Hence it is likelv that
endogenousdepressionis a biologicallyhetero-
genous synclrome,and a single hypothesis
explaining the mode oF action of all anti-
clepressantdrugs is probably not feasible.
Other compounds that are not considereclto
be anti-clepressants but clo inhibit monoamine
uptake include chlorpromazine,benztropine,
chlorpheniram ine and methaclone.
Cllnlcal Incllcatlons of Antl-depressants :
(l ) Depression,
(2) Enuresis,
(3) Chronic;:ains,
(4) Obsessivecompulsive phobic states
(5) Catalepsyassociateclwith narcolepsy,
(6) Acute pain attacks,
(7) School phobia and attention cleficit
clisorclers
in children,
(8) To prevent onset of cluster ancl migraine
headaches.
Combinatlon Therapy : At times, it is
preferreclto give two tricyclic anti-clepressants in
combinationthan a single one. This way one can
prevent some side-effects. A TCA with an anti-
psychoticis also given at times, a commonly usecl
combinationis with perphenazine.Lithium is
combined for psychosisand bipolar depression.
Chlorcliazepoxicle is aclcteclif anxie$ syndrome is
severe.
To combat over closage, O O Ca ln e . o r
:ropranololmay be given.
I O.8 ANXIOTYTICDRUGS
The antianxiety agents or anxiolytic clrugs are
:nemicalagents which are used to control the
---.of stress ancl the feelings of cliscomfort,
: - fearful anticipation of untowarcl events
*a I r' lr'roria in patientswith neurosesanclmilcl
;,tr r:1i,-,: states.In aclditionto the disturbance
:r' rr:,r: -,,Deranxietyusually involves changes
tr- -n'':'*f :"ndautonomicnervoussystem.
-e .-: : systemoF the brain locateclin the
-:s- :-- - . e part of the cortex ancl in the
:l".:.:t-ira-
__< is the seat of the emotions. The
rer c-,:- '_ -::ion of the brain is involved in
anxt er. sri:-a: : -.ce the weal<ening
of its inhibitory
action trea:s-: :. e:sri:nulation and anxietv.
Psychotropic
Drugs
The antianxieg agents also produce skeletal
muscle relaxant efFects.With the possible
exception of benzodiazepines,most anxiolytic
clrugsare either sedativesor shareatleastsome of
the propertiesoFtraditionalseclatives.
Alcohols, centrally acting drugs lil<e barbi-
turates (amylobarbitone), neuroleptics,propane-
cliols (meprobamate)etc. have been usecl to
alleviateanxiety but theseare now outdatecl.
Benzocliazepines, due to their low toxicig and
clinical effectivenessare the most widely usecl
anx ioly t ic s . I n a d d i t i o n , t h e y h a v e a l s o
anticonvulsant,muscle relaxant, sedative ancl
hypnoticproperties.
Mechanlsm of action of anxiolltic drugs :
The limbic system incorporatesa balanced
complex of excitatoryancl inhibitory components.
The emotional states result partly by
(1) the natureof the activig generatedin the
limbic systemanctpartly by
(Z) the intensity of the arousal response
evol<eclin the cerebral cortex by the flow of
impulsesalong the ascendingreticularsystem.
The spontaneous increased activigr of the
limbic neurons is inhibitectby benzodiazepines
through a probable interactionof benzodiazepines
with either GABA or glycine (the major inhibitory
neurotransmitters in brain), result ing int o
presynapticinhibitory processesin both brain ancl
spinal cord.
Structure-Activlty Relatlonship of Benzo-
dlazeplnes :
(l) Ring A Substitution:
Electron withclrawing substituents(Cl, NO2,
CF3)at position 7 increasethe activitv while substi-
tuents at positions 8 and 9 anclelectronreleasing
substituentsat position 7 decreasethe activitv.
(2) Ring B-Substitution :
Methyl group substitution at position
increasesthe activitv.
Introcluction oF a carbonyl function at
position Z and/or a phenyl substituentat position b
5 increasethe anxiolytic activity.
The following moclifications decrease the
activitlr :
(i) Reduction of the carbonyl function at
oosition 2.
(ii) Introcluction of a hydroxyl group at
position3.
(iii) Heteroaromaticor cycloalkylsubstituents
at position 5 (exceptionbromazepam.
 of MedicinalChemistry(Vol.ll)
Principles 1C2 PsychotropicDrugs

Table lO.3 : Currently avallableanxlolytlc drugs

\.-
R.r

Generlc Name R2 IUPAC Name

Diazepam H 7-chloro-1,3-dihydro-1
-methyl-5-
phenyl-2H-1,4-benzodiazepin-2-one
Oxazepam 7-chloro-1,3-dihydro-3.hydroxy-S-
phenyl-2H-1,4-benzodiazepin-2-one
Nitrazepam 1, 3-dihydro-7-nitro-5-phenyl-2H-1,
4-
benzodiazeoin-2-one
Medazepam 7-chloro-2,3-dihydro
{

phenyl-1H-1,4-benzod
ta
Flurazepam (CHz)z
N ( C2H5)2 7-chloro-1 m
-(2-diethyla
(2-fluorophenyl)-1,
3-di
benzodiazepin-2-one
Prazepam lcHr,,. 7-chloro-
1-(cyclopropylmethyl)-1
,o'
-CHz-cH- cH2 dihydro-5-phenyl-2H-1,4-
benzodiazepin-2-one
Lorazepam 7-chloro-5(-o-chlorophenyl)-
dihydro-3-hydroxy-2H-1,4-
benzodiazepin-2-one

H OH
Nq6./NHCH''
\ \a -.oo*
CH,',
J 'o

Bromazepam Chlorazepate Chlordiazepoxide

l, 3-dihydro-5-(2-pyridyl)- 7-Chloro-2,
7-Brorno- 2-
3-dihydro-2, 5-phenyl-
7-Chloro-2-methylamino
2H-1.4.benzodiazeoi
n-2-one I H-1,4-
dihydroxy-5-phenyl- 3H-l, 4-benzodiazepine-4-oxide
benzodiazcpine-3-carboxylate
 of MedicinalGhemistry(Vol.ll)
Principles 194 PsychotropicDrugs

Table 10.5 : Pharmacoklnetlcparametersof benzodlazeplnes

Compound Half'llfe Metabolltes

Alprazolam 1 2 - 1 5 h o u rs alpha-hyclroxyalprazolam

Chlordiazepoxicle 5 - 30 hours desmethylchlordiazepoxide, desmethyldiazepam,

oxatLepam

Clonazepam 18 - 60 hours 7-ar'ninoclonazeparn

7-acetamldoclonazepam

Clobazepam tO - 5Ohours desmethylclobazepam

Desmethyldiazepam 46 - 78 hours

Diazepam biphasic desmethyldiazepam,ox.vepam, temazepam

Flunitrazepam 19 -ZZhours 7-aminoflurazepam

3-hyclroxyflurazepam
7-acetamicloflurazepam

Flurazepam 47 - 1OOhours N-desalkylflurazepam

Lgprazolam 7 - 15 hours

Lorazepam 1O- 20 hours Lorazepamglucuronide

Meclazepam - 2 hours normedazepam,diazepam,clesmethylcliazepam

Miclazolam - 4 hours 1-hydroxymiclazolam

4-hydroxymidazolam

Nitrazepam 17 - 48 hours 7-aminonitrazepam

7-acetamiclon!trazepam

Oxazepam 4 - 11 hours cliazepamglucuronicle

Prazepam 0.6 - 2 hours norcliazepam

3-hyctroxyprazepam

Temazepam 3 - 13 hours temazepamglucuronide,oxazepam

Triazolam 1 . 9- 2.7 hours 1-hydroxymethyltriazolam

4-hydroxytriazolam
 Principlesof MedicinatChemistry(Vot.il)
195
PsychotropicDrugs
(3) Rlng C-Substltutlon :
The following compounclsare the new
leacl
Chlorineand fluorineat the ortho positionancl nucleiin the anxiolytics.
clisubstitutionin both ortho positions increases
the activity. Any substituent at meta or para
position decreasesactivigr.
Modifications in the structure of ring
systems, which include l, S_benzodiazepines
(e.g., clobazam)and the replacement cooc,H5
of fusecl
benzenering (A) with heteroaromaticsystems
tike
thieno (e.g., brotizolam)or pyrazolohave yielclecl
compounclswith similaractivigl.
(2)
Newer Benzodlazeplnes:
( I)
(a) Trlazolobenzodlazeplnes:

N
I
N-.

cH,
\

(3)
CI g= J
X

Triazolobenzodi
azepi
nes
F,C
0 E st azolam:R=H;
X=H. CH.,
(ii) A lprazolam:R=CHr;
X=H
(-1)Gabamodulin
inhibitor
(iii) T riazolam
:R=CHs;X=Cl
(iv) Miclazolam:R=CHe;X=F

(b) Atypical anxiolytics are a new class of

related clrugs called, serenics,which are
anti- H'C
aggressiveratherthan anxiolytic; e.9.,
Hrco
FrQ
o HrCo
NHz (5) Benzodiazepine
antagonrst

Fluprazine
 Princlplerof ltledicinalCh€mistry(Vol.ll) 1$ PeychotopicDrugs

Thcrapeudcuses of benzodlazeplnes:
( I ) In acuteand chronicanxiety
(2) In mixed anxietydepressionstates
coocH2cH3 (3) Statusepilepticus
(4) Myoclonicand petit mal seizures
(5) Neuromuscular disorders
(6) Alcoholwithdrawalsyndrome.
Adverse Effects : Theseinclude skin rashes,
(6) Benzodiazeplneantagonist muscletendemessor weakness.
lllrccllencour Anxlolytlcs :
(el F-blockcrs : Propranololand slow release
formulatlons of oxprenolol hydrochloride are
sometimesadministeredin combinationwith
dlazepamIn chronicanxietycases'
(b) AmoxePlnc:

cH,cH2

,7) Antianxiety BZ-relatedcompound completely N=C

clevoid of anticonvulsantand sedativeproperties. I

I
H

It is an anti-depressantdrug, particularly
usefulin mixed anxietydepressivedisorders.

iSyntheslsof Dtrezcpam
-

*t -a= o
NHz NHCOCH.'CI
I
Chloroacetylation NH, cH.'
C= O C=O cl C= O l

Chloroacetamido
derivative

Dimethylsulphate/
cH. ICH,
I' CH,ONa
Prlnclple!ol MediclnalChemlstry(Vol.ll) 1gl Drugs
Psychotroplc

Non-benzodLezeplne
anxlolytlcs : (C) (a) Pyrazolopyrldlnes:
(A) Propanedlol C-arbamates: e.g. Etazolateand cartazolate
(b) Zoplclone : Zopiclone,a pyrollopyrazine
o has a veqr high affinity for the central benzo-
ll dlazepine receptors.lt ls very active anxiolytlc
hypnotic that does not show hangover effect or
reboundinsomniaafterwithdrawal.

o
Meprobamate
CO
o l,n
cH'o-
tl NN - CH.,
\,__,/

l- " _ NH:
cH.r- cHrcHl Zopiclone
cH,o-
o cooc,Hs
Tybamate
CH:
o I
tl C:Hs
Ilrazolopyrldlnes
(c) Busplrone is an example of anxiolytic-
o antidepressantdrug. lt acts as a partlalagonlstof
serotoninat 5 - HT11 receptors. Geplrone,
lpsapironeancltandospironeare the examplesof
more selectiveanaloguesof busplrone.
Felbamate
Felbamatewas syntheslzed by Wallace
LaboratorlesNew feney In 1954. lt acts at the N
N-methyl-D-aspartate(NMDA) receptor and - cH?cHrcH,cH"
remalns effectlve agalnst Intracerebroventrlcular N
NMDA-inducedclonusIn mice. lt also modulates
Na-channelconductance. Busplrone
(D) IlllscellaneousAgent:
(B) Dlphenylmethanes:

CI

CI
-cH'cH,ocHrcH.,oH

Hydroxyzine Chlormezanone
 of MedicinalChemistry(Vol.ll)
Principles 1S PsychotropicDrugs

Table lO.6 : Newer Benzocllazeplnes

H H
H N N
N

Br

C N
il
(Scrcni rl ( ScPltzonl9'74)
Cloxaz.olirrtr Patn( L e x o ta n i1l9 7 4 )
ti lonraz-e
Oxuzo l am 197I )

ct{r t- H .C : C H
I I .o
N N

o.N CI
CI
F

(RohypnolI 975) (Dornll I 975t

Pinlzepirrn
Estazolltnr Flunitlazcpanr

CH, CH,
I I
N N

CI
o.N C

I 97'i)
(MYolastan
Tetrazcpam
Ciullx;/c|ilnl{ I977)

030
 1 1 . 1 INTRODUCTION
r r.t tNTRoDucTtoN
Analgesiamay be defined ai a state of relatr,,e
I 11.2 OPIUMALKALOIDS insensitivityto pain, where the capacityto tolerate
pain is increasecl without the loss of
consciousness.The term "analgesic"is generally
11.3 OPIO]DRECEPTORS
applied to the agents or actions required to
produceanalgesia.
11.4 CHEMISTRY
OFOPIOIDS Classlflcatlon :
Analgesicsare clivlcledinto two main classes:
1 1 . 5 NARCOTIC
ANTAGONISTS 216
(1) Narcoticanalgesics(Centrallyacting clrugs)
I (2) Non-narcotic analgesics (Peripherally
1 1 . 6 ENDOGENOUS
OPIOIDS 217
actingdrugs)
(l) Narcotlc analgeslcs:
11.7 THERAPEUTIC
USESOF OPIOIDANTAGONISTS
220
Serturner,in 1805, isolatedanclcliscovereclthe
potent analgesicactivity of Morphine, an alkaloid
isolateclfrom the juice of unriped seed capsulesof
the poppy plant, Papaversomniferum.
The term opioid is used generallyto designate
collectivelythe drugs (naturalor synthetic)which
bind specificallyto any of subspeciesof receptors
of morphine and produce, to varying clegrees,
morphine like actions.They are often known as the
narcoticanalgesicsdue to their abili! to produce
drug dependence.With the developmentof many
analgesicswhich are morphine derivatives with
little tenclencyto produce physical dependence,
the term narcoticis no longer useful.

(l e e )
Pdnclphsol MedlctnatChamlstry(Vol.il) u OploldAnalgetlc

Other actlons which are assoclatedwith (b) Benzyllsoqulnollnes:

narcoticanalgesicsare sedation,and constipation
(usefulin the controlof diarthoea).In therapeutic H.rCO
doses,morphinesometimesproducesnauseaor
vomltlng.Therelatedcompound,apomorphlneis a H.rCO
powerfulemeticagent. CH' ocHr

"r",
N Papaverlne

.HCl 'i uro

- CH.,

HO cHro HC ocH.l
I
Apomorphlnehydrochloride o
TI.2 OPIUM AIKALOIDS o
Noscaplne
Opium contalns 25o/oby welght alkaloldal Oplolds act as agonistsof endogenoussub-
compounds.The oplum alkaloldscan be dlvlded stances known as endorphlns (a group of
chemlcallyInto two dlstinct classes: morphlne like peptides),Interactlngwith stereo-
(a) Phenanthrenes specificblnding sites or receptorsin the brain and
: e.g., morphlne,codelne
other tissues.Enkephalinsrepresentthe simplest
and thebaine. membersof endorphins.They are located In short
(b) Benrylisoquinolines: e.g. papaverlneand intemeuronspredominantlyin the areasof the CNS
noscapine. which are related to the perceptlonof pain, to
movement, mood, and behavlourand to the
Oplum dkalotds I regulatlonof neuroendocrlnologlcal functions.
(a) Phenanthrenes s Opioid mediated Inhibltlon of transmttter
releaseIn varlous mammallancells has been
reportedto Involve either a reducflonIn the influx
of Ca++ through activation of k - receptorsor an
increasedoutward K+ conductancethrough Ca++
activatedK+ channelsfollowlng actlvationof elther
lr or o receptors.The inflow of potasslumlons
hyperpolarlzesthe membrane potential. Thls
resultsIn decreasein neuroneexcltability.
Oplolds have been shown to inhibit either
basalor neurotransmitter-stlmulated increasesin
erdenylateqyclaseactlvity In several areas of the
(l) Morphlne,R= H; R = H mammallan CNS. The mechanlsm for opioid
(2) Codeine;R= CHr;R = H Inhibitlon of adenylateqyclaseappearsto involve
stimulationof a i,igh affinity membraneassoclated
(3) Thebalne;R = CH3;R = CHr, A double GlPase,reflecting an actlvation of the guanine
bond between C5and C5. nucleotlderegulatoryr binding proteln,G.
Princlplesof MedicinalChemistry(Vol.ll) nl OpioidAnalgetics

Terminals

Presyna nerve
Opioid ________,?a
receptors .
Blocktherelease
Enkephalin
-+{ of neurotran
smiiter
(opioid) aa
o
Enkephal
incrgir:neurorr
flg. I l.l : Role of enkephalln In paln
lmpulse perceptlon
Thus uncler the influence of enkephalin, pre- The structuralfeatureswhich are recogniseclto
synaptic terminais fail to release neurotransmitter be essential for the perfect fit of a narcotic
in the synaptic cleft ancl pain impulse is not analgesicon receptorsare representeclby A, B, C
receivecl by post-synaptic neuron. The opioicl
anclD.
mecliateclfall in cyclic AMP levels also contributes
to procluceanalgesia.
It is assumeclthat all opioicls(morphine like
drugs) produce their effects by mimicking the
actions of enclogenousenkephalins.
IT.3 OPIOID RECEPTORS
Morphine causes analgesia by selectively
acting on receptors situatecl both in the higher where A Phenylor aromatic portion
centers ancl the spinal corcl. The existence of an B = Quaternarycarbon
opioiclreceptoris suppofteclby :
(l ) SARof morphinelike compouncls.
c Ethylenebriclge

(z) close structural similarities between D = Tertiary nitrogen

opioid agonistsand antagonists. Beckett and Casy (1954) proposed that an
(3) Competitive inhibition of actions of opioicl receptor is composed of three Drominent
mo r p h in e a g o n is ts by narcotic Parts.
antagonists.
The ideal narcotic analgesic structure is
representedby Morphine. Approximately
7.5- 8.54
Atleast(r.,5A Anionicsite
Focusol chargc
/CH, Clvity
N
Flntsurlirce

tlg. lt.2 : Beckett and Casy'smodel of the

Morphine analccslc recentor she
 Prlnclpbeof Medtctna!
Ch€mtstry
Oot.il) &2 OploldAnalgrdcr

(1) A flattenedpart whlch holds the aromatic

p9rtl"l an analgeslcmdleculethroughvan der
-of
Waals'forces.
Anionicsite
(2.) A cavlty or a hollorv portlon whlch enuaps
.
the ethylenebridge.
(3) An aniontcslte whtch holds the tertiaryr Cavity
nitrogen which ls assumed to be lonlsed at
physlologlcal pH. The pKa values of most of
anafgesicsfall In the range of T.g - g.g so that Antugonist
site
tertiary nltrogen ls equally present in ionized and
un-ionizedforms at physlologlcalpH. The drug Flattened
crossesthe blood-braln banler as the free basE Portion
while Interactswlth the receptorln ionlc brm.
The fact that these sttes do not blnd other
substancesand are saturatedby even ve4l low
concentratlonsof oplolds explains the htgnty tlg. ll.3 : Receptor-Druglnteractlon
stereospeclfic orlentatlon of these thJel Sodlumlons are reportedto reducethe affinttlr
componentsof oplold receptols.
of oplold receptorsfor agonlstsand to lncreasethe
SlmilarlyGTP,GDp and tbg non-hydrotyzable affinigrfor narcotlcantagonlsts.lt ls suggested
analogueGpp (Nn)t, reduce-gontstaffintt5rwhite
clivalentions suchas magneslumIncreaselgonist that Na+ protects the sulfhydryl group of
affinlgr.Sodlumlonsand Gpp (NH)pwere foundto receptorsfiom the allglaflng agentsby changing
d9-crease the blndlng of agonistsio p sltes more the conformatlonat oplold receptors.And whlle
effectivelythan to 6 sltes wlth blnding to k sites dolng so, Na' ions modiff the oplold bindlng sltes,
least affected. which are now more sultable for blnding of
The narcotlcantagonistscompetitivelyInhiblt antagonlstmoleculesthan that of the agonlsts.
the accessand blndlng of morphlneagonlststo
WIth the observationthat some anaigeslcs
fh.e..opioid leceptors but tack the Intrinjlc acflvit5r
(abilitltto inlttatethe blologtcalresponse). exhlbit a partial analgeslcaction, there ls a
The lrregular dlstributionof these oplold possibilltythat an opioid receptorconsistsof an
receptorsln the varlousreglonsof centralneryous independent groups of agonlst and antagonlst
system explains the untowardeffects assoclated blnding sltes.That is the relaflveaffinit5rof a drug
with the opiolds; ilke, euphoria,sedative and to these blnding sites, governs the observecl
emetlcactlons. biologlcalresponse.

TSodium
,/ uinding-*lte

Opioid REccptcr Opioid

Nu, Receptor

A nionic
srte Bindingsire
fbrantagonists Bin din sgit e
tbr antagonists

Agoniststructul-e structure
Antagonist
Hg' l1"4 r Sodlumlon effect on oplold receptor as proposcd by Snydcrand co,workers
Prlnciplesof ltiledlclnal
Chemistryfiol. [) & OpioidAnalgetics

Molecular dlssectlon of morphlne :

Morphine is a complex pentacyclicskeleton
which was consideredto be responsiblefor a
number of aclverse effects associateclwith
morphineskeleton.Henceattemptswere macleto
iclentify the pharmacoclynamicallyessential part
through the applicatlonof moleculardissection
concept.In this attempt, varlouscomponentsof
the skeleton are gracluallyremoveclone by one.
Since the resulting new skeletonswere founclto
retain the activity, the part removed, was
consiclereclnon-essential for the analgesic
activity. Various series which can be obtained
through the applicationof molecularclissection
conceptto morphine,are shown as below.
/'^,
N
N-Mcthyhnorphinan
Mor p h i n e
- CH.,
- CH,
H thiambuteneand benzimiclazole
Bc'nzomorphan Meperidine
II.4 CHEMISTRY OT OPIOIDS
Thoughmorphineitself is a potent analgesic
agent, the serious side-effects(like, euphoria,
seclation,respiratorydepression,aclclictionand
tolerance)associatedwith morphine, ihitiated the
attempts for moclificationof this structure, in
order to increasethe therapeuticusefulness and to
widen the clifferencebetweendesirableactionand
toxicity synclromes.
The various modificationsof the morphine
moleculeare categorisedas
(l ) Earlychangeson morphinenucleus.
(2) Moclifications carrieclout in 1929 by Small,
Eclclyancl co-workers.
(3) Moclifications carrieclout in 1938 by Eisleb
and Schaumann.
(4) Moclificationscarried out by Grewe in
1946.
Like other simple semisynthetic analoguesof
morphine(lil<e,cocleine,heroin,hyclromorphone,
hyclrococlone)many other classesof chemically
distinct opioids have been preparecl,some of
which have been employeclclinically.These
incluclethe morphinans,benzomorphans, metha-
dones, phenylpiperidines, propionanilides, and
derivatives.All
these classessharecertaincommon characteristics
with the protoglpe,morphine,which are shown
by heavylinesin the structureof the morphine.

- CH, /cH\
cooc.'Hi

'N- ococ,H,
I HO
BL'ntidone CH ' Prodine Morpliin
o (l) Early changes on morphlne prlor to the
ll stucly of Small, Eddy and co-workers !
N_ c - c)H5
The analgesicpropertiesof morphineare found
coHs in the (-) enantiomer which has the absolute
coH, -l N( CHr ) : configuration 5(IQ,6(5),9(R),l3(S), l4(R).
N cH.. Prior to 1929, many analoguesof morphine
I Methadone haclbeenpreparedby attemptingsimplermolecular
Fentanyl cH2CH'C6H5 moclifications. Lxcept hyclromorphone ancl
Principlesof MedicinalChemlsfy(Vol.Il) u OploidAnalgetlcr

hydrocodone,which remain in clinicaluse, none (c)

were fioundto be superiorto morphine.
Slrnplcr derlvatlves of morphlne pdor to 1929 z
(A)

/t''
N

oR'
(1) Codeine,
R= CHe;R-= H
R= CzHs;R - = H
(2) Ethylmorphine;
(3) Heroin;R= CHsCO;
R-= CHrCO
Codeine, is only one tenth as analgesic as
morphine. This inclicates the need of a free
phenolic hydroxyl for greater potency. While
heroin is more potent despite having a significantly
weaker opioid receptor binding affini!. Reasons-
(1) Heroin is more lipophilic than morphine. (2) lt
gets rapidly converted in vivo to the active
metabolite,o-acet5llmorphineand morphine.
(B)
(l) Dihydromorphine; R= H
(2) . Dihydrocodeine;R = CHr
All the above compoundswere preparedby
modising only the easily changeableperipheral
groups and not accordingto the priniiples of
structure-activityrelationship.
(2) Modlflcatlons carrled out after 1929 by
Smdl, Eddy and co-worhers :
Priorto i929, all morphineanalogueshad been
prepareclthrough non-rational,random searchfor
new drugs.
The first systematiceffort hacl been made by
Small, Eddy and co-workers to investigate the
structure-activity relationship in morphine
moleculeduring their 1Oyear slmthesisand testing
programme, initiated by the National Research
Council of United States. Though their studies
were far more comprehensive,the principaltargets,
chosen for modlficationsin morphine structure
were,
(l) The peripheralgroups and simple skeletal
modificationson aliqyclicring.
(2) The peripheral group and simple skeletal
modificationson aromaticring.
(3) The tertiary nitrogen.
Perlpheral groups on Morphlne :

l6
R = H; R' = H; R" = H.
( 1 ) Hydromorphone, Alicyclicdoublebond
;:--
(zl Hydrocodone;R = CH3;R' = H; R" = H. Alcoholic
,r--- hydroxygroup
R = CHr;'R'= OH; R" = H.
(3) O>qycodone;
(4) MethylhydromorphoneR = H; R': H. --- Etherlinkage
Phenolic
hydroxygroup
R"= CH:.
 ftinciplesof MedicinalChemistry(Vol.ll)
(l) Modlflcatlonson allcycflcrlng:
(a) TheC-6 a-hydroryl group is methylated,
esterified,oxidised, removed or replaced by
halogen in order to get more potent analgesics
e.g., codeine,heroin,chloromorphide.But there is
alsoa parallelincreasein toxicigr.
(b) The C.€ prcscnts thc next slte for
modlflcatlon:
It has got a hydrogen atom and a double
bond. The outcome of catatytichydrogenatiol is
the compounds dihydrocodeinJ ainya'ro-
morphinewhich are the pre<ursorc of"nJ
more potent
ketones, dihydrocodeinone and dihydromor_
phinone.Similar! C-8 p-halo derivativesare fiound
to be more potent analgesicsthan morphine.
(cl C'- 14 z
Introductionof t4-OH group in dihydroforms
yielded the still more potent t 4-hydro4ydihydro_
codeinoneand 14-hydrorydihydromorphinone.
Bridging of C6 and C14 through a ethylene
linkage is also tried e.g., etorphine.lt is about analgesic
2OOtimes more potent than morphlnein man.
CH.,
OH
Etorphine
(d) Introduction of any new substituent
further,does not enhancethe activity. Methyl
dihydromorphineand azidomorphines may be the
exceptions.
( l ) R=H
( 2 ) R =OH
Azidomorphines
& OpioidAnalgettcs
(2) Modlflcatlonson phenyl rlng:
(a) An intact benzene ring is, in general,
essentialfor analgesicactivity.
(b) Modification of C3 - phenolic hydroxyl
group causes a decrease in analgesic
activigr.
(c) Any further substitution in phenylring
generally diminishes activity. The only
exception is l-fluoro codeine which
possessesthe same analgesicactivigl as
that of codeine.
(3) The tertlary nlbogen :
(a) When R ts methyl, n-pentyl or n-hexyl
chain,it resultsinto opioid agonists.
(b) The N-phenylethyt group enhancesthe
activig in desmorphine, cocieine ancl
heterocodeine.
(c) N-allyl ancl N-rycloatkylmethylfunctions
impart narcotic antagonistic properties to the
molecule.e.g., /R
HO o H
R - CH:
Morphine:
CH. - C H =C H z
N
H
N-allylmorphine
(Nalorphine)
Nalorphine was the first clinicaily useful
narcotic antagonist. Its unpleasant psycho_
mimetic and hallucinogenicpropertiespreclucle
its
use as analgesic,though it is a potentiailyvaluable
non-addictdrug with partialagonisticfeatuies.
Principles
of Medicinal
Chemistry
ffol. ll) ffi OpioidAnalgetics

/",

Rro Hl

R, = CH.1
Thebaine;
;R 1 = H
Oripavine
Oxymorphonc N-CH,

(l) Naloxone : lt is a hyclrazoneof naltre-

xone. It is a long acting antagonist with a
comparableduration of action.
R= - C Hz CH =C H z
(2) Naltrexone :
cHr

R= CH,
I
OH
o' ocHr
(Pureagonist
Etorplrine )
This compouncl(l) is about 7OOtimes more
potent than morphine.
(l) Etorphineis a pure agonist (IOOOtimes
more potent than morphine). Becauseof its side-
effect profile its use is restricted to veternary
HO
meclicineas a seclativefor largeanimals.
N a l b u p h in e (z)
Derlvatlves of Thebalne :
Since most of the opioids discoveredin this
periocl(1929 - 38) of morphine protbgpe, though
more potent than morphine, are also associatecl
with the undesirablepsychotomimetic effects. So
Bentley and Hardy postulateclthat it rnight be a
more rigiclmolecularstructurewhich is importantto
act with a single pain relieving receptor ancl not
with other side-effectsevoking centres.This led to
the synthesisof thebaine clerivatives. HO ocH.r
Diel-Alcleradducts of the diene system .in (Partial
Buprenorplrine agonist)
thebaineare known collectivelyas oripavines.
Principles
of Medicinal (Vol.ll)
Chemistry xI| OpioidAnalgetics

Buprenorphineis about lOO times active as It had iived upto its expectations and had
morphine as agonist ancl four times as active as moderate antispasmodic as well as sedative
nalorphineas antagonistand is therefore non-
properties.When Schaumanntested it in the cat,
adclicting anclwithout psychotomimeticeffects.
(3) he was surpriseclby an exhibitionof Straub'stail, a
phenomenon (test for analgesic activity)
associateclwith morphine. Further studies
inclicateclthat mepericlinehacl lO-1Zo/oof overall
activity of morphine. Schaumannsucceededto
spot the segment in morphinestructuresimilarto
cl.lr
I mepericlineas a resultof moleculardissection.
The discoverv of analgesic properties of,-
OH meperidineopeneclnew avenuesfor the searchof
simpler, relativelysmall, structurally uncomplicated
(Antagonist)
Diprenorphine analgesics.

Diprenorphineis a potent narcotic antagonist cHr

(1OOtimes more potent than nalorphine).. The
aclditionalalkyl substitution at C-7 is able to
procluceagonist, partial agonist and antagonist
which suggests an eviclence for an aclditional
lipophilicbinclingsite at the opioiclreceptor.
In general, in morphine series,replacementof
N-methyl group by larger alkyl groups not only
Morphine
lowers analgesic,activity but potentiatesnarcotic
antagonisticpropertiesof the molecule.The only
e x c e pt ion to this ge ne rali s at ion, is t he /'n'
N- phenethylseries. N
(3) Modlflcatlons carrlecl out by Elsleb and
Schaumann : 2

The l93Os saw many new antispasmodicsof

general formula ArCO2(CHz)zNR2, AT2CHCOz- o'
(CHz)NRz and similar structures.The rules of I
isosterismemerging at that time emphasizeclthat c?H-s
reversed esters could be a good variation to Meperid
ine
improve anticholinergic activity. This lecl to
synthesisof mepericlineby Eislebin 193O.
cooc,H

N-CH r

cH,,
o Meperidine
Meperidine
Prlnclplesof MedicinalChemlstry(Vol.ll) NB OploidAnalgetlca

Meperidine was not clesignedby molecular (5) Seriesof compoundswere preparedwhere

dissection.lt was of "reversed"antispasmodlc piperidinels enlargelto 7- memberecl azepinerlng.
structure and its analgesic properties were
observeclcluringpharmacologicalworkup. Proheptazlnels among the more active
analgeslcagents in hlgher rlng homologueof
The various modificationsof mepericllneand
relateclcompoundsare vaguely divideclInto fiour meperldine.
majorcategories:
(a) meperidines
(b) bemiclones OCOC'Hs
Hrc
(c) proclines
H, C
(cl) fentanylseries
N
Structure-Actlvlty Relatlonshlp : I
(l) Replacementof 4-phenyl group by cH.1
hyclrogen,alkyl, aroalkyl or heterocyclicgroup 3, 3- Dimethyl-& phenyl-4- propionoxy
resultsin reducedactivity. hexahydroazepine(proheptazine)
(2) Man y N- s u b s t it u t ed a n a lo g u e s of
(6) Substitutionof the plperldine rlng with
mepericlinehave been prepared.Anilericlinets
employedclinically. 5- memberedpyrrolidinering is alsosuccessful.

I ooc,H5
QCOC"I{5

N N
I I
CH,'CH, CH l

Procliliclene
Anilericline:R=-NHz
(71The presenceof m- hydroxyl group in the
Ph e n e r id inR=-H
e:
(3) Replacement of carbethoxyl group phenylring resemblesthat of C3phenolichydroryl
(-€OOCzHs)by acyloxygroup (OCOC2H')results group ln the morphine.Bemldonerepresentsthis
in better analgesicactivit5l. class.
(4) The replacementof N-methyl group by cooc.,H5
variousaralkylgroups can increasethe analgesic
property mgrkedly.

N
I
CH.3

Bemidone
Replacement of the ester molety by a ketone
functionin the bemiclone,ylelded a new seriesof
- NH- CoHs
(cH2)3
Piminocline compouncls,ketobemidone.
 \

Prlnciplesol ltlediclnalChemlstryOol. ll) N OploldAnalgetics

o o
tl tl
N_C - czH,
I - CzHs
cH,ocH.1

N
I cH2cH'
cH.r

Ketobemlclone Sufentanll
(8) Prodines are the reversecl esters of Ph
meperidines. Here the ester of meperldlne IN.
(COOC2Hs)is replaceclby (OCOCzHs)proplonory
function.
N
I
R
ococrHs
(a) Alfentanil;
cH.r

Rt = cH,'cl-|2
- N N - crHs
cHr \ /

N: N

Prodlne R2= CH2OCH3

(9) In all the abovestructures,phenylrlng and'
& = - CHzCHz- Ph
(b) Carfientanyl;
aryl group are directly attachedto the piperidine
ring. In funtanylseries,phenylring and aqylgroup & =-COzCzHs
are ftom the ring by a nitrogen. Fentanylis about 5OOtlmes as potent as
-parated pethidine.Some of the 4, 4-dlsubstitutedpiperi-
o clines,alfentanyl,sufentanyland carfentanylare
ll even more potent. The latter two have a much
N_ c - c2H5
R2
longer duration of analgesiaand respiratory
depresslonand indicatea differenttherapeuticuse
e.g. anaesthesia.
Methadone Serles :
cHzcH2c6Hs The furthersimplificationof morphinenucleus
by opening of the nitrogen ring, resulted into
Fe n t a n Y! : =
R1- H; &= H
methadone serles of compounds. Methadone,
: Rt = g11u;Rz=-COOCzHs
Lo'fenatanyl
itself possessesanalgesicas well as spasmolytic
Sufuntanills a recentexamplefrom funtanyl properties,
t€fl€s.
 I
rl
')
I

crinciplesol MedicinalChemistry(vol.ll) no OpioidAnalgetics I

Similarlyattempts were also macle to replace

the propionyl group by amicle ,functions
e.g. Racemoramide;it' is more active than
senes
Metnagone methadone.

:Hs o
ll

CH,
Methadone
CHt
of methadonestructurewith
The resemblance,
Racentoranrdc
neperidinestructurecan easilybe seen.

(4) Removal of any of the two phenyl rings

Coc.'H5 results into decreaseclactivity.
(5) The climethylaminogroup is replaced by
CnH: heterocyclicrings like morpholine ancl pipericline.
Hr The clinically employecl agents from this class
I are :
CHr
Methadone

cH - cllr
coc2Hs N

cH - cH3
o
Plrenndoxonc
I
cHr
lsomethadone

itructurc-Actlvlty Rclatlonshlp :
( I ) Unlike meperidineor bemicloneseries,the - cHr
insertionof m-hydroryl group in one of the phenyl
'ings of methadonecausesa markecl clecreasein
rnalgesicactivity.
(2) The methadone derivatives are generally
(and Dipanone
more potent analgesics also more toxic) than
the isomethadoneanalogues. (6) The following are N-demethylated deri-
(3) The replacementof propionyl (COCzHs) vatives which are metabolites of methadone
group by hYdrogen,hydroryl or acetSrlory,led to analoguesin man and are found to retain the
decreasein activi$1. analgesicactivity.

\
Principles
of MedicinalChemistry(Vol.ll) A1 OpioidAnalgetics

Molecularmodificationsof Methadoneinclucle
/'c'tl\ : homologationand cyclizationof cli CH3 -amino
group, reductionof CO to - CHOH, removaland
relocationof CH3branching,isostericreplacement
of one or both phenylsby thienyl,etc. Examples:
Replacement of the keto group by an amiclegroup
resultsinto dextromoramicle.Insertionof an ester
oxygen between blocking groups and carbonyl
H,C H
(as well as a benzyl insteaclof one phenyl) gave
of alphlcctyIrrrcthildol
Mctaholite
clextropropoxyphene. In thiambutene, the
blockingthiophenerings convergeon an amlne
chain and insteaclof an electron rich carbonyl
group, a cloublebond is introcluced.
olt
I

N ((-,Hi).

cHr
llrc
Mctabolitcol' ntcthrtdonc Thiurnhutene

Table I l.l : Compounds from methadone serles

Name R.l R2 R,3 R4

1. Methadone - QHs - QHs - coczHs - cHzcH(cHr)N(CH3)z

Z. lsomethaclone -Q Hs - QHs - coczHs -CH(CH3)CH2N(CH3)z

3. Normethadone - QHs - QH s - coczH5 - cHzcHzN (CHs)z

4. Alphacetylmethadol QHs - QHs - - cHzcH- (cHr)N1611r;,
tHczHs
o - cocH3
5. Dextromoramicle - QHs QHs
_ CHCH,

o ICH,

6. Propoxyphene CoHs cH2qH5 o - ct l - CzHs -cHcHz N (CH3)2

o CHr
Principles
of Medicinal
Chemistry
Uol. I1) n2 OpioidAnalgetics

Table ll. 2
Compounds frorn meperldlne serles

R'4 Rl

(Ro= g, excepttrimeperidine)

Name nr R3 R.4

l. Mepericline CHs - cooczHs

z. Bemiclone CHr - cooczHs -o H
3. Procline CHr cHr - ococzH5
4. Trimepericline CHr CHr - ococzHs
1pu= cH3)
Diphenoxylate -cHzcHzf-(c6Hr1' - cooczHs
CN
Loperamicle - cHzcHzc--(coHs)z
- N(cH3)2
f
o
(rv)Modlflcatlons carrlecl out by Grewe l n These compouncls lack the ether briclge
r946 between the carbonatoms 4 ancl5.

Variouscompounclsbelongingto morphinan Structure-Acttvtty Relatlonshlp :

and benzomorphanseries have been synthesizecl
(l ) The laevo form of morphinan possesses
ancltesteclclinically.
the analges'rcactivity while the dextro form (dextro
methorphan) is having cough suppressant
activity.
N (2) Introductionof a hydroxyl group at C - 3
l(r
enhancesthe analgesicactivity.
7
(3) The ethers ancl acylatecl clerivativesof the
N- n r c t h y l m o r p
nha rn
3-hyctroxylform also have considerableanalgesic
activigl.
 of MedicinalChemistry(Vol.ll)
Principles A3 OpioidAnalgetlcs

(4) The 14-hyclroxylationresults in potent

derivatives with both agonist ancl antagonist
propenrese.g.

( - ) Cy c lor p han

HO
(Strongantagonist)
Oxilorphan (5) Benzomorphans :
The fact, that the removal of ether bridge and
all the peripheralgroups in the aliqyclicring of the
morphine clicl not clestroy its analgesicactivigr,
encouragedMay and Murphy to synthesizea new
seriesof compoundsknown as benzomorphans
(in which the aliqyclicnng was replaceclby one or
two methyl groups).

/cH'
Butorphanol N
R,,

(5) N-substitutionmay result into either

agonist or antagonistdepending upon the nature
HO
of substituente.9., the N - phenylethylor N-p- (R, =R ,=H )
Bcrrzomorphan
amino phenylethyl derivative of levorphanolare
potent analgetics.The N-furylethylancl N-aceto-
Structure-Acttylty Relatlonshlp :
phenone analogues are also potent analgetics.
(l ) Amongst the various substitutions at
while N-allyl derivative (cyclorphan) possesses
Z' position,followingSARis observed
antagonisticproperties.
OH > H>NHz, NO 2, Fanclcl
(Z) The trimethyl compound (R1= Rz= CH3)is
= CH,
about 3 times more potent than the dimethyl
N analogue( R = H ; Rz= CHE).
(3) Insertionof methyl group at c-9 lncreases
analgesicactivity.
(4) Insertion of hyclroxyl group at C-9 (which
is equivalent to l4-hydroxylation in morphine
Levallorphan
series)decreasesthe activigl.
Principlesof MedicinalGhemiatry(Vol.ll) A4 OpioidAnalgetica

(5) The N-phenylethyl analogues always

possessgreater potenqy over N-methyl analogues.
N-CHr
(6) A clear-cutseparationof analgesicactivity
and adcliction liabiliW can be observed in two
o
isomeric forms (cis and trans) of the same
cH.r
compounde.g.
CH.,

(a)
Tonazocine
/CH,

HO CH,
cH'cH'cHr

N
Further separation can also be observed I
L ll,
between the enantiomers of the cis isomer (h)

e.g. (-) isomer is a stronger analgesicwithout

acldiction,while (+) isomer is a weak analgesicwith
high physicaldependencecapacigr.
H1
(7) Pentazocine ancl cyclazocine are the
classicantagonistsfiom benzomorphanseries.
/*
Metazocine
R=CHr
Pentazocinc
R=CH..'CH=C(CHr): (c)
Xorphanol
Cyclazocin
R= - CH" An N-allyl or an N-qyclopropylmethyl group
frequently confers antagonist activity. However,
there are numerous exceptions to this.
e.9., tonazocine (a) is an antagonist ancl the
4-phenylpipericlineclerivative(b) has greater anta-
gonist potency with an N-methyl than with an
N-allyl or N-cyclopropylmethyl substituent.
HO Cyclaztlcine Within the morphine skeleton,a C - 14 hydro4y or
Cyclazocineancl pentazocineare usefulmixed alkory group a n c l a C - 6 k e t o n e a r e necessaryfor
agonist-antagonists.Unfortunately,the former pure antagonist a c t i v i t y ( e . 9 . N a l o x o n e ) .
has considerable hallucinogenic properties, Xorphanolis founclto be a partialagonistat the k-
although pentazocineis a very usefulanalgesic. receptorand antagonistat the p-receptor.Snycler
has suggesteclthat the steric effectsof the C - 14
 Principles
of Medicinat
Chemistry(Vol.ll) A5 OpioidAnalgetics

hyclroxyl group of n.tloxone makes the N,allyl

Etonitazenecan be relateclto morphine.lt is a
subst'ituent equatorial ancl this stabilizes the benzimiclazolederivative ancl is highly porent,
receptor in an antagonist rather than in an havingabout lOOOtimes activigrof morphine.
agonist conformation.The oripavine clerivative,
(6) Antltusslve-oploldal agents : A
l6 - methyl cyprenorphine, is the most selective
compouncl synthesizeclas, and founcl to be, a
nonpepticledelta antagonist.
narcotic antagonistturneclout to be a potent ancl
long lasting antitussive,is (+) butorphanol.
-- cH,<
CHr-€
I
N
C_ OH
IcFlr
ocHr
Cy p r c n o r p h i(nRc= H )

B u to l n l r a n o l
(8) Introcluctionof N-furfurvlgroup into the
benzomorphanshave provicled a new series of
potent agonists and antagonists that are now
unclergoingclinicalevaluation. N- Ct I

- c'H,rS
OII
c,'llr
HO t
I C Hl D i n tctl r o r Ph l r r r

The (+) isomer of climethorphanis essentiafly

new benzomorphan,bremazocineis a
powerful k - agonist of long clurationof acldictive
propertiesancl respiratoryclepressantactivity. lt is
about 2OOtimes more active than morphine.
clevoiclof analgesicancl aclditive propertiesbut is
effective antitussiveagent.
Other examples of antitussive skeletons
inclucle

N
oc.,H5
N
I
cH. ),N(C.H5)'
Hr CO
Etonitazene Dextrolncthorph
ln
Principbsof MedicinalChemistry(Vol.ll) A6 OpioidAnalgetic

- CH.,

c-. R
IOH
HlCO ocHr Morphirranc

6.I 4-endo-Ethenotetrahvdro-thebaine
(7-substituted-
I 6 methyl)
R=
LC\ i l()fl) n, I r
,11.5NAncoTtcANTAGONISTS
R = -('H .
Ciyclorpltrrtt

N/v
-R

OH
HO

OH
( 1940)
Nalorphine I 1-Hydroxyurorphiniurc

R= - CH,

Oxilorphan
N-R
R= - CH,
OH
Butorphanol

-cHt{
o
4-Hydroxymorphone

C- R'
IOH
ocH_]
Oripavine
R =/V
N a l o x o n(eI 9 6l) R =H , R =t - B u
Buprenorphine.
R= -cHr-{
R=CHr,R:CH3
Naltrexone
Diprenorphine
Principles
of Medicinal (Vol.ll)
Chemistry n7
- cH,--{
cH2cH2cl
Chlornaltrexamine
Other examples of narcotic antagonists
include cyclazocine and pentazocine (benzo-
morphan series).The recently describedchlornal-
trexamine,which acts as an irreversiblealkylating
affinity label on the opiate receptor, can maintain
its antagonisticeffect for the astonishingperioclof
3 clays.
Narcoticantagonistscompetitivelyantagonise
the effects of opioid analgetics by binding at
severalsubspeciesof opioid receptor.
The original concept of opioid receptor was
first postulated from the stereo-selectivestuclies
of Beckett and Casy (1954). They proposed a
mode! of opioid receptor. In the early 1970s bio-
chemical binding experiments with raclio labelled
naloxone, whig.hantagonisesthe pharnnacological
effects of morphine, lecl to the identification of
stereo-specificopioid receptorsin mammalianbrain
tissue. ln 1976, Martin classified.opioiclreceptors
into three subtypes: p receptors(morphine-like),k
receptors (ketozocine-like)Ethylketozocine,an
analgesicthat is chemicallyunrelatedto morphine
and o receptors(N-allylnormetazocine-like) on the
basis of effects of opioicls on respiration, heart
rate ancl locomotoractivity.
n STenc tneorv of opiate agonists ancl
antagonistswas proposeclin 1983 by Martin. This
theory helps to understandboth agonisticand
antagonisticfeaturesof opioid. The antagonistic
activity of N-allyl or N-cyclopropylmethylsubsti-
tuent can be explained on the basis of van der
Waals interaction of these substituentswith the
receptor.This may result in moving the nitrogen
away from the positionrequiredForagonism.
OpioidAnalgetics
lolcl rece
Martin and Gilbert tn 1977 have postulateclthe
existenceof three subspeciesof opioid receptors,
designateclas p, k anclo. While Lord et al., in 1977
designated 6. lt is thought that
(i) p subspeciesare involveclin producing :
analgesia,resplratory clepression,euphoria ari:{
aclcliction.
(ii) k receptor subspecies are involved in
producing : spinal analgesia,euphoriaancl addi-
ction.
(iii) o subspeciesare involvecl in producing :
dysphoria, hallucinations,respiratorystimulation
and
(iv) 6 subspeciesrelationshipis still unclearas
selectivecleltaagoniststhat can penetrateBBBare
lacking.
An agonistic or antagonisticactivity of the
drugs depenclsonly on their relative affinity for
these receptor subspecies.
Opiates may cause respiratory depression
which is attributed to the stimulation of both p
ancl 6 receptorspresent in areasof the brain stem
associatedwith control of respiration.Thus p ancl
6 agonist appear to alter respiratoryfunction by
reclucirrgthe responsivenessof both central
chemoreceptorsin the brain stem ancl peripheral
chemoreceptorsin the carotid Lroclyto carbon
clioxide.
TT.6 ENDOGENOUS
OPIOIDS
Enkephalinswere the first endogenousligancls
to be isolatecl from pig brain by Huges ancl
Koesterlitzin the micl l97Os.
The tenn endorf)irirl (enclogenousmorphine)
is used to describe any enclogenous opioicl
 Principlesof MedicinalChemistryOol. ll) n8 OpioidAnalgetics

substanceincluding the two enkephalins,e.g. c[-, Elevatecl levels of imrn unoreact ive
p- , or y- enctorphinancldynorphin.
ft-enclorphinanclenkephalinhave been reported in
The term 'opioid' is applied to any substance human plasma after exercise ancl after surgical
which produces its biological effects through an stress.
interactionwith any of the three major types of Metabollsm :
opioicl receptor (p, k or 6) ancl whose actionsare The enkephalinsancl dynorphin have a much
reversed by naloxone. An opiate is an opioicl shorter half-life than p-endorphin in vivo because
whose chemicalstructureand biologicalproperties of faster hycirolysisby a variegr of non-specific
metallopeptidases. Consequently,p-enclorphinis
are similarto morphine.
the only enclogenous opioicl which cause-s
The three families of peptides that have been sustained analgesiaafter i. v. administration to
isolated and identifiecl are, the Enkephalins,the mice. The two major metabolic processesfor the
Enclorphinsancl the Dynorphins.Met-enkephalin enkephalins are the cleavage of Tyrr- Glyz by
has a sequenceof amino aciclsidenticalwith that membrane bouncl aminopepticlases, which are
inhibitecl by bestatin or kelatorphan,ancl the
of residues 61- 65 of the pituitary hormone
hyclrolysis of Glyr- Phea by a variety of
p-:'lipotropin.This fragment itself has-a potent-
metalloendopeptidases inclucling'enkephalinase',
opioicl activity. which is inhibiteclby thiorphan or kelatorphan.
The opioicl pepticlesare formeclin the brain, the pituitary glancland in the aclrenalmeclullaby the
proteolyticcleavageof three protein precursors;theseare preproopiomelanocortin (POMC)[alsoknow,nas
T
corticotropin-p-lipotropinprecursor (ACTH-p-LPHprecursor)l;preproenkephalinA (also known as
preproenkephalin)ancl preproenkephalinB (also known as preprodynorphin).

Tyr-Gly-Gly-Phe-Leu Tyr-Gly-Gly- Phe-Met

Leu- enkephalln Met- enkephdln

Tyr- Gly-Gly- Phe-Leu-ArgArg- lle- Arg- Pro-Lys-Trp- Asp-Asn-

Gln
Dynorphln

lTy-ClfqfPhelrilet-Tfr-Ser-GluLvs-Ser-GlnThr-ProLeuVal-Tfr-LeuPheLys-AsnAla-l
e | |e Lys-AsrAhTf
-Lp.LpOfcV
i p- Endorphln

i , t ,'
:f!'
cr- Enc'lorphinl- l6 sequence
F Enclorphin1- l7 sequence
6- Endorphinl- 27 sequence

tlg. ll.6 : Structuresof endogenous oplold peptldcs

Principlesof MedicinalChemirtry(Vol.ll) a9 OpioidAnalgetica

processes
Minordeactivating Dipeptidylaminopeptidase Carboxypeptidase
bv kelatorphan
lnhibited

Tyr-GIy-Gly-Phe-Leu/Met

processes
Majordeactivating Aminopeptidase Enkephalinase
Leucineaminopeptidase and
Inhibitedbv theorphan
Inhibitedby bestatinand ' kelatorphan
kelatorphan

Flg. ll.7 z Enzymatlc dcgradatlon of enkephalln

Over 1OOOanaloguesof enkephalineshave
been synthesized.Creater stability towards meta-
bolizing enrymes can be attained by conversionof
the terminal carboryl to - CONH2,or by insertinga
D-amino acicl at this position. The tyrosyl group
which provides a link between the enkephalinsand
thebainederivatives,is an essentialfuature.A 1O.O N
N I
I 1.1 A distance between the aromatic rings of I H
Tyrr and Pheamay be important in the clesignof H
enkephalinswith other aromaticmoieties.
Enkephalinaseinhibitors' might be of use as
analgesicclrugs but to clate there is little clinical EnkephalinanalogueGyr- X- Gly- Phe- Y)
data to support this. Schering and Plough are
reportecl to have developecl an orally active
enkephalinase inhibitor, Sch-34862, which is
currentlvin clinicaltrials.

Me Me

Other physico-chemicaltechniquesthat have

N N. /co'H been used to study the conformations of the
I enkephalins lead to the conclusion that the
H
enkephalinsare flexible moleculeswhose confor-
mation depends upon their molecularenviron-
ment. In aqueous solution at room temperature
they may aclopi several different conformations.
Sch- 34862
 ol MedicinalChemistry(Vol.l1)
Principles a OpioidAnalgetics

Table ll.3: Effect of the positlon of thlomethylene llnkage on the half-llfe of synthetic
Leu-enkephalin derlvatlves
Amicle boncl Half-llfe (min) In human Opioid blncling (versus
Structure replaced serum at pH 7.4 (HPIC etorphlne) (nM) affinig
assay)
Tyr-Gly-Gly-Phe-Leu 12 . 5 256
Tyr-ry(CH2S)Gly-Gly-Phe-Leu | -z 11 . 8 1060
Tyr-Gly-ry(CH'S) Gly-Phe-Leu z- 3 8 s.5
(CH2S)Phe-Leu
Tyr-CIy-Gly-\U 3- 4 13 4
Tyr-Gly-Gly-Phe-y(CHzS)Leu 4- 5 31 8
7O mg parenteralclose of metkephamicl II.7 THERAPEUTIC USESOT OPIOID
(Tyr-Ala-Gly-Phe-NMeG ly-NH 2) was equivalent ANTAGONISTS
to l0O mg of mepericlinein treating post-operative (1) In the treatmentof opioiclinducedrespi-
pain. Side-effectsincluclecla sensation of heavy ratory clepression.
limbs, dry mouth, redness of eyes ancl nasal (Z) Chronic aclministrationof nalorphine
stuffiness which are clifferent from p-selective along- with morphinepreventsor minimizesthe
opiate clrugsand may be clueto the relativelyhigh developmentof clependence on morphine.
affinityof metkephamidfor 6-receptors. (3) Therapeuticagents in the treatment of
The 6-selective pepticle (Tyr-D-Ala-Cly- Phe- compulsive users of opioicls.
D-Leu) has been found to procluce effective (4) Reclucethe intensig of various untoward
analgesiaafter intrathecaladministrationto cancer effects of opioids, e.g., euphoria, drowsiness,
vomiting anclmuscularincoorclination.
patientswho haclbecome tolerant to the analgesic
(5) An abstinencesyndrome characterizeclby
effects of morphine.
abnormal pain, irritabiligl, colcl sweats, diarrhoea,
Classlflcatlon : nausea and 'romiting. These effects usually last
Depencling upon the activity, clrugs can be 4-1O weel<s. N a l o r p h i n e precipitates the
withdrawal symptoms in patients acldicted to
classifieclas :
heroin and methadone.
(a) Pureantagonists: Naloxone (6) ln acute poisoning clue to morphine and
(b) Partialantagonist : Nalorphine,Levallor- related compouncls.
phan ancl Cyclazocine Other narcotlc analgeslc leacls :
(c) Partialagonistsof morphine: Propiramancl
H"rCO
Profaclol.
In particular,the pure agonistmoleculecan be HrCO
converted into a partial agonist or a pure anta- cH"cH., CI
gonist by relativelyminor changesin the structure.
The most common substitutionis that of a larger
moieg (likean allyl or methylqyclopropylgroup)for A chloro homolog of laudanosine,an alkaloid
the N- methyl group of an opioicl. that occursin opium.
Prlndpbs of M6dl-hd Chembtryffol. ll) 2l OploldAndgEt€

p receptors= supraspinal
analgesla;resplratoql
depresslon,mlosls, reduced Gl-motl'llgrand
euphorla.

MeO
Me

Me

Thiorphan (Enkephalinase
Inhlbltor)

H
N- C
Valorphln(p-selectlveagonlsts)

fifluadom (Kappareceptoragonist)

Nephopam
Itlsa novel analgeslcagent having ve4l rapid
onset of action. lt possessesmtntmum side-
R
effects.

9Hr
H,c
csH,'
CHr
CH,t

: R: CH3; CHzC = CH
Aza-cannablnolds
(Cannabisstiva)
Prlnclpbsof Medtclnal
Ghemtsrry
Ool. il) zz2 OploldAnalgetlcs

Table I1.4 : Non-narcotlc antltusslyc agcnts

o p-CH3
o
ttt\ tl
- cHr o -c -c"Hi
o
ocHl/cH

c ocH.r Hrc cHr

Noscapine
tl
o Dextromethorphan Levopro6rxyphene
, OH

'cH'cH?N(CH.r),' c{H,)NH c -o - (cH.,cH.,o),,cHr

tl
o n = 9 (avcragc
)
Chlopheclianol e
lilcnzonatat

o o
il .
ll .c(,Hso7
lCuH c-o--cHrcH,N(c,Hs):j CuHs C- O - CH,CH,N(C.,H.),
cHrso.rH

Caramiphene
Edisylate Carbetanentanc
Citlatc

ooo
 r2.r TNTRODUCTTON
The clrugsacting on CNSare generallyclassified
as specificand non-specificwhich is characterisecl
122 CLASSIFICATION 24 by the close-responserelationship oF that
particular clrug. The specific drugs (either CNS
ANALEPTICS
stimulants or clepressants)do usually atfect
several CNS functions to varying degree at high
concentrations.These effects other than desired
124 PURINES action are regardeclas limitations in selectivityor
unwanted side-effects;e.g. some clrugs exhibit
12,]5 CENTRAL
STIMULANT
SYMPATHOMIMET]CS prominent central stimulation at toxlc level and
others produce milcl stimulation as a side-effect.
12:6 MISCELLANEOUS
AGENTS Examples are found in the local anaesthetics
(cocaine),parasympatholytics(atropine),sympa-
127 HALLUCINOGENS
thomimetics(amphetamine)anclsalicylates.
Thus, the clrugs having the main effect (and
not as the sicle-effect)to increasethe activity of
112-8 PSYCHOTOMIMETIC
DFUGS
various portions of the central neryous system are
collectively called as central nervous system
stimulants. Most prominently, these drugs are
useclin clinicalpractice,as,
l. Analepticsor convulsantsand
Z. Respiratorystimulants.
Therapeutlc Appllcatlons of CNS Stlmulants :
(l) Analeptlcs : Theseagentsfind their use in
elevating the CNS activig in order to lessen
narcosis brought about by the excess of
depressantdrugs.

(2231
 of MedicinalChemistry(Vol.ll)
Principles 24
(2) Respiratory Stlmulants : The respiratory
stimulationmay be broughtabout by either :
(a) clirectstimulationof respiratorycentreof
the medullaby the clinicallyusectCNSstimulants,
cyanideion, anclammoniainhalation, or
(b) by changingthe pH of the blooclwhich is
supplieclto the centre, e.g., carbonicacicl. and
carbon clioxicte.
Since emetic centre is also locatecl in the
meclulla,at therapeuticcloses,a few CNSstimulant
clrugsexert an effect on this emetic chemoreceptor
zone and may be used as emetics in the treatment
of p o iso n in g . CNS stimulant clrugs are also
supposecl to be associated with an effect on
'appetite control centre' and are used to decrease
appetite in the control of obesig (anorexogenic
agents).
Limftatlons of CNS Stlmulants :
(1) Unfortunately,the margin of safeg of
CNSstimulantdrugs is generallyvery narrow and
unpreclictable because a balance between
excitatory anct inhibitory influencesin CNS is
normallvmaintainedwithin relativelvnarrowlimits.
(Z) Theseagents lack selectivit5r of action.
(3) Since on molecular level, the basic
elementsinvolveclin CNSstimulationare similarto
those in CNS clepression,it is not possible to
stimulatethe nervoussystemover a long perioclof
time. This is because the ctrug inclucectCNS
excitability is followecl by clepression,proportional
in depth to the intensigr and dur.rtion of the
stimulation.
II
Mechanlsm of Action
Most of the CNSstimulantclrugsact either by :
(a) blocking the inhibition of CNS activity
incluceclby CI\'ISclepressionof any origin, or
(b) enhancingneuronalexcitation(which may
involve increasedneurotransmitterrelease,more
prolonged transmitter action, stabilizationof the
post-synapticmembrane or decreasein synapric
recoverytime.)
| 12.2 cr.AssrHcATroN
1. Drugswhich are mainly used as analeptics
z. Purines
3. Centralstimulantsympathomimetics.
4. Miscellaneousagents.
CentralNervousSystemStimulants
I2.3 ANAI.EI'TICS
Both inspiratoryand expiratorycentres are
located in the reticularformation of the medulla
ancl together are responsiblefor spontaneous
resprrauon.
Many physiologicalfactorslike temperature,
blooclflow, (changein amount supplied.decrease
in pH ancl oxygen content and increasein CO2
content), irritation of respiratory passages,
vomiting, swallowing,joint movementetc. alter the
rate and clepthof respiration.
Analeptics (take up) stimulate the entire
nervous system (particularly meclulla),therei:yr
counteractingthe respiratorydepressionresulting
from overdose of clepressantclrugs,Theseagents
act as competitive antagonist strychnine)of the
inhibitory transmitter at post-synapticinhibitory
sites.
Large closesof an anaieptic is necessaryto
overcome a highly clepresseclstate of respiration,
these agents may produce convulsions clue to
their abilitv to stimulateall parts of the brain and
hence theseagentsact as an analeptic(ratherthan
a convuisant) , better in the presence of slight
clepression.An aclctitional benefit is gaineclclue to
adrenal catecholamine release resulting into
brochoclilationwhich helps to improve air flow in
the lung. Since in the light of current l<nowledge,
the terms analeptic and convulsant are virtually
synonymous,the respiratorydepressionis best
treateclby other supportive measureslike artificial
respiration, oxygen aclministration,periton..al
clialysisand forced cliuresisfor the treatment of
patientspoisoneciby depressantclrugs.
However, if any analeptic agent is usecl,it is
contraindicatedin epilepsy, hypertension,cardiac
cliseaseancl hyperthyroidism.
Analeptlc agents ln current use :
(1)
\ I f Vc lll) | r ) c
 Principles
of Medicinal
ChemistryffoL il) % CqntralNervousSystemStimulants
Glycine is the simplest amino acicl neuro_
transmitter founcl in brain-stem,,spinal corcl ancl (6)
probably the retina. lt is an inhibitory neuro-
transmitter.Strychnineseems to bincl to the Hrc coN(C2Hs)2
ionophore.The highly lethalconvulsantactionof
strychnineis thusa resultof gtycineantagonism
in
the spinal corcl. Glycine involveirent in cHl
anaesthesiais proposecl.
(z) Cycliron

(7)

C H _r - C = C H :
Picrotoxin
(nolongerused)
ICH,CH3 Hro
J-h.- antagonist,picrotoxin cloes not clisplace
- -
CABA from its receptorsite. But it blockspartiallv DoxapramHydrochloride
at the.GABA-ergicionophore.Severalhypnotii (g)
ana€stheticand anticonvul_sant agents act, at
leastpartiattyas ionophoreagonists.
(3)

Pentylene
tetrazole
(4) Amiohenazole
oN(c,F{s)2
(e)

OR
N
OH
I
(i) Ethamivan: R= cHr R4
(ii) Anacardiol: R= CzHs VariousBemigricleclerivatives
(s) ( 10)

coN(c2Hs)2

Nikethamide Dioxone
Principlesof MedicinalChemistryNol. ll) % CentralNervousSystemStimulants

Posslble mechanlsms for actlon of analeptlcs : STIMULANT

I 2.5 CENTR,AL
(1) Blockage of post-synaptic inhibition : OR
SYMPATHOMIMETICS
e.g. Strychnine. ANALEPTICS:
PHENYTETHYTAMINE
(2) Blockage of pre-synapticinhibition :
e.g. Picrotoxin
(3) GABA antagonist: e.g. Picrotoxin,and
bemegride
(4) Cholinergic augmentation : Pen$tlene-
tl Rr
R:
tetrazole, nikethamide, strychnine.
(5) Decreased energy levels : Pen$tlene'
tetrazole.
(6) Prostaglandinrelease : Picrotodn' pen- Amphetarnine
glenetetrazole,strylchnine Methamphetamine
(7) Low surface activitY Pic r ot ox in, Phentermine
bemegride,pen$denetetrazole. Benzphetamine - cH2c-6H5
12.4 PUnINES
The Z, 6-dihydroxYlatedPurines or xanthine Diethylpropion
derivativesdiffer only in potency and have a mild
stimulatory effect.
In case of benzphetamineand diethylpropion,
the structurecontainsa tertiary amrne.1.e.,

*'-N1 C :H s

3 and
N r)

I
R.l
Other sympathomimeticswith CNS stimulant
R r = R r = Rr = H;
(Xanthine activity.
Derlvatlve Rr Rl R? (1)
Caffeine CHr CH: CH:
Theophylline cHr CHr H
Theobromine H CHr CHr
Caffeine is the most potent xanthine, H
producingcorticaland medullarystimulationwhile F.C
Fent'luramine
theobrominestands last in the list. Caffeinealso
helps to combat fatigue and sleepiness ancl
stlmulatesmental alertness. (z\
The medullarystimulationclueto theseagents
resultsinto increasedrate and depth of respiration
but is less significant in comparison to other
analeptics.
Xanthine derivatives also cause a positive
inotropic effect, diuresis, relaxation of bronchial cH.r
smooth rnuscle (hence useful in bronchialasthma) Chlorphentermine
and increasedgastric secretion.
Prlnclpbcof MedlclnalChemlstryflol. ll) m CentralNeryougSystemSllmulants

(3)

CH.,

Chlortermlne Mazindol
The phenylethylaminederlvatlveswith potent
adrenerglcactlvlty, by vlrtue of structuralfuatures
and physlcalpropertles,exert a slgnlfrcanteffect
on the CNS,whlch ls usefulln the treatmentof
varlous psychogenlc dlsorders related to
depresslvestates. However, due to the toxlclty
and tolerancellabillgl these agents have been
Phenmetrazlne largelyreplacedby trlqycllcantldlepressants, MAO
Inhibltors and the derlvatlves of }-benzyl-
Phenmetrazlne {Appetlte suppressantwlthout plperldlne and 2-phenylmorphollne.Phenethyl-
CNS-stlmulanteffiect) amlne derlvatlvesare generallyprescribedln the
managementof obeslty,narcolepsy,mlnimalbrain
dysfunctlonand In casesof mlld depression.
These agents exert thelr actlon through
bllowing mechanlsms :
1. Inhlbitlonof re-uptakemechanismsfor
es.
I
z. euronal release of
cHr catecholamines.
3. Dlrectcr-adrenerglcreceptorstimulatlon
Phendimetrazine and
4 . Inhibitionof monoamlneoxldasein higher
concentrations,
Stucturc-Acttylty Rehtlonshlp r
(1) Any decreaseln dlstancebetween the
aromatic rlng and the heterocycllc nltrogen
decreasesactivlty.
cHcoocH3 (2) ThebranchedCH3group (amphetamine) or
N
I similarsubstitutionllke, an Incc
H nltrogenIn a rfn-gsySfem(phenk
lmportantfuatureof thesedrugs,slncelt plovldes
Methylphenldate resistanceto enzymatic Inactlvationby steric
protectlonof the aminogroup.
(3) In phenidateseries,actlvltyis ma<imalat
the methyl ester.
HN
(4) In the morphollne serles, aromatic
substitutlonsand replacementof aromaticring by
C- OH heteroqlclicgroupsleadto decreasein activigr.
lletabollsm :
The prototypeamphetamlne,may be meta-
bolised In human to glve norephedrine,para
hyclroxynorephedrine (whlch accounts for the
tolerancedevelopedafter repeatedamphetamlne
Plpradrol phenyl acetone,benzoicacid ancl
aclministratton),
hlppuricadd.
Mazlndol ls malnly used as an anorexintwhlch Sinceamphetamineis a base,ln amphetamlne
acts by blockage of neuronal uptake of toxiclty, the chloride Induced lonisatlon of
amphetamlneprevents its tubular reabsorptlon
noreplnephrlne. and thus accelerateslts excretlonthrough urine.
 Principles
of Medicinal pol. ll)
Chemistry CentralNervousSystemStimulants

Slde-Effects: mimicking of psychosis).Psychoclelicsprocluce

(l) Amp h e t a m in e congeners, if usecl as distortions in perception or thinking even at low
dose, as a primary effect. Hallucinogensproduce
anorexogenic (to decrease appetite), lead to
dizziness,tension, perceptualchangesof size,
insomnia and restlessnessclue to their cNs
stimulantproperties. time and distance, visual hallucinations,a
(2) other eftects include nervousness. crossoverfrom hearingto seeing(coloursmay be
'heard'and soundsmay be "seen"),mooclchanges
irritability, anorexia and possibility of cardiac
irregularities. ancl potential panic. This category represer)ts
I2.6 MISCELLANEOUS severalchemicalclassesand differentmechanisms
AGENTS
(l) PemollneMagneslum : of actions.
Fsychotomimetics are the agents which
inducetemporarrlychangesin moocl,perceptionor
behaviour that may result into vivid dreams,
N hallucinationor nightmares.
H Theseagents are classifieclmainly into
l. True psychotomlmetlcs : e.9., phenyl-
Pcmoline magncsiunt ethyl amines, indole ethylamines and some
m iscellaneous compounds.
The clrug is useclto treat the clisease,minimal
(which 2. Psychodellcs : These agents are highly
brain dysfunction is clefinedin 1963 by the
Task Force of the National Institute of Blinclness effective in altering moocl and perception and are
used illegally for this purpose e.g. lysergicacid
and Neurologicalcliseasesas a syndrome affecting
"chilclrenof near average or above average cliethvlam icle,mescaline.etc.
intelligence with rnilcl to severe clisabilitiesof
Hr C O
learning or behavioural type associateclwith
deviationsof functionof CNS).
(2) Deanol acetamidobenzoate : H, CO C II,C H .,N I{ .
it has been proposed that deanol penetrates
the central nervous svstem and serves as a H. C O
precursorto choline anclaceglcholine.The clrug is
considerablysafe for use and is inclicatedin the Mcscir ) C
treatment of a varie$ of milcl depressivestates It is obtained from 'mescal lruttons the
and for alleviationof behaviourproblems ancl floweringheaclsof the peyote cactus,Liphophora
learning clifficulties(minimal brain clysfunction)of williamsii.lt procluceshallucinations of more visual
school-goingchilclren. nature.
There is a state of heightened awarenessof
sensoryinput but a diminisheclcontrol over what
o is experiencecl.The person feels that one part of
tl
HOOC NI I C - CH. the self seems to be a passiveobserver of the
eventsand happeningswhile another part of the
Delutolitcctarn
idohcnzolitc
self participates and receivesthe vivicl and unusual
sensoryexperience.The surrounclingenvironment
I2.7 HALLUCINOGENS OR,PSYCHODETICS OR. seemsto be beautifulanclharmonious.Commonly,
PSYCHOTOMIMETICS there is a diminishecl capaci\l to clifferentiatethe
Since prolongecl psychotic episodes sorne- bounclariesof one object from another and to the
times occur after psychodelic use, the word self from the environment.These.effectsare better
hallucinogenic(feelingof exhilarationor realistically representeclby the term "minclexpancling"clrugs.
erotic clreams)runs parallel in meaning with the Examples: LSD,psilocybin,psilocin,ctimethyl
,I wor d p sych os e s ( i. e . p s y c h o to m i m e ti c s , tryptamine(DMT)ancidiethyltryptamine(DET).
Principles
of MedicinalChemistry(Vot.tl)
(3) Drugs from other pharmacologlcal classes :
Unclercertainconclitionsor at toxic dosages,
several classesof clrugs (e.g. anticholinergics,
bromicles, antimalarials, opioicl antagonists,
cocairre,amphetamines,veterInary anaesthetics
(phencyclicline), insecticicles (parathion) alrd
corticosteroiclscan induce illusions,hallucination,
clelusionsand other alterations of moocl and
thinl<ing that are observecl in spontaneously
occurrinq psychotic states.
Pharmacology :
Set and settin.gof the clrug usecl,cletermines alters the behaviour.
the pharmacologyof these agents. Here set refers
to the psychologicalattitucle of the person at the
time of clrugadministration. When one is upset or
clisturbecl,
the clrug eftect will be totally different
than those proclucedin a happy person,exhibitirr.g
a positive attirude towards the outcome.
ln general, all psychotomimeticsexhibit the
tuil range of psychicalterations(like psychicstate, followeclby glucuroniclation
autonomic and somatomotor activities,metabolic
effect ancl clirect action on bronchia,uterus)with
only quantitative differences. All these agents
cross the bloocl brain and placentalbarriers.
Mechanlsm of Actlon :
Manv theorieshave been pro;;oseclto explain
psychotominreticeffects.
(l) Signs of sympathetic stimuiation occur
after the aclministration of lysergide which
suggests that it may accelerate or induce
procluctionof hallucinogenicmetabolites from
noradrenaline.
(z)Theseagents may cause:
(a) changes in cerebral bloocl f low and
permeabilityof cerebralcapillaries,
(b) alterationsin levels of aclrenalcorticoiclal
anclthyroiclhormones,or
(c) changes in synthesisor metabolismof
serotonin, norepinephrine,acetylcholineor other
potential transmitter. Since serotonin is an
inhibitory neurotransmitter,the removal of its
inhibitioncould leaclto behaviouralchan.ges. But it
is not yet possibleto fincl out the ways which
clisturbmonoaminergicfunction thar manifests
itselfas a hallucinatoryexperience.
n CentralNervousSystemStimulants
( 3 ) P h e ncycliclineanaest het ic: I t blocks
transmissionfuomthe thalamusto cortex. Sinceit
is also psychotomimeticagent, it is thought that
tlre hallucinatory activigr is not necessarilVa
manifestationof increaseclmeaningful sensory
information from tl-re brain, whic.h may release
resistanceancl precipitate clistorted thought
processes, resultinginto hallucinogenic activi!.
(4) Cerebralfunction is extremely depenclent
on the utilisationof energy in the form of ATp.
Psychotomilneticsmay clisrupt cerebral energy
procluctionor utilisation in such a fashion that it
Metabollsm :
The psychotomimeticdrugs after aclmini-
strationare rapidly removed from the bloocland
distributedto various bocly tissues.The maior
metabolism takes place in liver but some
cletoxification of LSD is also reported to occur in
muscle and brain. ln general hyclroxylat.ion.
constitutethe fate of
these agents.
Slcie-tffects :
These include psychic toxicity, paranoia,
confusion and tolerance.Tolerancenecessitates
the use of increasinglylargerdosesto achievethe
clesiredlevel of action whictr if exceeclsthe fatal
overdose,resultsinto a cleathof the patient due
to respiratoryclepression.
I2.8 PSYCHOTOMIMETTC DRUGS
(True Psychotomlmetlcs)
These drugs have a number of svnonvms
incluclingschizogen.psychotogen,phintasiica,
psychosomimetics and psycholytics.The maior
clrugs from this category are relatecl to the
neurotransm itter substances, either to :
t. 5-hyclroxytryptamine(serotonin)ancl are
clerivatives of indoleethylamine.
Z. Norepinephrineand are derivativesof
p-phqnylethylamine.
Psychotomlmetlc Drugs :
(l) Indole ethylamlne clerlvatlves
Lnl- Nr-t.
ScloItlttrt.t
Principlesof Medicinal (Vol.ll)
Chemistry zn CentralNervousSystemStlmulantr

Table l2.l
Effectlve lndole derlvatlves from Psychotomlmetlc catcgoly

R.r

Name
Dimethyltryptamine (cH2)2N(CH3)2 HI H H
Diethyltryptamine (cH2)2N(CzH5)2 HI H H
Bufotenine (cHz)zN(CH3)2 HI OH H
Psilocvbin (cHz)2N(CH3)2 oPo(oH)zI H
Psilocyn (cHt2N(cH3)2 O HIH " H
6- hyclroxycliethyl-tryptamine (cH2)zN(C2H5)2 HI H OH
5 -Methoxyclimethyl-tryptamine (cH2)2N(CH3)2 H I ocHt H
Dimethyltryptamineoccurs naturallyin the seedsof Piptadeniaperegrina.A powder preparedftom
this seeclis known as COHABA SNUFF.The compound is not effectiveorally but is effectivewhen it is
inhalecl.Psilocinand its phosphateester, psiloqybin,occur in a Mexicanmushroom(Psiloqybe)-
Hamaline
is an alkaloiclobtaineclfrom Peganumharmala.
Serotonincloesnot causebehaviouralchanges and dipropylamine analoguesare less effiective.
since it cloesnot effectivelypenetratethe central The effective indole derivatives are listed in
nervoussystem.This categoryof clrugsmay be Table 12.1.
further subdivicleclinto :
(a) lnclole clerivatives HO
o
(b) Carbolineclerivativesancl
(c) Polycyciici{erivatives. HO N
(a) lndole derlvatlves : All agents from this I
CH r
class(exceptaclrenolutin,are N, N-dimethylamino
ethyl clerivativesof indole nucleus. N, N-diethyl Adrenolutin

Table t2.2
(b) Carbollne derlvatlves :

CH,'

Name & R7 Posltlon of double bond

l. Harmine H cH30 1,3
Z. Harmaline H cH30 'I
3. 6-Methoxyharmalan cH30 H I
4. 6-Methoxytetrahyclroharmalan cH3o H
Principles
of Medicinal
Chemistry
Pol. tl) 81 CentralNervousSystemStimulants

(c) Polycycllc clerlvatlves :

l. Yohlmblne ancl lbogalne :
H 1 ( 'o

C:Hi

H
lhogairre

O n May z, t938, Albert Hoffman first

synthesiseciLSD. LSD has markecl effects on
I serotonergic symptoms in the C N S . Central
OH
sympathomimetic stimulation occurs within 2O
Yrhi mhi nc
minutes of oral ingestion. Receptions are
2 . Lyserglc Aclcl derlvatlves :
heightenedand may become overwhelming.After
imagesare proclucecland may overlap with ongoing
Rr O C
perceptions.There may be a sense of unusual
clarity.Time seemsto passslowly. Mood is highly
variableancl labile ancl may range from expansive
reactions (euphoria.and self-conficlence)to a
constricteclreaction markecl by clepressionand
panic. One pg of LSD per kg of bocly weight will
inclucea hallucinogeniceffect in man.

Name

cl-Lysergicaciclamicle NHz
z. cl-Lysergicaciclethylamicle NHCzH5
3. cll-Methyllysergicacid ethylamide CHr NHC2H5

cll-Acetyllysergicaciclethylamide cocH3 NHCzHs

cl-Lysergicaciclclimethylamicle N(CH3)2

d-Lysergicaciclcliethylamicle N(C2Hs)2

7. cll-Methyllysergicaciclcliethylamicle CHr N(CzHs)z

cll-Acetyllysergicacicldiethylamicle cocH3 N(C2Hs)2

Mlscellaneous Halluclnogens: Many compouncls,though not belongingto any clefinitefamily or a

classdo exhibit hallucinogenicaction in man. Researchis still continueclto clefinetheir structure-activigr
relationshipanclmolecularfeaturesessentialfor hallucinogenicactivity.
Princlples
of MedlclndChcmlstry(Vot.lt) & CentralNorvourSystemStlmulan

It is an actlve lngreclientof marlJuanaancl

hashishancl is produceclby the hemp Cannabls
sativa. lt, in extremely high closesmay lead to OH
paranoiclclepersonallsation.
One of the cannabinoidderivativesIn cllnlcal
H,C
use, nabilone, has a very selective anrlemetic C- cH, - csHil
activity in patlents suffering from toxlc side- HrC I
CH:
effectsof cancerchemothera;ry.
Nabilone
MlscelleneousHalluclnogenlcAgents

(l) (2)
NHCHT

Hydrochloride
Phencvclidine Ketamine

(3) (4)

CH, ' NH.

Iboten
i c acitl
Muscimol
( 5) 9H:
(6)
OH OH

N
H,,C I
(CH,)4CHl cH.r
Hrc
9 Adrenochrome
(-) A -trans-Tetrahydrocannabinol

ooo
13.1 INTRODUCTION B I3.I INTRODUCTION
13.2 BIOSYNTHESIS,
STORAGE
ANDCATABOLISM
234 A number of substanceswith widely cliffering
structuresand with cliversifieclpharmacological
13.3 HISTAMINE
RELEASE ffi activitiesare normally present in the bocly.These
13.4 HISTAMINE
LIBERATION ffi include histamine, serotonin, prostaglandins,
angiotensin,braclykinin,kallidin, etc. Sinqetheir
13.s PHYSIOLOGICAL
ACTIONS m pharmacologicalactivities do not permit to call
13.6 HISTAMINE
AGONISTIC
AC"TIVFY a7 them as hormones or neurohormones,they are
groupecl together in a class, known as autacoicl
13.7 ANTIALLERGIC
AGENTS n [Greekword : autos (self)anclakos (medicinalagent
13.8 MECHANISMOF ACTIONoF cLASSTC or remecly)].Though autacoidsplay an important
ANTI-HISTAMINICS 247 role in the bocly's economical system, their
physiologicalfunctions can not be stated with
13.9 FATEOF ANTI-HISTAMINES
IN THEBODY 247
assurance.
13.10 SIDE- EFFECTS 247 Histamineis widely clistributeclin plants and '
animal tissues.Due to its wide-spreadoccurrence,
13.11 THERAPEUTIC
USEFULNESS 28 in body tissues,it was named histaminewhich
13.12 ANTI-SECRETORY
DRUGS 28
means 'tissueamine'. lt was first discoveredin
1907 by Windaus and Vogt. Its vasodepressor
13.13 H2-RECEPTOR
AGONTSTS effectwas reportedin 19lO by Daleet al.ln 1977,
it was first isolated from liver and lung tissues.It is
13.14 MECHANISM
OF ACT]ON E1 found to be involvecl in the diversified
13.15 ABSORPTION,
FATEANDEXCRETION E1 physiological processes.It is released in body
usually,in responseto tissueinjury, inflammation,
13.16 THERAPEUTIC
USES and allergicor hypersensitivit5l reactions.
13.17 H+- K+- ATPasePUMP
13.18 H3-RECEPTOR

Histamine
(233)
Pdnshls! of lledlclnalChemistry(Vol.ll) 4 Anti-Histaminic
Agents

Histamine is comprised of an imidazole ring I3.2 BIOSYNTHESIS,

STOR,AGE
AND
connected to an amino group through ethylene CATABOLISM
bridge. Both, imidazolering anclamino group are
basic and get protonatecluncleracidic condition. The major sourceof histaminein boclyappears
Chemically,it is p-imidazolyl ethylamine. The to be decarboxylationof the naturally occurring
structuralfeaturesof histamine permit it to exist in amino acid, histicline,under the influenceof L-
ionic, tautomeric and conformericforms which histidine decarboxylase.lt is highly specific
constantly get interconverted to each other. enzyme whose activig is governeclby histamine
These forms cliffer mainly in the electronic charge itself,through negativeFeedback inhibitionmecha-
clistribution and in the position of hydrogen nism. This conversionutilises pyridoxal-5-phos
phate as a coenryme. Histiclineis also converted
atoms.
to histamine by a pathway of minor importance
There are many clrugs with histamine like that is catalysed by non-specific enzyme,
properties.Theseclrugsmay contain the following
aromatic-L-amino acid clecarboxylase(dopa
molecularfra5;ments. clecarboxylase).Almost all mammalian tissues
contatn varyrngamounts of histicline,L-histidine
--N = C-CHz-CHz-NHz decarboxylase and enzyrnes that metabolise
histamine.The higher concentrationof histamine
ol
ll however, is found in the skin, intestinal mucosa,
= N-C- C H2 - CHz - NHz lungs and bone marrorl'. These are the organs
These fragments seem to be necessaryfor which are exposecl to external environment. In
attack of histamineon receptor centersof target brain,histamineis presentin significantamount.
cells.
cHrcH.,NH) cHrcH,NH., cFt2cHo cHrcooH
+ ........................-...*
-H
MA O Aldehyde
dehydrogenase
CH., cHr cHr
( l)
H i sti l tni ne
Methylhistamine/t\ Methyl i mi dazol(3)
c
acetrcacid
Diamineoxidase
(histaminasc) CHTCH?OH

N
N cH,cooH H
tl
I midazole (5)
ethanol

H N cH,cootl
acetic acid(4)
lmidazole

I
CH- CH-CH-CH -cHroH
I I
OH OH
Riboside
t 6)
o
Flg. l3.l : Hlstamlnc lnact{vatlon ln body
Princlplesof MedicinalChemistryffol. ll) 85
The tissue fixed mast cells and bloocl baso-
phils (circulatingcounterpartsof mast cells)are the
principalcells where histamine is synthesiseclancl
is stored in secretorylgranules.Besidesmast cells,
histamineis also present in skin, gastric mucosa
anctCNS where it is biosynthesizeclancl stored in
non-mastcells. Here histamineusuallyundergoes
rapid turnoverand is releasecl,rather than storecl.
It is this histamine which is probably of greater
physiologicalimportance.
Some histamineis also synthesizecl in the gut
lumen by bacteria.But most of it, is inactivatecl
during absorptionin the gastrointestinalmucosa,
liverand lungsto N-acetylhistamine.
Figure13.1 shows the principalpathwaysby
which histamineis inactivatedin the body.
Except (2) and (3), rest of the metabolitesof
histamineretain little or no physiologicalactivity.
In general, conjugation reactionsrarely utilise
ribose as a substrate. Histamine seems to be
among such rare compounds,which are biotrans-
formed through the conjugation with ribose
moiety. Acegllation and N-demethylation are
other metabolic pathways of minor importance.
Urine serves as the principal vehicle for the
excretionof these inactiveproducts.
Specificas well as non-specificenzymes are
involved in the inactivationof liberatedhistamine
into the body. lmidazole-N-methyl transferaseis
present in the tissues but not in blood whereas
diamineoxidaseis presentin high concentrationin
intestine,kidney, liver and thoracicduct lymph. lt
also utilisesother diaminesas its substrates.lt is
mainlyinhibitedby antimalarialdrugs.
T3.3 HISTAMTNE R,EIEASE
At almost every site of action, histamine is
biosynthesizedlocally ancl is then storecl in
subcellularorganelles.Under normal conditions,
much of the body's store of histamineremainsin
an inactive form within the tissues. The tissue
bound mast cells and basophilsare the principal
cells for histamine storage. Thus almost every
organ is suppliedwith blood containinghisramine,
released by basophils. Within the secrerory
t cells and basophils,histamineis
parin-proteincomplex,to which it
.
is loosely bound with ionic forces. The sensiti-
Anti-Histaminic
Agents
sation of mast cell is causeclby an antigen when it
interacts (through bridge formation) with two
membrane-bouncl antibody(immunoglobin)mote-
cules resulting into initiation of a chain of events
that ends into an expulsion of the contents of
secretory granules by the process of exocytosis.
It is Ca++ and Mg++ ion dependent ancl energy
required metabolic process.Histamine is released
from its heparin-proteirrcomplex by an exchange
program, probably involving calcium ions. Cyclic
AMP inhibits the releaseof histamine,presumably
by closing the calcium channelswhite c-Gt4P
facilitatesthe calciuminflux and incluceshistamine
release.
The concentrationof c-AMP is governed by
the membrane-bounclaclenylatecyclase enzyme
which is activatedby norepinephrine(a-adrenergic
agonist), epinephrine (p-aclrenergicagonist), pro-
staglanclinsancl by histamine (negative feedback
inhibition by activationof H2-receptor)itself, while
the concentration of c-GMP is governecl by
another membrane bound guanylate cyclase
enryme which is activatedby cholinergicagonists.
Both these second messengerscontrol the
breakdown of phosphatictylinositicles ancl the
generation of phosphorylateclderivatives of
inositol which are involvecl in the regulation of
calciumchannels.
" Antl.gcn
Calciumchannel
E
tr(
Nor-epinephrine
I
I
I
I + Epinephrine
Histamine
a.)
Prostaglandin
E \O
Jecfc(orvgranules
lntracellu
lar
':+' R;'leased
histamine
cil lcl um
flq. t 3.2 : Hlstamlne release from mast cells
The intracellularconcentrationof free calcium
is important for the exocytotic releaseof hista-
mine. ln certaincases,non-exocytoticmechanism
may also be involveCin tlie releaseof histamine.
Theseinclude morphologicalchangesin the mast
 ol MedicinalChemistrygol. ll)
Principles m Antl-Histaminlc
cells resulting into mast cell lysis or physical
displacementof histamine. Chlorpromazinemay
cause the histamine release from mast cells by a
cytotoxic mechanism.
Since activation of H2-receptorsites on mast
cell membrane,resultsinto elevationof c-AMP, all
physiologicalactions of histamine that are initiated
by H2-receptoractivation,will be associatedwith
elevated intracellularc-AMP level. Similarly the
physiologicalactionsof histaminethat are due to
H1-receptor activation in general may then be
associatedwith elevated intracellularc-GMP levels.
In hypersensitivityreaction, the mast cell is
sensitiseclby an interaction of specific antigen
with the cell bound antibody (lgE or reagin),
resulting into degranulation and subsequent
releaseof granularcontents.Histamineis released
along with other autacoids like, plasmakinins,
angiotensin,prostaglandins,serotonin, platelet
activating factor, slow releasing substance of
anaphylaxis(SRS-A)and eosinophill chemotactic
factor. These chemical mecliatorsleacl to patho-
logic responsessuch as increasedvascularperme-
ability, change in smooth muscle tone and
increasedsecretion of mucous.
There are two different mechanisms that
trigger the releaseof mecliatorsfrom mast cells.The
first triggering mechanism is atopic or IgE-
mediated. This mechanism involves allergen
specificIgE antibocliesattached to receptor sites
on mast cells (and also basophils) thereby
sensitisingthem. Thesecell-bound lgE antiboclies
act like a trigger or fuse.
The other broad categoryof mast cell triggering
mechanismis calleclnon-atopic or non-immune.
Thesenon-lgEmediated mechanismsact clirectlyor
indirectlyon the mast cellsor target cell membrane
to bring about the same results-releaseof hista-
mine and other mediatorsanclconsequentpatho-
logic responsesas occur with atopic triggering.
Someof the non-immunetriggersare ace\rlcholine,
complement components, oestrogen, prosta-
glanclins,chemicals,clrugs,conclitionsanclevents
such as weather changes, respiratoryinfections,
air pollution,anxie$rand stress.
T3.4 HISTAMINETIBERATION
Histaminereleasemay be increasedin urticarial
reactions,mastoqytosisanclbasophilia.Similarlyin
certain patients, many drugs may produce hlper-
Agents
sensitivig reactionsby sensitisingmast cells. In
some cases, these drugs or their metabolic
productsmay act as antigenwhile few of them can
directly or indirectly activate the calcium ion
channel. This may result into an eventual
expulsion of the granular contents of the mast
cellswhich includeheparinand other mediatorsof
anaphylaxis alongwith histamine.
Chlortetracycline,morphine, pethidine,
amphetamine, tolazoline, cl-tubocurarineand
atropine are some of the drugs which causethe
histaminerelease.Hencetheseclrugsare termed as
histamine liberators. They do not deplete
histaminestoresfrom non-mastcells.
r3.5 PHYS|OLOG|CAIACTTONSOr
HISTAMINE
(l) An ability of histamine to dilate the
capillariesand to increase their permeabilify,
suggestsits basic role in the beginning of the
inflammatorylreactions.
(Z) In allergic reactions,(antigen-antibody)
histamineplaysa role along with other autacoids.
(3) Histamine exerts a variety of actions on
the cardiovascularsystem.
(4) A "nascent"histamine may play a role in
anabolicprocesses.
(5) Histamineis unevenlydistributedin the
brain and may also act as a central neurotrans-
mitter.
(6) Histaminestimulatessensorynervesin the
skin and if these sensory impulses continue into
CNSto sufficientintensig, this resultsinto itching
or paln sensaflon.
(7) By causing the dilation of intracrania
blood vessels, histamine causes an intense
heaclache.
(8) lt causescontraction of smooth muscles
of GlT. This action, coupled with its stimulatory
action on the secretion of gastric hydrochloric
acid, causesepigastricclistress,nausea,vomiting
and diarrhoea.
(9) Excessivehistamine release may cause
peptic ulcerationand asthmaticconditions.
(lO) Histaminewhen injected into the skin, it
producesdilation of both the capillariesand the
neighbouringarterioleswhich is associatedwith an
increaseclpermeability of these vessels and the
increaseclexudation of tissue fluicl (giving rise to a
Prlnclplesol MedicinalGhemistry
Uot. il) zn Anti-Histaminlc
Agentg

weal). These three effects i. e. , dilat ion of In summary, these observations clearly
capillaries,formation of weal and dilation of the showed that for H1-receptoragonism,a nitrogen
arteriolesconstitutethe term 'triple response'. next to the ethylamineside-chainis sufficient.A
tautomericNzr-Nt systemas in histamineitself is
Axonrel'lex
vasodilation
not necessary.
(b) Substftutlon at the lrnldazole rlng : The
5-alkyl-substituted histamine derivatives are
Bronchospasm Direct therefore relatively H2-receptorselective agents.
vasodilation Methyl substitutionat position 2 leaclsto a rather
potent and selectiveH1-receptoragonist. Methy-
lation of the two N atoms clearly shows that the
Bronchial+-- Histamine Increased lone pair of the Nn atom of histamineis essential
secretlon va scu la r for H1-receptor agonism, whereas an Ntr - Nt
perrncability tautomericsystemis not a prerequisite.Moreover,
substitutionon the other two positionsresultedin
Gastric Pain both selective H1- and H2-receptor agonists.
secretlon Whereas 5-alkyl substitution is in favour of H2-
receptor agonism (by decreasing H1 effect), 2-
I mmunosupression
substitutionyields quite potent and also selective
slolo cal actlons of hlstamlne H1-receptoragonists.Verylinteresting is the obser-
| 3.6 HISTAMINT,-AGONISTICACTIVITY vation that some Z-phenylhistaminederivatives
(I) lttodlflcatlons of the Imldazole Molety of are highly potent compounds, whereas the
Hlstamlne : saturateclanalogueis inactive.This might inclicate
that an extra aromatic binclingsite is involveclin
(a) Replacement of the lmldazole molety by . the binding of the Z-phenyl-histamines to the
other heterocycllc rlng structures : Replacement H 1-receptor.
of the imidazole moiety of histamine by other (ll) Modlflcatlon of the Ethylamlne Slde-
aromatic heterocyclic ring structures leads to chaln of Hlstamlne :
severil relatively selective H1-receptor agonists, (a) a- and p-substltutlon : Introduction of
and some interestingobservationsconcerningthe substituents into the ethylamine side-chain has
mechanism of action at the Hy-receptorcan be not resultecl in very interesting results. Methy-
made. lation at the a- or p-position leaclsto a reduction in
When the imidazole ring is, for example, H1-receptoractivity.
replaceclby a Z-thiazolering, a Hr-receptor filon of the amlno group : The
selectivity is encounterecl.The corresponding group is the only position in the j
3- and 4-pyridyl analogues are both inactive ule that allows the introductionof
(Durantet al., 1975; Cnnellin,l98Z), inclicatingthe a methyl group without concomitantrecluctionin
demand for a nitrogen atom neighbouring the agonisticactivity (Hepp and Schunack,198O).The
ethylamine sicle-chain. aclclitionof a single methyl group yielcls N-cr-
C H,' C H ,N H . cH'cH2NH' methylhistamine.This compounclis approximately
equipotentwith histamineitself. A seconclmethyl
HN- group, however,is alsowell toleratecl.Higheralkyl
/N substituentsare not well tolerateclat terminal NHz.
(c) Replacement of the ethylamlne slde-
CH,'CH2NH, chaln by other baslc groups : Besides simple
CH"CH,NH,
substitutionof the ethylaminesicle-chainat the c,-
or p-carbonatoms and the terminalamino groups,
more drastic changesin this part of the molecule
H1- receptoragonists have also been performed.
 of MedicinalChemistry(Vol.ll)
Principles m Anti-Histaminic
Agents

Forexample,Schunacket al. have incorporatecl partialtyeffective.This is becausehistamine is but

the ethylamineside-chaininto several rigicl or one of a batteryof autacoidsreleaseclor formed
semirigidring structures. cluring the reaction.An antiallergicagent ideally
shoulc{prevent production or releaseof these
autacoidsby inhibiting responsesof sensitised
mast cells and basophils to specific antigens.
Numerouscompouncls,incluclingascorbicacid and
bioflavanoicls,have been used becauseoF their
CH2CH'NH' antiallergicactivity. According to the chemical
featuresthey share,theseagentsare classifiedas :
HN 1. Ethylenediamine clerivatives
/N Z. Aminoalkyletheranalogues
1.0
0 .- s=0 3. Cyclicbasicchainanalogues
PD:= 6.6 4. Monoaminopropyl analogues
5 . Triqyclicring system
6. Newer agents.
Classlcal H,-Receptor Antagonists :
Researchon antihistaminicdrugs werr initiated
o in 1933 iir France by
DOVet ancl tourneau
who reDortecl rhat
0 {- tn cr(= (J ItiJrcloxttt
cH2cll
prperoxan prorecrs
PDz 'N(cll-11)?
t ne ant m a ls r r om
H bro nch ial spasm
N ln auc eo DV aer o -
50 ZeO nlstamlne.
Fouryears later, Staub reported a more potent
compound having cliethyl amino function in place
of pipericlino moie!. The initial discovery of
HN antihistaminic by Bovet ancl Staub in 1937 is
fN
Followed by a vigorous search for other
0.78 C[ = ll (l/
compouncls in rnany laboratories.As a resrrlt,
v"2 - 4 . M
^I-r PDz various potent specific antagonists were
introduced for clinical use to treat hay fever and
acute urticaria.ln 1942, Halpern reported a study
T3.7 ANTIALLERGIC AGENTS
of 24 derivativesoF ethylene cliamineof which
(CLASSTC ANT|-H|STAMTNES) phenbenzaminewas founcl to be most potent. It
Histamine binding to the H1-receptor can thus became the first clinically used anti-
cause stimulation of smooth muscle and produce histaminic.
allergic and hypersensitivig reactionssuch as hay Rocastinehas been clescribedas a rapiclacting,
fever, pruritus (itching), contact ancl atopic non-sedatingHl -antagonistwhere no CNS activity
clermatitis, drug rashes, urticaria (oeclematous was observecl. Moreover it cloes not possess
patches of skin) ancl anaphylactic shock. Antihi, anticholinergic,antiadrenergicor antiserotonergic
stamines are used wiclely to treat these symptoms. properties in vitro. This "new" structure shows
Thoughhistaminehas dramaticeffectswhen it some remarkable resemblancewith the first
is liberateclinto the tissuesduring allergicreactions, H1-antagonistsdiscovereclby Bovet and Staub
the treatment with histamine antagonistsis only (1937).
Principlesof MedicinalChemistry(Vol.ll) 239 Anti.HirtaminicAgent3

Generalformula

.cHro CH' Prornethazine

\
cHr
N
Tricyclicstructures
Pyrilamine A disubstituted terminal group (usuaily a
dimethylaminogroup) is connectedto an atom X
via a short carbon chain. The chain can be
Ethylenediamines saturated,unsaturated,branchedor part of a ring
system,whereasX can be an orygen, nitrogen or
carbonatom; X links the side-chainto an "aromatic
heacl",This aromatic head generally containstwo
aromaticrings (e.g. phenyt, benzyl, Z-pyridy!).
which may be fused.
Substitutionof the aromaticring can influence
the H1-receptorantagonistic activity. Whereas
ortho-substitutionis highly unclesirable, meta-
Diphenhydramine substitutionis either ineffectiveor unfavourable.
anclpara-substitution in only one of the rings can
Aminoalkvlethers increasethe biologicalactivi! if the substituentis
lipophilic(e.9. Cl, CH3)or has electron-reteasing
properties(e. g. OCH3)
Stnrcture-Acttvlty Relatlonshlp :
Like histamine,most of the classicantihista-
cHr mines may be described by a substituted ethyl-
cHcH2cH2 aminemoiety i.e.,
cHl
Chlorpheniramine N
4
(t) Aryl grcups:
Aminopropyl compouncls
In the above structure,Ar is aryl (inclucling
phenyl and heteroaryl group like 2-pyridyl) and Ar'
is aryl or aryl methylgroup.
(2) Naturc of X :
HC - cHr The nature of 'X' provides the basis of
chemical classificationof classicanti-histamines
e.9.,
whenX = Orygen (aminoallqyl
etheran+logue)
Chlorcyclizine when X = Nitrogen(Ethylene-diamine derivative)
when X C.artlon(Mono aminopropytanalogue)
-
tG"='

f,
 (Vol.ll)
,Prhciphsof McdicinalGhemistry /0 Antl*lirtaminicAgFrtr

Sometimes,the two aromaticrings are bridged, and in chlorqyclizine,and still retainshigh anti-
which constitutes triqyclic ring derivatives. histaminicactivigl.
(3) The dlryl chaln :
Most of the structures of classic antihista-
mines contain an ethylene chain. Extensionor
branching of this chain results in a less active HC -cHr
compound (promethazineis possibly an excep-
tion). Homologationhas played an important role
in the development of neuroleptic and tricyclic
anti-depressants from anti-histaminics. All
contain, in general, the chain -C-C-NR2,and Chlorcycllzine
However, substitutions on the Ar groups,
although some of them have a neuroleptic
replacementof the aliphatic dimethylaminogroup
component,antipsychoticactivig is not unveiled
with small basie heterocyclic rings, increased
in most cacesuntil the carbonchain is lengthened
to C3-NR2. branching on ethylene chain and substitutions
(4) Termlnd nftrogen atom ! betwe€n X and N, all modil, the poiency, meta-
bolism, ability to reach the site of action, toxicigl
In general,the terminalN atom should be a 3o
and side reactions in vivo.
amine for maximum activi\r. Unlike many anti-
5. Since the structures of anti-hir{rmines
cholinergics and local anaesthetics,here the
have a close resernblancewith structures of
dimethylamine derivatives are found to possess
cholinergicblocking agents, most of the classic
better antagonist activi\r. The terminal nitrogen
anti-histamines do exhibit anticholinergic activity.
may be a part of heteroqyclicring as in antazoline
The reverseis also true.
Table l3.l : Andellcrglc egcnts or Classlc And-hlstenrlnc egcltr
(l) Ethylenedlamlnederlvatlvcs : cHr

cHr
Name Arl Ar
furilamine
cHz ocH3

a. Tripelennamine
CHz

Methapyrilene

Thonzylamine
Principlesof MedicinalChemistry
ffot. il) u1 Anti-Histaminic
Agents
(2) Amlnoalkyl ether analogues :

Ar
I
Ar

Diphenhydramine

Bromodiphenhyclramine
p-bromophenyl
Doxylamine

CH:

4. Carbinoxamine

c(',lls
o-cH2-CH:
o CH,

e I
cHr

Dimenhydrinate
Prlnciplesof MedicinalChemistryOol. ll) 2A AntFHistaminic
Agents

(3) Cycllc baslc chaln analogues

HC _R ,

Name Rl R2

l. Cvclizine H cHs
Z. Chlorocyclizine cl CHr
3. Buclizine ct
CHr c(cH.1).r

4. Meclizine cl
- CH,

CHr

(4) Monoamliopropyl analogues

(a)
cHr

Name Ar' Ar
1. Pheniramine

Z. Chlorpheniramine

3. Brompheniramine
 Principles
of Medicinal pol. [)
Chemistry A3 Anti-Histaminic
Agents
(b)

Narne Ar' Ar
1. Triprolidine

cH..

z. $rrrobutamine
//\
- CHt
\/

(5) Trlcycllc rlng systems : (Phenothlazlne analogues)

N
I
R

Name R,
1. Promethazine CH.,
CH, - CH
ICH cH.,

Z. Trimeprazine
cH,-CH-c
ICH:
3 . Methdilazine

Phenothlazlnes: Extensionof clialkylaminoethylene chain to dialkylaminopropylene

is not conclusiveto
antihistaminicactivi$r but promotes neurolepticactivig. in chlorprothixene,'t-rans
isomer in which the
amino alkyl group lies on the sicleof unsubstitutedaromatic riing is more anti-histamini
inic than the cis
isomer,while reverseis true for neurolepticactivity.
 1.-:

Prlnclplesof MedicinalChemlstry(Vol.ll) AtL Agentr

AntFHlstamlnlc

(6) MlscellaneousagenF : (s)

(l)

cHo - cH.r

N
ICH ,
Diphenylpyrallne
In dlphenylpyrallne,the baslc side-chainof
Antazoline. dlphenhydramlneis tied back so as to link the
(z) benzhydrylcttrergroup wlth N-methylpipericlinein
the 4aqsltlon.
(6)

COOH

I
cHr

Azatadine HCI
Olopatactine
(3)
( 7)

CH,

Periactin(Cyproheptacl
ine) Phenindamlne
(4) (8)

HC- CH2 - N
CH
CH = CHCOOH

HsC

Acrivastine Dimethindene
Prlnclplesof Mediclnal ffol. ll)
Chemlstry AE Antl-HlstlmlnlcAg€nt!

(ei ( 11)

HO-C
CuHs OH C H-
CuHs
o
Terfenadine : R= {Hc ; Fexofenadine : R: {OOH
lf{s a butyrophenoneclerivativehavlng anti- Oxatomlde
Iristaminicactivigrwithout sedativeaction used in
the treatment of seasonalancl perennialallergic (rz)
rhinitis. Terfenadlnels not active itself but is
metaboliseclto form active drug, fexofenadlne.
(1 0)
-cH2cH2 0('Hl

ooc coo
cH.cH2cH3
Astemlzole
Nedocromll-Na
It is structurallyrelated to cromolyn but has
superiorand broader pharmacologicalactlons in
the treatmentof asthma.
(7) Newer agents under Investlgatlon :
(a) (b)

Tarpane Ketotlfene
(c) (d)

cH(cH2)2N(cH3)2
CH"
7-chloroketotlfune Dlthladene
Prlnclplesof lledlclnal Ghemlstry(Vol.ll) ffi Agents
AntFHlstamlnlc

(e) (0

ocH2cH3 Valiousderivativesof Dbenzazeplne

Loratidine (h)
R
I
N

Derlvatlvesof Derivativesof
6, I I -Dihydrodibenzothlazeplne, whereX= S; and 5,t 1-Dihydrodlbenzo ( 1,4)thlazeplne;whereX=S&
6,1l -Dihydrodlbenzoxepln, whereX = o 5,11-Dihydrodlbenzo (1,4)oxazeplne,where x = o
Cromolynsodlum : It InhlbltsantlgenInduceclreleaseof chemical
It ls a derivative of khellln, a vasodllatory, mediators,especlallySRS-4,hlstamlne.
benzopyroneisolatedfrom the umbelllferousplant Optlmlsatlonof p2-receptorexpresslonby
Ammlvisnaga.Cromolynbelongsto a completely reducing its tachyphylaxisresults Into asthma
novel classof compoundswhlch bring about their prophylactic actlvlty while optlmlsation of
antlhlstamlnlceffects by the suppresslonof H 1-blockade actlvlgl results Into antl-allerglc
release of autacolds durlng antlgen-antlbody action.
interaction. Astemlzoleand terfenadineare non-sedative
H1-blockers. These are qulte polar moleculeand
o o
cannot cross BBB to reach central H-receptors.
OH Astemlzolels especlallylong actlng.An Innovatlve
drug with a comblnedH1-5HT-leukotriene anta-
NaOOC COONa gonism is oxatomlde. lt ls usableIn asthma,where
ordina4rH1-antagonlsts are not approprlate.
Cromolynsodlum Nedocromll- Na and Na-cromoglycateseeln to
It bearsnelthera structuralrelatlonshlpto other act by phosphorylatlnga mast cell proteln and
commonlyusedantl-hlstamlnlc compoundsnor lt therebystablllsethe,cell,preventlnglts dlsruptlon.
possessesa smooth muscle relatant or broncho- The structuresof varlous classlcantl-hlsta-
dllatory actlvlty. mlnic agents revealthe fact that the agentsfrom
Bronchlal asthma and allerglc rhlnltls are other therapeutlcclass also exhlblt conslderable
diseaseswhere sodlum'chromoglycate ls the only anti-hlstamlnlcactlvlty e.g;, Phenoxybenzamin
drug br prophylaxis.Belnga mast-cellstablllser,lt (an adrenallneblocklngagent),many local anaes-
can be used only In the adults, that too In thetics, tranqullllsers(phenothlazlnes)and dl-
Inhalatlonform only. Ketotlfunels an orally actlve phenylmethane derlvatives(atroplnellke drugsand
agent wlth slmllar actlon, havlng prophylactlc the antiparklnsonlan agents).
propertles.lt ls a triglcllc derlvatlveof benzoqyclo qru-o-cI
heptathlophlneskeleton.lt ls usefulIn casesof
bronchlalasthma with Type I hypersensltlvltyas
well as allerglcrhlnitls.lt hasa llmited use In acute qH5-cHz
attack' lt has got antlallerglc,antiasthmatlcand
antl-anaphylactlcpropertles. Phenoxybenzamlne
Prlnciplesof MedicinalGhemistry(Vol.ll)
Forceclbv limiteclusefulnessdue to unvr,anted
sicle-effects,non-sedativeH1-antagonistswere
Ceveioped. These new non-sedative H 1 - a n ta -
gonists originate from several classicalH1-anta-
gonists but sometimes also comprises new and
unexpecteclstructuralelements. In contrast to the
classical Ht-antagonists, the new cleveloped
compouncl,sdo not easily cross the bloocl brain
barrierancl therefore act only peripherically.Some
oF the new H1-antagonists ( e .9 . a s te m i z o l .
terfen.rcline,
etirizine,loratadine)are now in clinical
use and appear to be of value for treating allergic
conclitions.
Seclation is the side-effect of the first
generation H1-antihistamines.Several antihista-
minics have been clerivedfrom classicalstructures
that have reduced ability to penetrate the CNS.
'fhey have little or no seclativeside effects.These
are collectivelyreferred to as the second gene-
ration (non-seclating) Hl-receptorantagonists.
zCOdH
.'O u which histamine normally bincls. In such case,
Cetirizine Rr=C l; Rz = H
R2
Efletirizine Rr=R z = F
Cetirizineis an excellentexampleof the second
generationhistamineHt-receptorantagonistwhich
is carboxylatedmetabolite of hyclroxyzine.It is a
long acting drug and free from centralsedationand
antimuscarinicactivi!. lt is used for the sympto-
matic relief of hypersensitivityreactions.
r3.8 MECHANISMOt ACTION Or CIASS|C
ANTI-HISTAMINICAGENTS
(ANTTATLERGIC AGENTSI
Sincehistaminealone, is not responsiblefor
allergic and anaphylacticconditions, the anti'
histaminesclo not necessarilyantagoniseall the
symptomsof above reactions.
Anti-histamines seem to act as antiallergic
agentsby more than one mechanisms.
(i) By those whose pharmacologicalactions
are oppositeto that of histamine.
247 Anti-Histaminic
Agents
(ii) Those that prevent the access of hista-
mine to its receptorsby competitiveantagonism.
Som e ant i - h i s t a m i n e s a l s o a n t a g o n i s e
serotoninanclbradyl<inin which are releasedalong
with histamineduring anaphylaxisreaction.The
classicanti-histaminesact competitively.Some of
them probably fit fairly snugly on the histamine
receptor but others can only occupy the minimal
area of the receptor-surfacethereby, preventing
the access of histamine through the steric
hindrance.The receptor antagonistcomplex, like
receptorhistaminecomplex is a reversiblereaction
but unlike the latter,when antagonistbinclsto the
receptor, it has no intrinsic activity. These
competitive antagonists are not very effective if
they are given after an anaphylactic attack has
b e g u n , h e n c e subst anceswhose act ions. rre
opposite to histamine's,like aclrenaline, are much
more usefulin theseconditions.
It is also possible that histamine and its
antagonistsclo not bincl with the same site on the
receptor.Suchbinclingis calleclas allostericbincling
anclmay causea small rewersiblemolecularpertur-
bation in the receptor,resultinginto a change in
structuraland chemicalnature of the active site to
histaminemay not be able to bind to the changed
active site or, if it cloesbincl, it may not exhibit an
intrinsicactivitv.
I3.9 TATT,OF ANTI-HISTAMINESIN THE BODY
Metabolite forrnation depends upon the
chemicalnatureof anti-histamineanclage, sex ancl
animal species in which the drug is studiecl.
Generallvsmall animalsexhibit simplerexcretion
patterns. Metabolism occurs through typicarl
meiabolic reactions like N-clealkylation,cleamina-
tion, sicle chain clegraclation,ring hyclroxylation
and oxidation. Prolongeclaclministrationleaclsto
an enhancedactivi$ of liver microsomalenrymes,
resulting into increasedmetabolism of the anti-
histamines.
I3.IO SIDE-EFFECTS :
Prominent side-eflfectsinclucle sedation,
clrowsiness,restlessness,irritability, muscular
twitching, convulsions,followecl by coma and
respiratoryfailure. The sicle-effectssusceptibility
is an age clepenclentprocess.
Principlesof MedicinalChemistry(Vol.ll) 28 Anti-Histaminic
Agents

At therapeuticdose, the classicalHt-receptor Histamine is a powerful stimulator of hydro-

antagonists generally produce sedation. This chloric acid secretionby the o4yntic cells of gastric
unwantecl effect is probably c.aused by mucosa.The large doses of histamine also arrg-
H1-receptor blockade in the central neryous ment the secretion of pepsin and serves as a
system(CNS). chemicalmediatorfor the secretoryr action of sub-
Concomitantwith this sedation,an impaired stances like gastrin ancl methylxanthines.It has
performance is often noted, possibly as a been establisheclthat gastric mucosa possesses
seconclaryconsequenceof the sedation. Other high levelsof histamine.
observed side-effects are Srrobablycaused by the In 1966 Ash and Schilclhypothesized(on the
anticholinergic activity of some of the evidenceparallel to the Ahlquist's hypothesisfor
compounds. the existence of two different aclrenaline
Interaction with noradrenergic,serotonergic receptors)that histamine should act via atleast
ancl dopaminergic uptake systems have been two distinct receptor subtypes. Black and co-
reported, and these activities may play a role in workers suggestedthat the histamine responses
behaviouraleffectsof these compounds. which are blocked by classic anti-histaminesbe
r3.1r THERAPEUTTC USETUTNESS Or classifiedas Hl-receptor responseswhile those
CTASSICANTI-HISTAMINES blocked by newer agents (or not blpcked by classic
(1) Histamine-incluced antihistamines) be classeclas H2.responses.These
contractionof smooth
H2-receptor antagonistsof histamine are also
muscleanclincreasein capilla4lpermeabilitycan be
antagonisedvia H I -receptor blockade, resulting ln termed as anti-secretorydrugs.
an improvement of asthmatic conditions and a 13.12ANTI-SECRETORY DRUGS
(H2'Antagonlsts)
reduction in formation of oeclemaand cutaneous
wheal. The classicalH1-receptor antagonists, One of the compounds showing weak Fl2-
antagonist activity, guanylhistamine,was the
however, are usually ineffective in bronchial
point of departure in the development of these
asthma,but they can successfullybe employeclin
the treatmentof allergicrhinitis, 'conjunctivitis drugs. Extension of the side chain was founcl to
and
increasethe H2-blockingactivity,but some agonist
clermatitiseffects.
(2) As hypnotic ancl rarely as local anaes- effects were retained. When the very basic
guanidino group was replaced by the neutral
theticse.9., promethazineanclctiphenhydramine,
thiourea, burimamide was obtained. Although
(3) In the treatment of Parkinsonism,e.9.,
effective.it lacks oral effectiveness.The addition
Orphenadineand cliphenhydramine. of a 4-CH3 group further improved binding to
(4) ln motion sickness. H2-receptor.Introductionof electlon withdrawing
(5) In cardiac arrhythmias,e.9., antazoline, sulphuratom into the side-chainreducedthe ring
dii:henhydramine. pKa. The proportion of the cationic form was
(6) As antiemeticin caseswhere, vomiting is decreased and the tele-tautomer became
caused by histamine liberation from the damagecl predominant.Reducedionisation improved the
cells. membranepermeabiliglof rnolecule.Oral absor-
(7) Due to their atropine-likeaction,they have ption (metiamide)was excellent. lt is I O times
beenused in cough mixtures. potent than burimamicle.However,metiamidestill
Eventhough the general term, anti-histaminic showed some side effects. in the form of
implies the inhibition of the actionsof histamine, haematologicaland kiclney damage, which were
certain prominent actions of histamine such as, attributeclto thioureagroup.
the stimulationof gastricacid secretion,relaxation Since 4-methyl histamine shows a weak but
of uterus and positive inotropic effect on heart noticeable inhibition of the secretion of gastric
(i.e., increasein force of contractionand heart rate) acid, it was chosen to study the proton
of guineapig were not blockedby the classicanti- tautomerism in its imidazole ring as well as the
histamines. steric interactionbetween 4-CH3group ancla-CH2
Principlesol MedlcinalChemistry(Vol.ll) 2N Anti-Histaminic
Agents

of side chain. The personal experience of investi- Replacementof the thione (= S) sulphuratom
gators with guaniclinessuggesteclthe replacement of metiamicleby a cyanoimino group yielded a
of thioureagroup by a guanidineunit [-NHC(= NH) potent H2-antagonist;
Cimitidine.
NHRI but it increasesbasicit5rand reclucesactivigl.
Hencebasicitywould be decreasedby introducing
an electronwithdrawing group into the guanidine H H
group e.g. -NHC (=NNOz) NHRor -NHC (=N-CN) I I
H.,C CH?SCH,CH,N -c - N- cHr
NHR.Henceqyanoguanidine [H2NC(=NCN)NHz] ll
N- C= N
was comparecldirectly with tnlourea. 5ucn a stoe'
N\ Ntt
chain was introducecl into 4-methvl imiclazole
resultinginto cimetidine.
A satisfactory replacement was found by Cimiticline
substitutinganother electron withclrawing group
Another recently introcluced potent H2-anta-
on guaniclinewhile retainingappropriatepKa. A
gonist is Raniticline.
cyano group provecl suitable ancl resulted into
development of safe ancl effective cimeticline.
H H
Lately, it has become clear that an imidazole I I
nucleus is not absolutely necessary for CH,SCH,CH,N -
H2-blockingactivi!. The furan derivativeraniticline CHNO"
and famotidinewere found to be more active.
Since none of these compounds is lipicl
soluble, they clo not procluceany sedative action, cH.'N(CH3)'
as thev cannot cross BBB.
Raniticline
Bu rima m ic le wa s t h e fi r s t s e l e c ti v e
H2-antagonist produced by moclification of Raniticlineis a nitroethanederivative of fuian
histamine(Blacket al 1977). and on molar basis,it is five times more potent
than cemiticline.

H H
I I
-c-N
cH2cH2cH'cH,'N - CH-r cH2.s.cH'cH2.c.NH'
I
S.
tr\ Nu
Famoticline
\--

Burimamide It differs in having a thiazole nucleus rather

Burimamidewas poorly absorbeclorally and thana furanor imidazolinering . It is 20 timesmore
better absorption ancl higher activities were potent than cimeticlineand 7.5 times more potent
achievedby introducing a methyl $roup in the ring than raniticlinein inhibiting basaland pentagastrin
to yielclmetiamide. stimulatedgastricaciclsecretion.
H 2-blockers are generally very polar
H H
compoundswith pronouncedH-bondingability.
I I Theyare veryrhyclrophilicand don't enter the brain
- e -N
CH"SCH,,CH,N - cHr in more than tiny amounts.
ll
S The first brain-penetrating H2-blocker is
NIrNH Zolantidine (SK & F 952,82). However, the
physiologicalrole of CNS Hr-receptors is not
Metiamicle known.
Prlnclpbcof lrledlclnalChemlrtry(Vol.ll) a Antl-HlitrmlnlcAgenie

Other H2 - blockcrs :

ocH.r N

{ C H .,) + N H cllr

lcotidine Zaltidlne

N
MerNH, Me

Lupiticline
ilr-195
Sc huna c k d e s c r l b e c l a n e w c l a s s df
N compoundsin which H1-receptorantagonismis
combinedwith histamineH2-receptoragonlsm
MerNHrC
(e.g,VUF8531).

sK & F 93619

cl-lcHlcH1NH
- c - NHCFI,CH.CH.
O CHlCH, CH- , NHR
tl
NH
HNvN

Zolantidine; R vuF853r
The compoundsconcerneclare derivativesof
the potent H2-receptoragonlst impromidine,in
Roxaticline;R=- cocH2ococH3 whlch the S-methyllmldazole m olety has been
replacecl by the arornatlc part of the classlcal
H I-receptor antagonlsts.
H r3.r3 Hz-RECEPTOR AGONTSTS

cHz)3N(CH3)2

Mlfentidine Dimaprit

H2SCH2CH2NI-. c
NH
cH.r
cH2N(CHd2
Nlzatlcllne lmpromlcllne
Principlecof MedlclnalChemlsFy(Vol.ll) 61 Antl-Histamlnic
Agents

A substantialcontribution to the elucidation (2) Chaln

of the structure-activigl relationships of H2 A chain of four carbonatomsis optimalfor the
agonists occurred when it was establishedthat activigr. shorter chain, drastically lowers
dimaprit may interactwith the H2-receptorthrough antagonistactivity. The chain should contain an
its S- and N- atoms instead of its two N-atoms of electron withdrawing substituent. An isosteric
the isothiourea system. Undoubtedly, this thioether (-S-) link in place of methylenegroup
(1Il-1 leadsto more active compounds.
observationhas opened the possibility to design
new H2 -agonists. (3) Thc termlnal nftrogen group s
The tdrminatN-group shoutdbe a polar, non-
An adclitionalclassof H2-agonistsis formed by
basic substituentfor rnaximal antagonistactivity.
the impromiclineanalogues with the guanidino- Though a positively charged group
binds more
propylimidazolemoiegl as a characterigticfeature. tightly to the receptor, it leads to an agonist
From a therapeutic point of vlew, selective activity rather tha4 an antagonist activi!.
H2-agonistsmay become usefulin the treatment I3.14 MECHANISMOT ACTION
of heart failure and catecholamine-insensitive Mucus secreted by the gastric mucous cells
cardiomyopathy. combinecl with surface epithelial bicarbonate
Structure-Actlvlty R.elatlopshlp : secretion contributes to a barrier (the mucus -
bicarbonatebarrier) that prevents gastric acicl and
pepsin from damaging the gastric mucosa.While
the luminal pH is acidic, the pH adiacent to the
epithelial cell membrane is near neutral clue to
epithelialbicarbonateprocluctionanclthe presence
of the mucus layer.
/
/
In humans, the parietal cell secretion is
F{7-Antagonist estimateclto contain approximately 149 meq / litre
Unlike the H,-blockerswhich are grpically HCl.
lipophilicamine6,H2-blockerssuch as cimeticline The parietal cell is pyramiclalor triangularin
are very pola1. Furthermore, H2-blockers have shape, relatively large (approximately 25 prm in
longer uncharged side chains unrelated to the diameter)anclthe basalsiclebulgesinto the lamina
protonatecldialkylaminoallrylside chains found in propria. H+71+ -ATPaseis located within the cell
Hy-blockerp.In H2-blockerstructure,the imidazole membrane. The parietal cell also contains an
ring is believed to be important for receptor unusual! Iargenumber of mitochondriaoccupying
approximately 30 - 4O o/oof the qytoplasm.These
recognition.
are necessaryfor the high level of oxidative
(t) lmldazole rlng substltutlons : functioninvolvedin gastricaciclsecretion.
The gastric mucosa also secretes small
quantitiesof HCO3.At the luminalmembranethere
is a Cl-lHCCf exchangestimulated by glucagon as
*\z* H well as active HCO, transporter that is chloride
inclepenclentand stimulated by prostaglandins
(l) (ll)
and c-AMP. Hydrogenions are secretedinto the
The imidazole ring exists in above two gastric lumen by an active transport pump, the
tautomeric forms.'The form (l) seems to be H+7 ;1+ATPasepump. H+ ions for the pump are
necessaryfor maximalH2-antagonistic activig. In made available by carbonic anhyclrasewhich
most cases,when R = CHe,activity is potentiated. catalysesthe formation of H2CO3 from CO2 and
Principles
of Medicinal
Chemistry
Ool. ll) a2 Anti-Histaminic
Agents
Nerrrocrine
H2O. The H2CO3clissociates to H+ + HCOI . To
maintainintracellularneutralitvas H- t5 secretecl Errdocrine
A c e t y l ch o l i r r e
into the canaliculus(from where I'l+ ts released
Atropinc
throughH-lK--ATPasepump). HCO, is exchangecl
for Cl- across the basolateral membrane. The Adenylate
cyclase Prostaglandins
resultingincreasedintracellularCl- drives through
chloride conductive pathwaysacrossthe luminal
surfaceof the cell. The overall process generates
HCI secretionthat is followeclby passiveH2O ffow.
Sincethe parietalcell secretesH+ ions from the Pr0tein
intracellr.rlar
canaliculus using H+/ K+-ATPase rnases ADi)

pump, intracellular K+ concentration clevelops. P r o l ci n Plo t cin

High intracellularK+ and Na+ concentrationsare Phosphory
latcd

maintainedby Na+-K+-ATPase at the basolateral

me mb ra n e , while K+ also moves through
conductive pathways into the lumen thereby Orrrcprazo
le Syrrrpon
proviclingK+ for H+/ K+- ATPase.

Flg. | 3.4 : A moclel of the parietal cell

HCI
K
+ The current hypothesis states that the
ATPase
pump
HCOr
CO' + 11,66,
Three separatereceptorshave been identified
on the parietalcells that mediate HCI secretion.
These receptor $rpes interact with histamine,
gastrin ancl acellcholine. Stimulationof parietal
cell functionis linl<ecl
to either c-AMP-clepenclent
(e.g H2-receptor)or calcium-clependentmecha-
nisms.The cholinergicanclgastrinstimulationare
associatecl with increasesin intracellularcalcium.
Proglumiclewhich blocks the gastrin receptor,has
anti-secretoryproperties in vitro but its in vivo
potency is low. SinceH2 - receptorantagonistsare
potent inhibitorsof all stimulantsof gastric acicl
secretion,histaminemay be consideredas a single
common final mediator of acid secretionon the
parietalcells.
representlng the pathways of acld secretlon
H2-antagonistssimply inhibit the direct actionsof
histamine (by forming some sort of reversible
complexwith the Hz-receptors) on acid secretion.
The responsesto stimulation of histamine
H2-receptorsare mediateclthrough the activation
of adenylate cyclase, provicling yet another
analogy between histamine H2-ancl aclrenaline
p-receptors.
I3.T5 ABSORPTION,
TATEAND EXCR.ETION
Cimetidineanclraniticline are the clinicallvused
agentsfrom this category.By oral route, they are
rapicllyancl completely absorbed.However, the
Dresence of antacid mav interfere in their
absorption pattern. Both these clrugs get widel;,
clistributeclin the body. Cimeticlineis reporteclto
cross placental barrier. Metabolism of cimeticline
yielcls chiefly sulphoxicleancl 5 - hyclroxymethyl
clerivatives while N- oxide, S - oxide and desmethyl
clerivativesare obtained upon raniticlinemeta-
b o l i s m . Most of the administered dose of
Prlnclples
of Medlclnal
Chemlstry
ryol il) 2St Antl-Hlstamlnlc
Agente

cimetidineappearsln the urineas the mlxtureof

unchanged(ftee and conjugated)and lts meta-
bollteforms.Mlnor quantitymay be ellmlnatedln
stool.
Adverse effects are few and of mlld nature.
These lnclude nausea,diarrhoea,constlpatlon,
headache, skln rashes,and dizzlness.Dueto their
antlandrogenlceffect, they may cause sexual
dysfunction.Ranltldlnels devold of thls effect.
Clmetldine may also cause leukopenla.lt also
depressesthe actlvlt5lof metabollslngen4me and
may thr.rs potentlate the effects of other
concomitantlyadmlnlstereddrugs.
I3.16 THER,APEUTIC USES
Thesedrugs have Inhibitoryeffect on gastrlc
acld secretion,Hencethey are hlghly effiectlveln
treatlng conditions characterlsed by hyper
secretion of gastrlc acid. Thus they create a
favourableenvlronmentfiorrapld healingof gastrlc
and duoclenalerosions.
Antacids are commonly used along with
H2-receptorblocklng agents In the treatment of
peptlculcer.
13.17 INHIBITOR.S Ot H+-K+-ATPascPUMP
The gastric acid secretion ls regulated by the
functloningof H+ - K+ ATPasepump presentIn the
parletal cell membrane.It works just slmllar to
Na+-K+- ATPasepump and exchangesproton for
K+- Ions.Recentlysomeqgentsfrom benzlmldazole
classwere developed whlch appear to selectlvely
inhibit the functlonlng of this pump by getting
accumulatedin the parietalcell-membrane.One
such agent ls omeprazole which effectively
inhibits, both basal and enhancedgastrlc acid
secretion.
ocH3
ocHF2
Pantoprazole
ocH2cF3
cHs H
cHz- S
ll
o N
Lansoprazole
ocH2cH2cH2ocH3
cHs
N
o N
Raheprazole
coocHl
cHr
Picoprazole
o
tl
s-cH2
H3CO Hlc CH:
ocH.r
Omeprazole
It ls effectiveorally as well as parenterallyand
InhibltsATPasepump in the reverslblefashlon.lts
clinical usefulness promoted further the
developmentof drugs ftom thls category.
13.18H3-RECEPTOR
Histamine is both a local 'hormoneand a
neurotransmltter.Histamlnerglcpathwaysin the
CNShave been describedIn detall. The activigr
pattern of a neuronal system ls governed by
severalelements: actlon potentlal, transmltter
release,Interactlonof transmltterswith post-
synaptlcreceptor(s), inactlvationroutesincluding
neuronal reuptake and lnteraction with
presynaptlcreceptors.In 1983, a presynaptlc
inhibltory autoreceptor for hlstamine was
described.Presynapticreceptorsmodulate the
releaseof a neurotransmltterIn a quantltatlve
sense(autoreceptor).
Theseseem to be presynaptlcautoreceptorc,
controllinghistamlnereleaseand synthesls.They
are actlvated by hlstamlneconcentratlons.Thelr
Prfrdpbr d Hb[td Chcmlstry(Vol.ll) n Agent3
Antl-Hlstamlnlc

blockademay potentlally lead to Increascdblood

flow and metabollsmcombined wlth a. centrul
arousal,whereasthelr stlmulatlon(or tnhlbltlonof
centralH2 receptors)could havean antl@nvulsant
or sedatlveeftct.

cHz Clobenproplt'

HN-
rzN
lmmeplp N.
H3-receptoragonlst
Sclccllvc H3-reccptoregonlsts r N
H Clproxlfan
TheseIncludeR (a)-methylhlstamlne,
S (a)-
PerlpheralH3 receptor actlvationhas been
methylhlstamlne,lmetlt,-l-mmeplp.
shown to Inhlbit gastrlcacld secretlonInducedby
Sclecttvc H3-reccptor antagonlsts r bod and pentagastrlnIn cats, dogs and rabbits.
These lnclude thloperamlde,clobenproplt, The beneftclal effectsof H3-receptoragonists ln
clproxlfan, lodoproxyfan, lodophenproplt, neurogenlcInflammatlonand In migraineis also
carboperamlde, betahlstlne. suggested.Certalntypes of arrythmlr are shown
to be Inhlbltedby H3-receptorstlmulatlon.
While Hr-receptorantagonlstslike clproxifan
S
1l has been shown to enhancewakefulnessin cats
cHz -c -NH -and rats. H3-receptorstlmulatlon or blockade,
thus, ls suggestedto be a novel approachto the
HN- treatmentof sleep dlsorderssuchas hypersomnla
rzN or narcolepsyand to promote wakefulnessln
Thloperamide vlgilancedeficlts.
H3-receptorantagonlst
ooo
 r4.r NTnoDuciloN
INTRODUCTION Inflammationcan be definecl as a defensive
but exaggeratedlocal tissue reactionin response
CLASSIFICATION to exogenous or enclogenousinsult, It is a
complex phenomenon,comprisingof biochemical
SALICYLIC
ACIDDERIVATIVES as well as immunologicalfactors.lt is recognised
by the following symptoms :
l.,o.oPARA-AMINOPHENOLDERIVATIVES (1) Calor(Heat)
(2) Rubor (Redness)
145 PYRAZOLONEDERIVATIVES (3) Tumour(Swelling),and
(4) Dolor(Pain).
14.6 INDOMETHACIN
ANDOTHER Tissuedamage initiates or activatesthe locat
ARYLACETIC
ACIDDERIVATIVES release of various chemotactic factors that
provoke clirectlyor indirectly the appearanceof the
147 PHENYLACETIC
ACIDANDPROPIONIC mediatorsof pain ancl inflammation.Thesefactors
ACIDDERIVATIVES inclucle:
(a) Amlnes: Histamine,serotonin.
14,8 FENAMATES (b) Proteases: Kallikrein,plasmin.Releaseof
lysosomalenrymes usuallyoccursfrom mast cells,
149 MISCELLANEOUSAGENTS macrophages,polymorphonuclearleucocytesancl
platelets.
(c) Prostaglandlns.
14.I0MECHANISM
OFACNON
(d) Hagenan factor : This factor is activated
when it comes in contact with a foreign surface.
14.1.I
TREATMENT
OFGOUT
Once activated, Hageman factor is known to
act upon a number of macromolecularsubstraies
presentin the plasma.

(2ss)
Principles (Vol.ll)
Chemistry
of Medicinal ffi Analgesics
Anti-lnllammatory

Hageman factor is a serum globular protein complement is involvecl include glomerulo-

(F-globulin)ot high molecularweight (110 OOO). nephritis,rheumatoidarthritis,rheumaticfeverancl
The three main functions performecl by Hageman clrugallergies.
factor in the inflammatory reaction can be
Summarisecl as :
(a) Generation of thromboplastin activity in
the pathwaysleac{ingto coagulation.lt is
also termeclas coagulationfactorXIII. Cl )Det'encemechanism
CI
(b) Conversionof plasminogenpre-activator
VII
Factor FactorVII a
to plasminogenactivator in the pathway FactorXI FactorXI a
leaclingto fibrinolysis. PreKallikrein KallikreinI Fibrinolysis
(c) Conversionof-pre-kallikrein in the pathway
leadingto kinin Procluction.
HMW kininogen Bradykinin
Braclykininis the major final biologicallyactive
product of the kallikrein-kininpathway. Braclykinin Prorenin Renin
has been cited as mediating vasoclilatation, Angiotensinogen Angiotensin-I
increasingvascular permeability ancl proclucing
pain. Bradyl<ininalso increaseslocal lymph flow,
anothercharacteristic oFlocal inflammation. Hyclrolyticenrymes are releasedby cells from
(e) Other factors : These inclucle leucotoxin, intracellularvacuoles(known as lysoson'les)cluring
leucocytosis promoting Factor and lymph nocle phagocytosisancl also c{uringcell death. Thereare
permeabilitli factor. two classesof these en4y'mes.Those in the first
Complement is a complex cascade system group act at acid pH (3 - 5) and are normally
comprising about 20 components, many of which containecl within lysosomes that fr'tse with
are enzymes.The main immunologicalfunctionsof vacuoles to form seconclaryphagosomes.The
complement are the stimulation of phagocytosis activity of these acicl hydrolases is normally
and the lysis of Foreignorganisms. A number ot intracellular,but on cell death they may well be
complement components mediate various
liberatecl at the site of inflammation and cause
inflammatoryeffects,in particularC3aand C5a.C5a
considerabledamage.
in particular is chemotactic for neutrophils and
increasesvascular permeability. Conclitionswhere
Mastcel
degranulation
Braclykinin anclhistatninc
Histarnine\ release Ce lllysi s Neutlophil
chetnotaxis
activation,
Increased irndplragocytosis

etl'ects
I nt1a|rrmatory
of cor
./ -r' deposi ti on.
Vasodilation
Pain
Bradykinin Thrombin
Histamine
Blady k inin
Hist:tnrine
" l4,l z lnflammato effects of com onents
Prlncipleot lledlcln6lChemistryflol. il) 5l Antl-lnflammatory
Analgesics

Tissuetlumage

Local releaseof rnediators

of inllirnrlnation

o tn
@ a) lncleased
bloodtlow
t^
b) Incrcased
vascular
permeability

\-
Caoillarv c ) Cellularinfiltration

FI . 14.2: Acute lnflammatlon

The seconclgroup of hyclrolyticenzymes An inflammationmay be eithera primaryor a
consistsof those that act at neutral pH and are secondary_response to the , tissue clamage. A
containedin cell organellesother than lysosomes. primarylinflammationinvolvesclirectanclgenerally
Theseare probably more important in the early acute defence reaction whlle in the secondary
stages of tissue damage cluring inflammation. inflammation,it is an indirectconsequence of the
exaggeratect
Noimal phagocytosisseems to involve these pathological cell physiology, arising clue to
neutralpH en4ymes:they includecollagenase condition,e.g., rheumatoid arthritis.
and The anti-inflammatory analgesic agents, also
elastase. popularly known as non-steroidal -anti-infla-
All these mediators cause local vascular mmatorydrugs are associatedwith analgesicand
response,which is characterized by : antipyreticactivities.The peripheralnerve fibres
(l ) Increasecl blood flow to the affecteclarea. which concluctpain impulsesmay be categorised
(2) Increased vascularpermeabilitywhich may its :
causeoeclema. (a) The largemyelinatecl A fibresthat concluct
(3) Cellularinfiltrationof plateletsand macro- fast,more intenseanclprecisepain.
phagesfrom the capillariesinto the tissue (b) The myellnateclB fibresthat conductpain
spaces. lmpulsesof mediumintensity,and
So in brief, the sequenceof early events tn (c) UnmyelinatedC fibres that concluctslow
inflammation may be summarised as: and cliffirsecl
pain.
(a) Initial injury which causesthe releaseof :overed in this chapter, have an
inflammatorylmecliators. it the synthesisof thromboxane
(b ) Vasodilation. and prostaglandins. This fact was first discovered
(c) A glycoproteinE-selectinappearson the by Vanein 197t, who assignedthe therapeuticas
well as adverseeffiectsof aspirin-likedrug3to their
inner surface of vascular endothelium ability to prevent prostaglanclin
during inflammation.lt induces the biosynthlsis.
Consiclerable evidence has supported the
adhesion of WBCs by attracting the concept that non-steroidal anti-inflammatorv
tetrasaccharide sialyl Lewis X which is act by inhibitingthe biosynthesii
ctisplayedon the surfacesof WBCs.After ; which are the basiccausebehincl
furtheradhesionthe white blood cellsare pain, fever and Inflammatoryconditions.They
then able to squeeze through gaps have the afllity to sensitisethe pain receptorsto
between endothelialcells and enter the mechanicaland chemicalstimulation.The bio-
adjacenttissuesto help repairinjuqr.Thus, synthesis of prostaglandinsis catalysed by
this increased vascular permeability, microsomal enzymes present in almost eveql
mammaliancell grpe, except erythrocytes.
resultsinto cellularinfiltration. Prostaglanclins
(d) Migration of phagocytic celts to the _ are a group of iyclopentane
derivatives formed from poly-unsaturatid fatty
inflammedarea, resultinginto releaseof acids by most mammaliantissues.The baslc
lytlc enzymesdue to rupturingof cellular structureof all prostaglandinscontalnsabout ZO
lysosomalmembranes. calbon atoms having a cyclopentanering with two
adjacentsicle-chains.
Principles
of Medicinal
Chemistry
flol. ll) E8 Anti-lnflammatory
Analgeslcs

Arachidonicaciclservesas a precursorfor bio- ancl release of prostaglanclins.Thus, they have

synthesis of prostaglandins in humans. Arachi- minlmum CNS side-effects.They neither induce
donic acid is probably stored in tho phospholipid moocl alterationsnor have a tendency to cause
fractionof the cell. The biosyntheticroute for the drug dependence. Thusmorphinelike drugsact on
formation of various prostaglanclinsis shown in
CNSwhilethesedrugsact mainlyperipherally at the
F i g .14.3.
siteof originof pain.
Prostagianclin
releasehas been demonstrated
An elevation of bocly temperature is usually
unclera varie! of conclitions,br example,at the
seen in many infectiouscliseases.It is also often
sitesof inflammation(skin,joints, eye. white cells);
assocl&tedwith the inflammatory process. The
during anaphylacticreactions;'in plateletsduring
centrefor control of boclytemperatureis locateclin
aggregation;in the cerebralventriclesdurlng fuver,
the hypothaiamus,An elevation of the bocly
in subcutaneousfat cluring lipOlysls.'and ln'the tempeilatureoccurs due to the attack of pyrogenic
uteruscluringlabouror during menstruation..
substanceson this regulatorycentre. $lrogens are
Prostaglandinspotentiate the early lnfla- the metabolicproductsof bacteriaanclleucocytes.
mmat ory respo nse, ca using v as oc lilat ion, They induce changes in the normal regulatory
increasedpermeabiligr,facilitatingcellularinfiltra- process of body temperature resulting into
tion ancl sensitisingthe pain receptors.The non- reduced heat loss by peripheral vasoconstriction
steroiclalanti-inflammatoryanalgesicsclo not act associatedwith an increasein the heat production.
centrallyto intervenein the perceptionof the pain. The net resultis a rise in boclytemperature.
The act peripherallvto inhibit both, the svnthesis
Injury
lnitiatcs
activation

Membrane Complement MustCells Platelet ClIro lttll ng

Phospholipids System Aggregation syvste
s m

acid
Arachidonic C,a, Cta Hista m in e HT 5 .H T Hagem:anfactor
PreKallikrein Kallikrein
Increased
ilBo vascu Vascular
l-U(J.r lar
pcrnieability dilatation
Ic+
urD4
'(Pro-intlamrnatory
products)
PGl2
PGE2
PGD2 Antibodyfbrmation
FGF2 PMN Monocyte----* AB - AG complexes
-+
mrgratron migration complement activation

Inflammation
(Biochemical+ Immunological)
tlg. I4.3 : Mechanlsmslnvolved In Inflammatlones dlscoveredby Vane In l97t
 of MedicinalChemistry(Vol.ll)
Principles 2s9 Anti-lnflammatoryAnalgesics

Prostaglandin E1 is known to be a potent diseases.A long term therapy is beneficialin almost

pyrogen (fever inducing) and PGE2causespain, all patients with suspected heart attack or
oedema,feverand reddeningof the skin. unstable angina or with any history of heart
attack, stroke, angina, arterial bypasssurgery or
In an inflammatorydisorcler,the endogenous angioplasty,or other occlusive diseasesof the
pyrogen apparently passes into the CNS anct blood vessels,irrespectiveof age, hypertensionor
stimulatesthe releaseof prostaglanclin-likesub- diabeteis.Higher doses do not increase the
stancesfrom some specificsites within the brain. antiplatelet effect but onset of 'action is quicker.
The non-steroidal anti-inflammatory analgesic Because side-effects are possible, long-term
agents have antipyretic activi$. They block the aspirinintakemay even clo more harm than good in
synthesis and release of these substances, low-risk indi"iidual.Therefore,treatmentof normal
followed by peripheralvasoclilationand increased people with prophylactic aspirin is not
sweating, resulting into considerableheat loss recommended.However,it is rathersuggestedfhat
from the body. This brings down the bocly advice on a healthy life-style would be of greater
temperatureto normal. benefitsto the patient.
Anti-inflammatoryagents are believed to act (c) The gestation or spontaneousIabgur l s
by clisruptingthe arachidonicacid cascacle.These founclto be prolonged.
clrugsare widely used for the treatment of minor
pain and also for the managementof oedemaand (d) Due to their higher affinity for plasnra
the tissueclamageresultingfrom arthritis. proteins,theseagentscauseeasy displacementof
othei plasma protein-boundclrugs.This may lead
Theyalso provide reliefto the patient from the to a sudden, unexpected rise in the plasma
emotional trauma of Fever,pain and insomnia. concentrationof co-aclministered drug resultingin
Besides inhibiting the cyclooxygenaseenzymes potentially clangerouseffects.
involved in prostaglandinbiosynthesis,they also
(e) In some indivicluals,hypersensitivity
interfere with a varie! of other enzymes. The
inhibition of cyclooxygenaseenzyme is probably reaction may be seen during therapy which is
only one oF several mechanisms for the anti- characterizeclby oeclema,generalisedurticariaand
inflammatoryractivigl of these drugs, since inclo--sometimes bronchial asthma. Epinephrineis
methacindoes not block this enzyme.The adverse usually usecl to control such hypersensitivi!
effects, in part, can be accounteclon this basis. reac on.
The major adverse-effectscommon to different The anti-inflammatoryanalgesicspopularly
classesof these drugs are as follows : known as non-narcotic analgesic agents are also
(a) Except para amino phenol clerivatives, associated with antipyretic property. The
these drugs proclucegastrointestinalside-effects. prototype of this class is aspirin, ancl hence,
In the untreatecl normal person, the GIT. though this class comprises the chemically
membraneis protectedfrom mucosalclamageby unrelated heterogenous group of compounds,
prostaglandinslike PGI, and'PGE2.Thesedrugs thesecompoundsare often reFerred to as 'aspirin-
like' clrugs.They are valuablefor the non-specrfiq'
inhibit the synthesisof gastric prostaglandinsand
relief of pain of mild to moderate intensities,like
exposethe mucosalmembraneto increasedgastric
headache,arthritis, neuralgia, clysmenorrhea,etc.
acicl attack resulting into gastric or intestinal
Due to their ability to inhibit the synthesis and
ulceration.
release of thromboxane A2 (platelet aggregating
(b) Their ability to inhibit the biosynthesisof
factor),some of these agents are also useful in the
prostaglandinsenables them to prevent the treatment of diseasescharacterizedby platelet
formation of thromboxane A2, a potent aggre- hyperaggregationsuch as, coronaryartery disease,
gating agent. Thus treatment with non-steroidal myocarclialinfarction,etc.
anti-inflammatory drugs leadsto increasein the
Theiruse in rheumatismis, however,sympto-
bleedingtime.
matic only. The remissionof rheumatoid or osteo-
It revealed that medium close of aspirin arthritis requires corticosteroicltreatment, often
(75-325 mg claily)producedreductionsof about a combineclwith the use of penicillamine,anti-
quarter in heart attack, stroke or other arterial malarials,gold compounds (e.g., auranofin)or
diseasessuch as angina or peripheral vascular lmmunosuppresslve agenrs.
Principlesof MedicinalChemistry(Vol.ll) n Anti-lnflammatoryAnalgesics

Their effectivenessin various inflammatory

fable l4.l
conditions is due to their ability to inhibit the
Sallcvllc acld derlvatlves
biosynthesisof prostaglandins.Aspirin itself
inactivatesthe qyclooxygenaseenzyme by acety-
lating serine group at its active site. With the cooRr
exceptionof indomethacin,the aspirin-likeclrugs
irreversiblyinhibit the qycloo4ygenaseena/mes.
OR,
Besidesthis, some of these agents have an
ability to speed up the breakdownof muco-
polysaccharides,in adclition to inhibiting lts Name Yearol
synthesis.They also stabilisethe lysosomesand introduction
cool down other mecliatorsof inflammation. H
Salicylic
acid H 1838
Some of 'aspirin-like'clrugs have uricosuric
effect (i.e., promote excretionof uric acid) and Methyl CHs H 1844
hencemay be usefulin the treatmentof gout. salicylate
Sodium Na+ 1875
r4.2 ctAsstFtcATtoN salicylate
Ine vanous analgesic-antipyretic
anti-infla- Phenyl CoHs 1886
mmatoryagentscan be classifiedas salicylate
Non-Steroldal Antl-lnfl ammatory Drugs
J !/ J Acetylsa cocH3 1899
Aclcllc drugs Baslc drugs Non-acldlc drugs
acid(Asp _.i
e.9.,
Timegadine e,g.Indoxole Since,salicylicacid is so irritating, (that it c"'ln
inhibitsneutrophil Nictindole only be used externally)various clerivativeshave
degranulation
and been synthesizecl for systemic use. These
superoxide clerivativescan broacllybe divicledinto:
production (i) Estersof saliqylicacid :

Salicylates acid(1838),
: Salicylic Aspirin( 18es)
Paraaminophenols:Paracetamol cooR
Pyrazolones:
Phenylbutazones
Suxibuzone
Indole
acetic
acids:Indomethacin,
Clamidoxic
acid
Propionic
acids:lbuprofen,
Naproxen
Arvlanthranilic
acids:Meclofenamic
acid.Tolfenamic
acid
L_ Miscellaneous
agents:
Piroxicam,
Tenoxicam (ii) Saliqylateestersof organicacicls

I4.3 SATICYLICACID DERIVATIVES

COOH
Salicylicacid was first useclin rheumaticfever
by Mac Laganin 1877.The salicylicacicl clerivatives
are most wiclely employeclto treat arthritis.
o-c - R
cooH tl
o
(iii) Phenoxy derivatives
OH cooH
Saliqylicacicl
Theaspirinlike clrugsare mild analgesicsand are
effective against pain of low to moclerate
intensigi.
Prlnciplesof MedicinalChemlstrygol. ll) 61 Anti-lnflammatory
Analgesics

(l) Esters of sallcyllc aclel : The alkyl anclaryl (a) Aluminiumaspirin

esters are usecl externally, mainly as counter-
irritants. These compouncls have very little cooo
analgesic valuee.g.
Al@@o oHe
coocH.l ococH.3

OH (b) Calciumaspirin
Methylsalicylate
cooo
Methyl salicylate
A Fewinorganicsalicylatesare used internally cue@
as analgesics.These compounclsvary in their ococHl )

stomachirritationproperty.
These include the Followingsalts of salicylic Other compounclsof interestare :
acicl: (l) Carbethyl sallcylate : It is an ester of
ethyl salicylate ancl carbonic acid and thus is a
ia) Sodiumsalicvlate combinationof a gpe I ancltype ll derivativesof
(b ) Sodium thiosalicvlate salicylicacid.
(c) Magnesiumsaiicylate
(cl) Cholinesalicvlate
cooc2H5
(e) Lesscommonly usecl
(r) Ammonium saliqylate oo
(ii) Lithium salicylate
(iii) Strontium salicylate. (2) Sallcylamlde : lt gets excreted more
rapiclly than other salicylates and exerts a
(ll) Sallcylate esters of organlc aclds
moclerately quicker and cleeper analgesic effect
Exarhplesfrom this classare :
than does aspirin.

COOH
C ON H ,

ococHs
Aspirin
Aspirin
Aspirin is still the most extensivelyemployecl
Structure-Actlvlty Relatlonshlp :
analgesic-antipyretic ancl anti-inflammatoryragent
associatedwith few untowarcleffects like allergic
reactions (asthma and urticaria) and gastric
irritation(clueto its hyclrolysisto salicylicacid).
The name was coined by aclding an "a" for
acetyl to spirin for Spiraea,the plant speciesfrom
which saliqylicacid was once preparecl.
The following salts of aspirin appear to have
Fewer undesirable side-effects ancl to induce
analgesiafasterthan aspirin.
OH
Saliqylamicle
(a) Various substitutionson the carboxyl or
hydroxyl group result into change in
potenry as well as toxicig.
(b) The ortho position of the OH group is an
important feature for the action of the
salicylates.
(c) Benzoicacicl,though much weaker,shares
many of the actionsof salicylicacid.
(d) Various approaches have been made
towarclsthe clesignof a superioranalogue.
e.9.,
Principlesof MedicinalChemistryflol. ll) & Anti-lnflammatory
Analgesics

(l) Trlllsate : It is a complex salt ot salicylic (6) Flufenlsal : With the introduction of a
aciclwith cholineand magnesiumwhich possesses hyctrophobicgroup (F) at 5 position, the
longer duration of action ancl lesser gastro- compoundbecamemore potent, longeractingancl
intestinalirritationthan aspirin. with lessgastricirritation.
(2) Benorylate : It is the N-acetylamino-
phenol ester of aspirin. ooH

F ococHl
coo NHCOCH3

ococH3
Benorylate
(3) Difluntsal : It is recently introduced for
clinicaluse in some partsof the world.
COOH
OH
5-(2, 4-ctifluorophenyl)salicylicacid
(4) Fendosal : It possesses an analgesic
activity comparableto that of diflunisal.
OH
Fendosal
(5) Salsalate : lt is the ester formed between
two salicylicacid molecules. Since, it is relatively
insolublein the stomachand is not absorbeduntil
it reachesthe small intestine.it is said to causeless
gastricinitation.
Flufenisal
Local Actlons :
Salicylicacid and methyl salicylate,since,both
are too irritant to the gastric mucosa internally;
thesecompoundsare used for topic.rtapplications
clue to their keratolytic, antisepticancl fungistatic
actrons.
Salol Principle :
Salol, (phenyl salicylate)was introducedby
Nencl<iin 1886.'lt is an ester of two toxic sub-
stanceslike phenolanclsaliqylicacid.
When both the components(i.e., alcoholand
acicl)of an esterare activecompouncls,the esteris
calleclasTruesalolor Fullsalole.g. phenylsalicylate
(salol)anclp-naphtholbenzoate.When only one
componentof the ester (either alcoholicor aciclic
part) is active, toxic or corrosivecompound, the
ester is referreclto as a partial salol e.g. methyl
salicylateand thymol carbonate.
I4.4 PARA-AMINOPHENOLDERIVATIVES
Since p-amino phenol is the metabolite of
aniline (anilinealso possessesantipyreticactivi!)
these analgesicsare also being calleclas "coal tar
analgesics". The only agents of interest,from this
classare :
NHCOCH3 NHCOCHI NHCOCH3

o- C
ll
o OH oc2Hs
Salsalate Acetanilicle Paracetamol Phenacetin
Principlesof MedicinalChemistryflol. ll) 2fi1 Anti-lnf
lammatory
Analgesics

Acetanilicleis metaboliseclinto paracetamol the antipyretic action of aminopyrine was

and aniline.The toxicity of the latter compouncl discoverecl.Due to haematologicaltoxicity search
cliscourageclits use in therapeutics. for improvecl analogue of aminopyrine lead to
The p-amino phenol clerivativesare analgesics phenylbutazone.
ancl antipyretics. They do not have anti- (b) 3, S-$razolkllnetllone derlvatlves :
inflammatory activity.
I4.5 PYRAZOTONEDER,IVATIVES /R t
N
t\
rN
Rr
i.,-
H ( l ) Phenylbutazone
R2=C-6H5,&=n-C+Hs
Ilrazole l\razolidine (2) Oxyphenbutazone
Rz: p -OHC6Ha; fu=n - CaHn
(3) Sulfinpyrazone
Nlt R 2 :C 6H5;& =CHzCHz
j ,NH
NT
N-
H H

5-Pvrazolone To eliminate Gl-disorclersancl occasional

-3,5-Pvrazoliclineclione
(a) S-Pyrazolone derlvatlves : agranulocytosis,the n-butyl group of phenyl-
butazone may be replaceclby (CH2)2SOC6H5 which
increasesanalgesicactivig ancl uricosuricactivity
llrc /R, in sulfinpyrazone.
N
t\
Phenylbutazone,although analgesic itself,
was originallyclevelopedas a solubilizer,for the
insoluble aminopyrine. Compareclwith phenyl
butazone,oxyphenbutazoneis an equally potent
't
anti-inflammatoryanalgesicbut is slightly less
Compound
tox Ic.
Antipyrine cH H Phenylbutazonecompletely unclergoesmeta-
Aminopyrine cH N (CH3)z bolism by liver microsomalenzymes to (a) oxy-
Dipyrone cH N -CHz SO3Na
t
phenbutazoneancl (b) 1-hyclroxyphenylbuta-
c zone. Other compouncls of interest from this
Senesare :
Antipyrine is the parent clrug from this
category.lts modificationfurther resulteclinto the
introduction of aminopyrine and clipyrone in
clinicaluse.
Antipyrine and aminopyrinehave analgesic, N H
antipyretic and antirheumatic activities. Fatal IN a0 "f
agranulocytosiscaused by dipyrone ancl amino-
pyrine has limited their usefulness.Aminopyrineis
oll
no longer an official drug. Chemicallyaminopyrine
is N-phenyl-N-alkyl-substitutecl pyrazoline-3-one.
Being consideredas structuralanalogueof quinine, y-Hyclroxyphenylbutazone
\
Principlesof MedicinalChemistry(Vol.ll) M Andlgesie
Anti-lnflammatory

(a) Kebuzone : lt has similar properties ancl

actions as that of phenylbutazone. cH..,cooH
)nc e tr c:rcid
H.rCO
lndolc

I
N c_-o
IN cH.,cH,cocH
r p-cirloro
benzoyl

Kebuzone lnclomethacin
(b) Phe n a z o n e : In man, it is largely metaboliseclby O-cle
methvlation ancl N-deacvlation.Excretionis facili
tateclby conjugationwith glucuronicacid.
The most frequent sicle-effectsincluclepepti<
N ulceration, bloocl clisorclers,severe frotrta
IN CH,CH= Ct CHr ) : headacheand GIT clisturbances.
Structure-Actlvlty Relatlonshlp :
(l ) The following substituentsgenerallygive
expecteclactivities :
(a) Inclolesubstituents:
(c) Azapropazone : lt is a pyrazolo benzo- S-Methoxy,F, (CHr)zN;
triazineclioneclerivative,having similar activity as 5-Methoxy-6-F;Z-Methyl
that of phenylbutazone. (b ) Benzovlsubstituents:
P-Cl. F or CH.S
(c) Acetic acid substituents:
CH,CH'CHr a-CH3,CO2CH3
(2) The carboxyl group is necessaryfor anti
OH inflammatory activitY. The more acidic the
H ,C
carboxyl grouP, the greater the antirheumat
actrvrty.
(3) The 1-incleneisosterehas activigl simila
to that of inclomethacin.
Azapropazone cH..,COOH
HrCO
14.6 INDOMETHACINAND OTHER.
CH,
ARYLACETICACID DERIVATIVES
The possibility that 5-hyclroxytryptamine
CH
might be an important mediatorof inflammationled
to the discovery of indomethacin,after the labo-
ratoryevaluationof 35O inclolederivatives.
lntroduceclin 1964, indomethacinis a power-
ful anti- inflammatoryanalgesicagent.
Princlplesof MedlcinalChemlstry(Vol.ll) 265 Anti-lnf
lammatory
Analgesics

The study of SAR of this class resulted in the

developmentof following clinicallyuseclagents.

pH'cooH H
F
HrCO
CHr

CH l- Naproxen

cHcooH
O+S-CHr
IcrHs
Sulinclac
Sulindacis a pro-drug,the activeform being its
-SH derivative. lt is also an inclene isostere, Nanroxyrate
substitutedby F in the indene ancl by methylsyl-
phoxidein phenylgroup.
Plmoleacetlc acld derlvatlves :
(1) Tolmetin (Z) Zomepirac

o CHCOOH
tl
c CHTCOONa enoprofen
Ri Indomethacin,piroxicamand ibuprofeninhibit
PG - synthesisby macrophages(presentin infla-
Tolmetin: R1= g' Rz= CHg
mmatory exudates as well as by syncoviocytes
Zomepirac:Rt = 6gr' Rz= CI ancl chondrocytes which contribute to infla-
ACID AND PR,OPIONIC
I4.7 PHENYTACETIC mmation of joint) almost to the same extent.
ACTDDERIVATIVES Etodolac is also suggesteclfor the treatment of
osteoporosis. lt is a potent anti-inflammato4lclrug
Numerous phenylacetic acid and proplonlc
acid derivatives have been synthesizedancl found with a high gastric tolerance. The apparent
to possessanti-inflammatoryactivigl. The most eliminationhalf-lifeis 7 hours.It extensivelybinds
commonly employeclagents from this classare : to plasma-proteins.Etodolacis found to possess
potent anti-inflammatory, anti-arthritic and
analgesicactivig. lt is superior to other NSAIDsin
havinglessfaecalblood loss.Chemicallyit is 1, 8 -
CHCOOH cfiethyl- 1, 3, 4,9 - tetrahydropyrano t3, 4-bI
cHr inclole-1- aceticacicl.ln man,a doseof 2OOmg per
clay is suggestedas minimum effectivedose for
..-;zlbuprofen the reliefof activciheumatoidarthiltis.
Principlesof MedicinalChemistry(Vol.ll) ffi Antl-lnflammatory
Analgesics

Several other arylacetic acicl derivatives are Mefenamic acid. flufenamicacicl and meclo-
under clinical trials. These inclucle alcofenac, fenamicacid are the clinicallyusefulfenamates.
fenclofenac,pirprofen, prodolic acicl, ketoprofen (1) Mefenamicacid: R1= Rr = 611,
ancloxepinac.
(z)Flufenamicacicl:R, =H,Rz= CFr
(3) Meclofenamicacid: Rr=Cl, Rr= 611r,
cHcooH Rr = C l
o Mefenamicacicl has moclerateanti-inflamma'
etoprofen
tory activigl ancl mainly usecl as a short term
analgesic.Diarrhoea,clrbwsiness anclheadacheare
among the principalside-effects.It is also useclin
the managementof primarydysmenorrhea, which
cH..,cooH is thought to be caused by excessive concen-
-/Oxepinac trations of prosfaglandins.
The following heterocyclic isosters 6f fena-
CH, matesare unclerclinicaltrials.
I
CHCOOH ( l) Clonix i n :
COOH
ncloprofen
A hybriclof fenamateand phenylaceticacid ts
diclofenac. cH,,cooH NH

(2) Flunixin:
/ Diclofenac COOH
The metabolism of substituteclphenyl acetic
aciclsinvolvesmainly aromaticor aliphatichyclro-
xylation followecl by glucuronicleconjugation at NH
thq hydroxyl andlor carbo4ylgroup.
I4.8 FENAMATES OR,DER.IVATIVES OI cH.,
N-AR.YLANTHR,ANILIC ACID
Replacingphenolic OH of saliqylicacid by an
CF.
aryl substituteclamino group which results in
isostersof aryl ethers of salicylicacicl.Fenamates
are a family of N-arylanthranilicacicls,which are
nitrogenanaloguesof saliqylicacicl. COOH
cooH

NH CH.,

R,
N-aryrlanthranilic
acid (i) Clonixin:R = _CHr
(Rr= H; exceptin meclofenamic
acid) (iD Flunixin JR = _CFr
Principlesof MedicinalChemlstryOol. ll) 6l Anti-lnflammatory
Analgesics

(3 ) Substitutedaza analogues: Metabolic studies in animal suggestedthat

OFI chlorine substitutedat 4-position of the phenyl
I ring extendedthe half-lifeand clurationof action.
co,'cH.,cHCH"OH
3. ZH- 1, 2 - b e n z o t h i a z i n e3- ( 4 H )'o n e -
I , I -clioxiclesas bioestersof tesicamwas synthe-
sized. This series clid not prove fruitful. Conse-
quently, the isomeric carboxamiclesof the
4 - hycfroxy- ZH - 1, Z - benzothiazine- t , 1 -
clioxiclewere preparecl.
N o
I OH N
Claphenine: 7-Cl tl
C
Floctafenine: 8-CF3
Glaphenine is a combination of 7-chloro-
quinoline ancl anthranilicacicl.Thesecompouncls
possessonly weak anti-inflammatoryr activities.
I4.9 MISCELTANEOUS AGENTS
(a) Many o-hyclroxy aromatic carboxylates Sucloxicam
have been tried (salicylicacicl) in which benzene
Sucloxicamis more potent than testicamancl
ring of saliqylicacid is replaceclby other aromaticor
quasiaromatic nuclei. The group of oxicams hasa longerdurationof action.
representsN-arylcarboxamicles of 4-hyclroxy- 4. Furtherresearchleclto piroxicamwhich has
1, Z-benzothiazine 1. l- clioxicles.
e.9.,prroxrcam. a half-lifeof 45 hours.
5. The tautomericstructuresimpart further
OH o stabilig to the enolateanion. Suchstabilizationof
ll
C _N H
the enolate anion woulcl thereby contribute to a
further increasein the aciclity of the conjugatecl
acicl.

Piroxicam
, Pfrzer(Feldene)
Log P= 0 . 2 6 ,p Ka = 4. 6 O,-H\N O : 6/ N: ' "
1. The initialcompouncls,isoquinolinecarbox-
aniliclesshowecl Al potency similar to phenyl- <F_.+
butazone.The enhanceclacicl properties of these
cyclic p - diketoneswere responsiblein part for
their biologicalactivities.
z. m tv
H
6€6.-H:.,,,.- oeo
t
N

Tesicam v VI
Principles
of Medicinal (Vol.Il)
Chemistry 268 Anti-lnflammatory
Analgesics

6. lt is assumeclthat first step of the reaction
involves a reduction oF the enzymatic Fe+++to
Fe+-f by abstracting H-atom at Ce of arachidonic
aciclto give a clelocalisedraclicalwhich reactswith
molecularoxygen. This results into formation of
superoxicleanion which is metaboliseclto reactive
oxygen species including HzOz, hyclroxylradical
anclsingletoxygen.Thesereactiveoxygen species
are thougtrt to contribute to the inflammatory
processand tissue destruction.
Piroxicamancltolmetin are recentlyclevelopecl
promising agents having goocl analgesic-anti-
pyretic ancl anti-inflammatory activities. Both
these agents have an abilig to inhibit cyclo-oxy-
genase enzyme. They are rapictlyancl completely
absorbeclfrom GIT, ancl get extensively bound to
plasma-proterns.
zo
\N
CH'
CONH
OH
Piroxicam
cH-1
o I
ll N
Hrc C CH,'COOH
Tolmetin
Piroxicam is metaboliseclmainly by hyclroxy-
lation in the pyriclyl ring followecl by glucuronide
conjugation,while tolmetin metabolism occurs by
the oxidation of para methyl group to COOH. The
metabolitesare excreteclin urine in both, free ancl
conjugated forms. Piroxicam is better toleratecl
agent, having long halF-lite.
Both these drugs cause gastric erosions and
increasein the bleeclingtime. The most frequent
adverse effects include nausea, vomiting, epi-
gastric pain, anxiety, sl<inrash, gastric ancl peptic
ulceration.
(b) Gold compountls : The clinically usecl
agentsfrom this categoryincludeaurothioglucose
auranofinanctgold socliumthiomalate.In all these
agents, the golcl is directly attached to sulphur.
Hence these compounclsare supposeclto act by
the inhibition of vital sulftrydrylsystemsin the
bocly. Golcl gets accumulated in the lysosomes
where it inhibits the activity of acid phosphatase
B-glucuroniclase and cathepsin enzymes which
have catalytic role in various inflarnrnatory
d isorclers.
In aclclition, golct compouncls lnhibit the
synthesis of connective tissues. Hence they can
be used in the treatment of rheumatoid arthritis in
patients wh6 clo not responclwell to ttre therapy
with aspirin-likeclrugs.
They are usuallyaclministereclby intramuscular
route, sincethe absorptionfrom oral route is erratic
ancl incomplete. They are extensively bound to
plasma-proteins.Their onset of action is slow and
signs of inflammation are reducecl in intensity
graclually.The slow rate of excretion of gotct
comDounds can be enhanced bv concomitant
administrationof sulfhyclrylagents like, penicill-
amine and climercaprol.They are primarilyexcreted
in urine and faeces.
The aclverse effects associatecl with gold
therapy inclucle cutaneous reactions, aplastic
anaemia, leucopenia,agranulocytosis,thrombo-
cytopenia, nephrosis, hepatitis and peripheral
neuritis. They are contraindicatedin patients with
anaemia,renal disease,hepaticclysfunctionand in
pregnancy.
(c) D-penlclllamlne Only D-isomer is
clinically used in the treatment of rheumatoid
arthritis because L-penicillamineis reported to
cause optic neuritis clue to its anti-pyridoxine
activigr.Being a metaboliteof penicillin,it has a
structural resemblancewith cysteine. In certain
cases,combinationof D-penicillaminewith aspirin-
like clrugs may give better results. lt, alongwith a
ctisulphictemetabolite is excretecl in urine and
faeces. Due to its high toxicig, it shoulcl not be
useclfrequentlyor for a long-term treatment.

ocH3
QH,OC
o o S- Au+-P(C,'Hr),
ll H
HjC - CO CHCOONa
OCOCH
-Au I
H OH H ococH.r S- Au

Aurothioglucose Auranofin Gold socliumthiomalate

Principlesof MedicinalChemistry(Vol.ll) 269 Anti-lnf
lammatory
Analgesics

(cl) Other agents whlch have beneflclal Cyclooxygenasecatalyses two enzymatic

effects ln the treatment of inflammatory processes(1) The incorporationof oxygen in a
dlsorclersInclude : dioxygenase step to form PGG2and (Z) the
. (i) Antimalarial agents: Chloroquine ancl subsequentperoxidationto PGH2.The reactionis
hydroxy chloroquine.
initiatecl by the stereospecific abstraction of
(ii) Glucocorticoicls
hyclrogenat C13followecl by oxygen attack at C11
(iii) lmmunosuppressiveagents: Azathioprine,
and C15anclring closurebetweenCsanclC12in next
cyclophosphamicle.
reaction.The presence of hematin and molecular
(iv) Sulphonamicles:Diflumidone.
oxygen is required. Most of NSAIDs act by
14.r0 MECHANTSM Ot ACTTONOt NON-.
inhibiting cyclooxygenaseby preventing the
STEROIDALANTI-INTLAMMATOR,Y AGENTS
abstractionof hydrogen from C13and therefore
(a) Blosynthesls of prostaglandlns : The
blocking peroxidation at C11ancl C15.This action is
biochemicaleffectsof NSAIDsinclucleinhibitionof
lysosomalmembrane stabilization,inhibition of the highly specific, for similar abstractionancl peroxi-
biosynthesisof mucopolysaccharicles, uncoupling dation reactionsat other points in the fat\r acicl
oxidative phosphorylation,fibrinolytic activity, moleculeare not inhibitecl.
sulfhyclryl disulfide stabilization, collagenase On the basisof mechanismof action, these
procluction and at times suppression of chemicallv cliversifieclNSAI DS can be broacllv
lymphocytic functions. clivicleclinto :
]----> Tissuedarnage
Timegadine Adr c nal
cortcx
In h i b i (s::cutr oPhil
dcglanulntiort andstrpcroxidc
Irolipids
Phosp Lipocortin
[orrnation N apl r tl r y r i di ne

A,
Phosplrolipasse Chloroquinc
Mepacrine

cooH
Rcvcrsihlc
acid
Arachidonic Paracetarnoln o lt - co n lp ctlll vc
frccradical trappcr
Benaxoprofen
Reversihlc
Ihuprol-cn
conrpcti(ivc
.E x l 0es 9-Et

5-LO
f
(
Cyclooxygcnase As pi irn

tL)
I rreversibl
Antiaslhnralic Lr
Leu tiTB.r
et otrrenes (! PG-Enc (] CS "4. blocker
,t Ic,r a
*
activity
IDo Antiangirtal
F/ 'ts L activity
Prosl
29
Phcnthiopyridincs 2
4

Prostacyclitr
'rxA)
I
*
tor
Anti-plaleletaggt'cga Plateletnggregation
asodilation vitsocons[fl ct |0n
Ftg. t4.4
Principles
of Medicinal (Vol.ll)
Chemistry no Anti-lnf
lammatory
Analgesics

PAI N
likedrugs
Morphine
tors
Painrecep
(CNS)

InllamtmalLOrn
Y
Celldiam€
ag

Release
of ar:ach
a t drolnrcacid
I
I
Aspirinlikedrugs
I I
v I
I Hyperalgesia
Release
of Prostaelandins (a stateof mechanical
or chemicalstimulation)

. 14.5: Stlmulatlonof aln rece tor

(a) Reverslble competltlve Inhlbltors : action of salicylicacicl may depenclmore on other
Examples oF thls class are fatty acicls, closely mechanismssuch as inhibition of leukoryte eme-
relateclto the substratewhich have a comparable gration ancl lysosomalstabilization.
affinity for the cyclooxygenase (CO) and Aspirin like drugs block this releaseof prosta-
lipooxygenase (LO) enzymes but are not glandins in the brain, followed by peripheralvaso-
converteclto oxygenated inflammatoryproducts dilation ancl increaseclsweating resulting into
of CO pathway (i.e., prostaglandins) and LO considerableheat loss from the body. This brings
pathway (leucotrienes).Ibuprofen has a bincting
down the body temperatureto its normal.
affinity For cyclooxygenase similar to that oF
arachiclonicacicl. The carboxyl function of aryl I4.T I TREATMENT OI GOUT
acidic NSAIDs is said to resemble the terminal Gout is a term representinga heterogenous
carboxyl of arachidonic acicl while the planar group of genetic anclacquiled cliseasesmanifested
hyclrophobic groups bind to the enzyme to by hyperuricemiaancl a characteristicacute infla-
prevent hydrogen abstraction at C-13. The mmatory arthritis induced by crystals of mono-
presenceof aryl halogen is supposeclto enhance sodium urate monohyclrate. Some patients
this activi! due to its lipophilicit5r. develop aggregated deposits of these crystals
(b) R.everslblenon-competltlve Inhlbltors : (tophi) in and around the joints of the extremities
The reversiblenon-cornpetitiveinhibitors have that can lead to severe cripping. Many patients
anti-oxidantor radicaltrapping properties.During develop a chronic interstitial nephropathy. In
inflammation, a continual presence of lipict aclclition,uric acid urolithiasisis common in gout.
peroxidesinducesa free radicalchain reactionthat Primarilygout is chiefly a cliseaseof aclultmen. The
sustains cyclooxygenaseactivity. This can be frequency of gout is increaseclin patients taking
blocked by an aclctitionof raclicalscavengersor cliuretics,especiallyof the thiazide group. Gout in
anti-oxidants(e.g. paracetamol)which acts as all oF its forms makes up about 5o/oof arthritis
reversiblenon-competitiveinhibitors. cases.Humans lack uricase,therefore, uric acid is
(c) lrreverslble tnhtbltors : The irreversible the end product of purine metabolism. In normal
inactivation of ryclooxygenase is clone by aspirin subjects, approximately one third oF uric acid
through the transacetylation of the lysyl amino disposed of each day is degraclectby bacteriain the
group in the enzyme which is important tor its gut and two third is.excreted unchanged by
activity.As salicylicacid is chemicallyincapableof kidney. Both increaseclpurine biosynthesisand
acylating the enzyme, the anti-inflammatory decreasecl renal excretion of uric acid play
 of MedicinalChemistry(Vol.ll)
Principles n1
important roles in the pathogenesisof primary
hyperuricemia.
--
- Oncethe uricaciclis filteredby renalglomeruli,
it is almostcompletelyreabsorbedinto circulation
from proximal tubules. In normal circumstances,
some of the reabsorbeduric aciclis again driven
back into the urine by clistaltubules.Due to low
solubilitv of undissociatedform of urates. the
crystalsof sodium urate (the end product of
purine metabolism)get clepositeclin the .ioint
cavitiesand on articularcartilages.Theirdeposition
initiates inflammator5rreactionswhich involve local
infiltration of phagorytes that, after ingestion of
urate also release chemotactic substancesand
probably lactic acid. Lactic acid further loweres
clownthe pH oFthe surroundingmeclium,resulting
into further deposition of uric acicl. The phago-
cytosis of urate crystals releasesa glycoprotein
which is responsible to produce acute gouty
arthritis.An acute attack of gout occurs as a result
of an inflammatory reaction. Usually small joints
are affecteclbefore larger ones.
Uricosuric agents enhance the rate of
excretion of uric acict by reducing the rate of its
tubular reabsorption.They thus relieve the signs
and symptoms of acute attack of gout and offer
symptomatic relief in this conclition.Phenyl-
butazoneis such a uricosuricagent.
(a) Colchiclne :
It is an alkaloiclobtained from colchicum
autuinnale.lt was clinically introclucedfor the
treatmentof acute attacksof gout in i763 by Von
Storck.
It cloes not possess analgesic activig. In
inflammatorvdisorders, it is effective only against
acute gouty arthritis. lt neither effectively inhibit
the prostaglandinbiosynthesisnor it influences
the tubular reabsorptionof uric acicl.lt probably
acts to inhibit the releaseof lactic acid cluring
phagocytosis oF the urate crystals. Its central
effects include, depression of the respiratory
centers. central vasomotor stimulation and anti-
pyretic action.
H.rCO
HlCO NHCOCHl
H3CO
Colchicine
Anti-lnflammafory
Analgesics
The alkaloid is readily absorbeclfrom Cff and
by intravenousroute. The clrug alongwith its
metabolitesis mainly excreteclthrough urine and
faeces.
The adverse effects are mild and include
nausea,vomiting, diarrhoea,abclominalpain and
leucopenia. These effects appear in the dose-
dependent fashionanclare reversedif, treatment is
discontinued.In severe toxicig, cleath usually
resultsdue to respiratorylarrest.
(b) Allopurlnol :
Chemically,it resemblesin structure with
hypoxanthine.lt inhibitsthe formationof uric acid
by competitively antagonisingxanthine oxidase
enzyme which catalysesthe conversionof hypo-
xanthine to xanthine the precursor for uric acid
synthesis. Due to the structural similarity, it
competes with hypoxanthine which is the sub-
strate for xanthine oxiclaseenzyme. At higher
concentration,due to the non'specific nature of
the enzyme, it acts as non-competitiveinhibitor.
Insteaclof hypoxanthine,allopurinolis attacked
by xanthineoxiclaseand is convertedprimarilyto
oxypurinol which is also effective enzyme
inhibitor.Thus by inhibitingthe uric acid forma-
tion, it lowers down hyperuricemiaancl prevents
the formation of uric acid stones. In order to
enhance therapeutic effectiveness,allopurinol
may sometimesbe combineclwith uricosuricagent.
The aclverse reactions include, nausea
vomiting, diarrhoea,gastric irritation,headache,
fever, clrowsiness,ancl cutaneousreactions.In
some patients, hypersensitiviglreactionsmay also
be seen.
OH OH
N
Allopurinol Oxypurinol
The pKa of uric acid is 5.6. The solubilig of
uncllssociatedurates is usually low. Hence, their
solubility can be increased by inclucing their
rontsauon.
Hence alkalinizationof urine is one of the
effective wavs to minimise the intra-renalurate
deposition.
Probenecidancl sulfinpyrevonealso mobilise
the uric acicl.They are also useful agents in the
treatment of chronic gout disordersthough they
lack analgesicand anti-inflammatoryractivities.
Principles
of Medicinal (Vol.ll)
Ghemistry 2n Anti-lnflammatory
Analgesica

Recently developed NSAIDS

9czHs
NHz
II
N
Hrc

Emarfazone(lapan,Nandran) ES-IOOZ(Germany)
inhibitsvascularpermeabiligland Centralmode of action
releaseof braclykinin

CH,,
.cooH

Ketorolac(199O)
NH

Tlmegadlne (1983)
inhibitsneutrophildegranulation
anclsuperoxideproduction

s-cH,
Oxlndole carboxanrlde (1989)
Dual inhibitor of CO and 5-LO
Phenthlopyrldlne ( | 987)
inhibitsimmunecomplex N:
induced inflammation N - (CH2h-

cHr

(cH.r)rc

HO
c(cHi)1
Naphthyldlne (1994)
lsoxazole (1993) induces releaseof endogenous
Dualinhibitorof CO & 5-LO glucocorticoids
 Principlesof MedicinalChernistry(Vol.ll) 273 Adti-lnflammatoryAnalgesics

o o\
il 20
S
c cH- cooH cHr
o

Tlaprofenlc aclcl
o
'l

Droxlcam (Abbott, 1990)

N

OH

Tenoxlcam(Hoffrnann-La-Roche,
|9EZ) H,C
OH
H,C
COOH

Zlleuton Seratrodast
(lt blocksleukotrienes ynthesis) (lt blocksthromboxanereceptors)

c H - c o -NH _ CH, CH.,- CH,C-)F

Amlnoprofen (Aldounlon, l99O) Nlmesulicle

o flr\-

H H
N

Zaflrlukast
(lt blocksleukotrienereceptor)
Thromboxane synthase .lnhlbltors : Low new enzyme, the platetets do not have the
.
dosesof aspirinimpair plateletTXA2 synthesis biochernicalmachinery
necessaryfor protein
with an effecton formationof prostacyclinby the synthesis.Therefore,the abili! of platelets to
vascularenclothelium.Aspirin aceglates the CO form TXA2is blockedwhile proitaqyclinsynthesis
and therefore the inhibitory effect remains recontinueafter exposureto
aspirin.Thisexplains
effectiveuntil new enqymeis produceci.Whereas the anti-thrombotic activi!
of aspirin. other
the vascularendotheliumis capableof generating specificthromboxanesynthaie
inhibitorsinclude
Prineipleof Medicinal
Chemistryffol. ll) n4 Anti-,lnflamrratory.Analges

cooH.HCr

Ben4ylimidazole
uazoxtDen
cFr

COONa

NHz
BW 755 C oKY1s 1 8
ao
15.1 INTRODUCTION 2@
r5.l TNTRODUCTION
15.2 MYOCARDIAL CELL 2m One need not stressupon the importanceof
15.3 ACTIN-MYOSINTENSION GENERATING cardiovascular system in the body. A rrrd.ierr
SYSTEM pharmacologicalaction of a number of clinically
15.4 MOLECULAR BASISOF MYOCARDIAL used agents is merely clue to their influenceover
CONTRACTION n1 cardiovascular system.Much advanceshave been
15.5 CARDIOVASCULAR DISEASES 273
witnessed in cardiovasculartherapy over the past
15.6 CARDIACGLYCOSIDES 216
2O years. For convenience of discussion,these
15.7 PATHOPHYSIOLOGY OF HEARTFAILURE zn
15.8 MECHANISM OF ACTION 81
drugs may be classifieclas,
15.9 OTHEREFFECTS OF DIGITALIS
GLYCOSIDES
& ( a) Pos i t i v e i n o t r o p i c a g e n t s : e . 9 . ,
15.10 PHARMACOKINETIC PARAMETERS N clobutamine, cligitalisglycosides,amrinone,etc.
15.11 THERAPEUTICUSES M (b) Vasoclilators: e.g., minoxiclil,prazosin,
15.12 ADVERSEEFFECTS M hyclralazine, etc.
15.13 DIGITALlS
INTOXICATION M
( c ) Dr ug s a l t e r i n g R e n i n - A n g i o t e n s i n -
15.14 TREATMENT OF INTOXICATION N
Alclosteronesystem : e.9., captopril, saralasin,
15.15 ALTERNATIVESTO DIGITALISTHERAPY N
enalapril,etc.
15.16 ANTIARRHYTHMIC AGENTS ns
15.17 ANTIANGINALDRUGS n1 (ct)Calcium ion channel blockers e.9.,
15.18 ANTl.HYPERTENSIVEAGENTS N nifeclipine,verapamil,cliltiazem,etc.
1520 ETIOLOGYOF HYPERTENSION ETI (e) Antiarrhythmic a.gents : quinidine,
1521 GENERAL CONSIDERAT]ONS m lidocaine,bretlrlium,etc.
1522" DRUGSAFFECTING SYMPATHETICTONE 301
(0 Beta-adrenoceptorblocking agents :
15,F, VASODILATORS 3@
propranolol,labetalol,oxprenolol,etc.
1524 AGENTSACTINGON RENIN-ANGIOTENSIN
SYSTEM 311 G) Centrallyacting antihypertensiveagents
1525 DIURETICS 313 e.g. clonicline,methylclopa,
guanabenzetc.
'ts26 CENTRALDEPRESSANTS 313 To understanclthe effects of these drugs on
'ts27 ATRIALNATRIURETIC PEPTIDE 313 the carcliovascularsystem, an unclerstanclingof

(2751
Frinciplesof MedicinalChemistry(Vol.ll)
The polarized state of the cell serves as an
electrical stimulus which causes conFormational
changes in the membrane to open ion channels
(molecular gates) that selectively allows the
permeationoF Na+ ions into the cell. This leads to
reduction in intracellularnegativity, by which
depolarization commences(phase4).
When this depolarizationreachesa certain
thresholcllevel (-7O mV), the permeabilityof the
cell membrane (opening of fast ion channels)to
Na+ abruptly increases,allowing more rapiclinflux
of Na+ as well as Ca++ to procluce spil<eaction
potential (phase O), resulting into complete
deooiarization.
This upstrokecausesthe releaseof intracellular
Ca++ ions from the sacsof sarcoplasmicreticulum
into the cytoplasm. This rise in the level of free or
"activator"calcium within the cell removes the
inhibition of troponin-tropomyosinsystem d,.uer
the contractile elements ancl initiates the
contractionof carcliacmuscle. Contractionof most
mammalian hearts is thus initiated by ancl is
proportional to the influx of extracellularCa* *
which in tum triggersthe releaseof adclitionalCa++
from the sarcoplasmicreticulum.
Following clepolarization,commences the
phase of repolarization. It is characterizeclby
removalof free Ca++ions from the cytoplasmback
into cisternae.It is an energy consumingprocess,
that occursin tf-rie.:'e
sub-phases.
i) A partial abrupt repolarization(phase I )
occursas a result of closureof the fast sodium ion
channelsand an influx of chloricleions.
(ii) A prolongeclrepolarizationi.e. plateau
region (phaseZ) occurs due to much slower K+
efflux along with the slow influx of Na+ and
Ca++ions.
(iii) Rapicl but not abrupt repolarisation
(phase3 ) occursas a resultof the closureof the
slow inwarclchannelsfor Na+ and Ca++ ions ancl
the opening of one or two fast outwarcl channels
for K+.
The extracellularCa++ ions that were influxed
during depolarizationare driven out (in fact
exchanged tor extracellularsodium ions) by a
transport-systemthat is governecl by concen-
trationgradientand the transmembrane potential.
Thus, at the encl of repolarization(phase 3), the
n8 System
DrugsActingon Cardiovascular
transmembranepotential is restoreclback again tc
fluicihas lost K-
- 90 mV but now the intracellular
and gainedNa+.
L:
+50
c:
25
u
CJ
'){
!-
<r )
,|J
L-
Itr ( ,
tlg. 15.4
HereNa+ - K+ - ATPasepump again plays a role
This pump utilizesATP to actively transportNa-
out of the cell ancl K+ into the cell to restorenormal
levelsof Na+ anclK+.The pump transportsNa+ and
maintainstheir respectivegradientsin a 3 Na+ : 2 K-
: ATP ratio. It uses energl fiom hyclrolysisof the
terminal phosphorylgroup of one molecule of
intracellularATP to transport three Na+ ions
outwards ancl two K+ ions inwarclsacrossthe cell
membraneagainststeep electrochemicalgraclients
to restore normal levels of Na+ and K+. It is a
dimericproteinwith an s-subunitof 1OOKD and a
0-subunitof 55 KD. The a-subunit containsihe
ATP hyclrolysis subsite, in which aspartate
accepts the 1-phosphateof ATP. The function of
glycoprotein B-subunitis not clear. The carcliac
glycosidebinclingsite, which is partiallylocatedon
the outside of the cr-subunit, inhibits the ATP-
clriven ion transport and the Na+ depenclent
conformationalchange.The pump system present
elsewhere in bodv has clifferent cr-subunits
showing clifferentsteroiclbinclingcapabilities.
T h u s , A TP , int racellular Na+ ions anc
extracellularK+ ions may be viewecl as substrates
ancl ADP, orthophosphate,extracellularNa* ano
intracellularK+ ions as procluctsof the enzymatic
process.Many low molecularweight, non-steroidal
inhibitorsof differenttypes have been stuclied.
They are usefulfor analyzingvariouspropertiesof
N a " _K + - ATPaserather than being used as a
prototype drug.
Prlncipleof MedicinalChemistry(Vol.l1) 279 DrugsActing on CardioVascularSystem

+
-- 2K

+ +
4Na -- 3Na
#
+
Na - C;r AIPase
pump Na- - K-- ArPase
pump

Flc. 15.5
The enzyme, Na' - I(* -ATPasewas cliscovered cliuretics, etc. or by decreasing myocarclial
in 1957 by .fensSkou in the cell-membrane.lt
hydrolysesATP molecule to releasethe energy
necessary for functioning of this pump. The
enryme and the pump, both are tightly bounclto
the plasma membrane. The hyctrolysisoF ATP the heart using drugs such as arterialvasodilators
moleculeneeclsthe presenceof Na+, K+ arrdMg**
tons.
15.5 CARDIOVASCUTARDISEASES
(a) Thromboembollc dlseases :
This group of cliseasesis characterizedby
aclhesionof platelets to the inner vascularwall
resultinginto the interferencein the functioningof
extrinsic or intrinsic blood clotting system. The
platelets adhere to the collagen exposeclclue to an
lnJuryto the vascularendothelium.The releaseof
thromboxaneA2 results into vasoconstriction
and
enhancesplatelet aggregation.The permanent
platelet fibrin clot initiatesa seriesof events that
may lead to myocardialinfarction(a region with
deficientoxygen supply) ancl to congestiveheart
failure.
The treatment of myocardial ischemia
(cleficient02 supply) may involve the therapiesto
improve coronaryblood supply. This can be done
either by means of clrugs such as nitrates or by
means of aortacoronary bypass grafts. The
myocardial ischemia can also be treated by
reducingthe heart work-load so that the heart mav
work efficiently even under cleficient02 supply.
Thiscan be done either by clecreasing the pre-loacl
(venousvasoclilation)using drugs like nitrates,
contractility (using clrugs like B1-aclrenoceptor
blockers).However, the latter approachmay result
in a clecreasein heart rate. Beneficialresultsmay
also be obtaineclby decreasingthe after-loaclof
or Ca++ antagonists.However, any attempt to
clecreaseheart work-load usually results in a
decreasein the carcliacoutput. This limits the
patient's capacityto carry out any work.
(b) Congestlve Heart fallure :
The force of carcliaccontraction is proportional
to the degree to which cardiac muscle fibers are
stretched.However, the contractilepower cleclines
if the muscle fibers are stretched beyond a critical
length. This is known as Frank-Starlinglaw of the
heart functioning. Under certain circumstance,the
activation of neurohumoral system (e.g. increased
releaseof catecholamines,elevation of plasma
renin activiglor plasma anticliuretichormonelevel)
mav result into increaseclbloocl volume. venous
Congesticrn
Oedema
Exercise LV
intolerance dysfunction
Arrythmias
CLINICAI-SYNDROMEOT HEARTFAIIUR"E
Princlples
of Medicinal
Chemiatry
flol. ll) m DrugsActingon Cardiovascular
System

return and end cliastolicvolume. The heart work- most-rapiclintrinsicrate (60-lOO/ min). Hence the
loacl increasesresulting into stretchingof muscle rhythmic contractionsof the heart are clue to
fibres beyond that critical length. lf such situation impulsesgeneratedby S. A. nocle.Therefore,if an
rerrrainsfor consiclerable perioclof time, this leads impulse is generatedfrom non S. A. node region,
to a progressiveclecline in the force of heart that may interfere into S. A node-organized
contraction.Blooclaccumulatesin the heart clueto contraction process,leaclingto arrhythmia.
its inabilityto eiect all the blood. So the heartwork- For the heart to function as an efficientpump,
loacl progressively increases resulting into the various contractileunits must operate in a
progressiveincreasein the stretching of muscle coorclinatedand rhythmic fashion.The generation
fibres ancl failure of the heart becomesgradually of carcliac impulses in the normal heart is
pronounced.The bloocl starts accumulatinginto representedin Fig. 15.6.An impulseis generatecl by
largeveins anclin the tissues,highly perfusedwith S.A. nocleand its concluctionthrough A.V. node is
bloocl.Thus congestionof both, pulmonaryancl shcrwnby P wave while its conduction through
systemiccircdationresurtsinto peripheraledema bunde of His and I'erkinje fibres ,is completed
(clropsy)and diminislred exercise tolerance. This when the wave reachesto point Q.
situationis known as congestiveheart failure. The ventriculardepolarizationis inclicatedby
It is characterized by left ventricular QRScomplexwhile STsegmentrepresentsrepoia-
clysfunction, reduced exercise tolerance and rizationof ventricles.
frequentventriculararrhythmias. An arrhythmiarnay arisedue to abnormalityin
Usuallyaclvancedage, hypertension,cliabetes (a) rate, regulari! or site of origin of carcliac
mellitus ancl ischemiqheart cliseasescontribute to impulse,or
the clevelopmentof congestiveheart failure.
(b) concluctionthat causesan alterationin
(c) Anglna pectoris :
the normalsequenceof the atriaand ventricles.
It is characterizeclbv a cliscomfortof carcliac
origin resultingclueto temporaryischemiaof the
myocardium.The myocarclialischemia results due
to cleficiencyof oxygen ciuring increasedmetabolic
activities. The increaseclclemanclfor oxygen can +15
not be fulfillect clue to coronarv vessel
constriction.The Pnmary cause of angina is
supposeclto be atherosclerosisof large coronary
arteries.This may leacl to reflex vasospasmof
coionary arteries that results into sudden, severe
-50
substernalpain which often racliatesto the left
shoulclerancl along the flexor surface of the left
arm. This occurs most commonly with exertion or
emotional stress. Breathlessnesssometimes - l(x)
occursalong with other discomforts.The duration
of anginal episoclemay vary from 3O secondsto
3O minutes ancl may be relievecl by rest or
nitroglycerin.Hypertensionand cigarettesmoking
are anrongst the principle etiologies of angina
pectoris.
(cl) Arrhythmlas :
The rhythmic contraction of the heart is ttg. | 5.6
possible clue to the presence of intrinsic pace
mal<ersand conductiontissuesin the heart. S.A. It may be sub-classifiecl as per the rate of
nocleis consiclerecl
as normal pace mal(erclueto its beatsancl its anatomicallocationas follows :
\
 ol MedicinalChemistryffol. ll)
Principles aI DrugsActingon Gardiovagcular
System

0) Slnus tachycerdla : both, ventricularfilling time and end-diastolic'

In this, an impulseis generatedby S. A. node volume also increase.lt usually occurs due to
that spreads through atria and ventricles using either increased vagal activity or decreased
'normalconcluctingtissues.lt is simply tachycardia efficacy of S.A. node (because of mlocardial
(increasein the rate of impulsegeneration)due to ischemia).
increased S. A. noclal automaticigl. Heart rate Bradyarrhythmiasare generally causecl by
rangesbetween 1OO-18O / min. It usuallyoccurs tissue damage, a decrease in sympathetic
even in normal inclividualsunder the conditionsof autonomictone or an increasein parasympathetic
exercise, anxie$r, stress or fright and ceasesas tone mediatedby the vagus nerve. Increasedvagal
soon as the underlying causeencls. tone causesAV block of varying degree which
l
During myocardialinfarction,increasein S.A. reduces the rate of impulses reaching the
node dischargerate may be due to inhibition of ventricles. lmmediate treatment is normally to
vagal suppressionor to sympathetic discharge. decreasevagal tone with intravenousatropine
Effortsto suppress S.A. node rate by producing which will decreaseAV block and increaseSA rate.
blockacle (propranolol) can leacl to If atropineis ineffective,intravenousadrenalineor
B-adrenergic
significantdepression of myocarclialcontractilitSl isoprenaline may be used.The only oral treatment
ancl is a potentially hazardoustherapy which available for braclycardia is slow-release
should be useclwith caution. isoprenaline which is not generallysatisfactory.
(ll) Atrlal flutter and flbrlllatlon : (lv) Slck slnus syndrome :
The severi\r of an increasecl automaticity It is a type of braclycardia(clecreasecl auto-
enhancesfrom tachycarcliato flutter and then to maticity) of no fixecl etiology. Abnormalities in
fibrillation.Atrial flutter is characterizeclby rapicl both, impulse generationancl conduction systeln
atrial firing at a rate of I5O-3OObeats/min of are witnessed.Electrolyteor endocrineimbalances
ectopic origin. Ventricular concluction ancl may contribute to its development. The early
contraction remain unaffectecl clue to filtering symptoms such as, fatigue, clizziness and
abilityof A.V. nocle. confusion may become severe upto congestive
carcliac failure,
if remains untreated.
In atrial fibrillation, rapicl, disorganizedatrial
rhythm at- a rate of 35O-6OO/minoccurs due to (v) Atrloventrlcular block :
random and changing firing (automaticity)of It is characterizeclby reduceclimpaired A-V
ectopic origin. A.V. node plays the role of filter to concluction.The bundle of His ancl Purkinjefibres
this rapid firing rate and censors majori$ of may also come under affectedarea. Both carCiac
impulses,entering into the ventricularmass.This (acutemyocardialinfarctionor AV noclaldisease)
leacls to random ancl irregular contractions of and non-cardiac (enhanceclvagal tone) reasons
ventricular muscle fibres. Both, atrial flutter ancl may causethe developmentof A.V. block.
fibrillationare more prone to occur in personswith Premature Atrlal Complexes (PAC) :
advanceclage. Atrial fibrillation is sometimes PACs usually represent the re-entry of a
clescribeclas 'slow' or 'fast' clepenclingon the stimulus,arisingin S.A. nocle,which "echoes"back
ventricular rate. A patient with slow atrial
to the atrium, either at the A.V. iunctionallevel or
fibrillation in which an effective A.V. node block
permitsonly a small proportionof impulsesto pass via intra-atrial conduction pathways. Less
from the atria to the ventricles may not need frequently, ectopic foci may become enhancecl
treatment. ln contrast.fast atrial fibrillationwhich anclcompete with the sinus node pace maker.
occurs in patients with an ineffectiveA.V. node (vl) Premature ventrlcular contractlons :
block featuresrapid and irregularventricularbeats Here S.A. noclalautomaticitlris not alteredbut
and consequentinefficientfilling of the ventricles additional impulsesare generatedfrom local tissues
and inefficientcirculation. in the ventricular region. The development of
(lll) Slnus bradycardia: ectopic foci in ventricular mass may be
It is just opposite to sinus tachycardiaancl pronouncedwith the presenceof carcliacdisease.
arisesdue to clecreasecl automatici$l(heartrate of Certain clrugs (e.9., catecholamines,methyl-
less than 60 beats/min) of S.A. nocle with no xanthines)may also increasethe frequencyof its
conductiondefects. Due to decreaseclheart rate, occurrence.
 Prlnclphrof McdlcinalChGtnittry(Vol.ll) Sy!-
DrugrActlngon Cardiovaecular

(vll) Paroxysmal (recurrent) supraventrlcular establish re-entry circuit. The disturbancesrn

techycardla (PSVT) conductioncan be partial or complete (delay w
The AV junction is not a single electrical complete block) or can be uniclirectionaloc
circuit but can be envisioned as bein_ecliviclecl bidirectionaland may occur with or without re'
into parallelpathways(much like separatestrands entryor circusmovement.
in a multicableelectricalconctuit).The parallelA.V. (lx) Venffcular flutter :
iunctional pathways may have clissimilarrecovery It is characterizeclby the ventricularrate .*:
times and, if challenged by a premature atrial | 50-3OO/ min generatecldue to rapid ancl reguLe'
stimulus,one limb may be accommodatingand firing from ectopic foci of ventricularorigin. .'
allow its transmission;the other may not be
remains untreated, ventricular flutter may D€
A convertedinto a more severeform, i.e. ventriculc-'
Block fibrillation.
(x) Ventrlcularflbrlllatlon :
It is characterizeclby the ventricular rate of
150-5oo/min generateclin rapicl anci randorn
fashion from ectopic foci present in ventricul..r
mass. The co-orclination between the ventricular
fully recoveredanclas a result, the antigrade signal
is blockecl.The initial stimulus may then pass contractile elements is lost vrhich results intc
retrogradethrough the blockecllimb and re-enterin clisorganised"1ndrandom ventricularcontractions
the A.V. junction with each circular passage This leads to iregular and ineffiectivepumping o:
stimulatingthe ventriclesand usuallyatria as well. bloocl from the heart.
The majority of regular supraventricular I5.6 CARDIACGTYCOSIDT,S
tachycarcliasare not ciue to the clischarge of an
Cardiacglycosidesare the example of positi"e
ectopic foci but rather due to re-entry of a
prematurestimulusin the A.V. junction (A.V. noclal inotropic a-qents (i.e.; which increasethe force o1'
re-entry). myocarclialcontraction).These positive inotropic
It is characterizeclby the appearanceof narrow agents are classifieclinto :
QRS complexes with a heart rate of l5O-25O (a) Carcliacglycosicles
beats/min.The principleetiologiesincludere-ent4l (b) p- aclrenoceptor agonists,ancl
and increaseclautomaticity of atrial ectopic focus. (c) Bipyriclineclerivatives.
Lidocaine is the preferred agent for the rapid
control of ventriculartachycarcla. All these agentsact by increasilig.the amount
(vlll) R,e-entry: of intracellularcalcium ions resulting into more
forceful contractionof cardiac muscles.However
The electricalsystem of the heart consistsof
intrinsicpace makersand conduction tissues.An they clifferin the chemistry,mechanismof action
impulse is generateclin S. A. node and it is and specific side-effects. All positive inotropic
conductedin bundle of His and Purkinjesystem agents have the dose-qlepenclent peripheral:
through A. V. nocle in antegrade (towards vascular effects, ranging from vasoconstriction
ventricles).clirection. Since the surroundingtissue (ctigitalisglycosicles)to vasodilation(bipyridine
is refractoryin nature, an impulse terminates in derivatives).Except bipyriclineclerivatives,these
Purkinjefibres. Thus the conduction system is agents also exhibit considerablearrhythmogenic
large enough so that the concluctionpathwaysare potential.
repolarizedbeforethe next sinusimpulsearrivesat
Carcliacglycosidesare naturallyoccurringclrugs
A.V. iunction.
which are presentin the glycosideforms,in a wicle
Due to the developmentof prematureatrial variegr plants and in a non-glycosidicform, in
of
impulsefrom any ectopic focusor clueto partialor
the poison of toacl. ln plants, the leaves of
complete block in conduction,an impulse after
I causing ventricular contraction, travels in Digitalispurpurea(purple foxglove)ancl Digitalis
retrograde (towards atria) direction. Thus the lanata(cohitefoxglove)containsdigoxin, digitoxin
impulse may continue around the obstacle to and cleslanosicle while seeclsof various speciesof
 Principles
of Medicinal (Vol.ll)
Chemistry I DrugsActingon Gardiovascular
stropanthus are the source of stropanthin
I
(S. l<ombe)and ouabain (S. lanata).Helleborus
speciesanclsquill (the freshlyclrieclbulb of Urginea
maritima)are botanicalsourcesfor other glycosicles
Iil<escillarenA.
Carcliacglycosiclesare the clrugs that increase
the force of contractionof heart muscleswithout
increasingthe oxygen consumption. Since they
exert a positive inotropiceffectrvithout involving
more expenclitureof energy, they are called as
cardiotonicagents.
Chemistry :
Since the clinicallyused agents from this class
(ctigoxin,cligitoxin)are cleriveclfrom the plants of
the genus Digitalis,these carcliotonicglycosicles
are collectively termecl as cligitalis glycosicles.
These glycosiclescan also be obtained through
synthetic routes, but the cost of production is
very high. Hencethey are mainlyobtainedfrom tlre
plant source. In some plants, the carcliac
glycosidesoccur in the form of their precursors,
which are themselvesglycosidesalong with a
moleculeof sugar.e.g. proscillariclin A. About 5OO
clifferentcarcliacglycosiclesfiom both, animalsancl
plant sources are clocumenteclin Iiterature.
Cardiotonic glycosicles are the conjugation
procluctsof a sugar ancla non-sugarportion callecl
as genin or aglycone.An agiycone is a steroiclal
nucleushaving a 5- or 6-memberedlactone ring
attacheclat C-17 position. The lactone ring is
usually unsaturatedhaving A a, 0 structure.The
saturationor loss of cyclic nature of the lactone
ring resultsinto clecreasedbiologicalresponse.The
aglyconeportion may have stiuctural resemblance
to steroiclalsex hormones and aclrenocorticoicls.
However, it cliffers from endogenous steroidal
hormonesin having unusualcis fusion of rings C
and D. The glycosicliclinkageoccursthrough C-3
hyclroxyl group. This C-3 hyclroxyl group of
\l.s\==s.\rs\=\-llNrsxrrl
x\\"=.lsrr\s'=s ts.\ s\sr reages\srsr sr\er \o ge\
semisvntheticderivatives.
The aglycone structures of different c.ardiac
glycosideshave been shown in the table I 5.1. All
aglycones exhibit similar set of pharmacological
actions.lt is the attacheclsugar moieties that'play
an important role in governing clurationof action,
partition coefficient,absolute potency and protein
bindingpropertiesof glycosicles. lt also inhibitsan
System
enzyrneinduced metabolicchange in the aglycone
configuration.
At a time, the aglycone portion may combine
with 1 to 4 moleculesof sugar.The sugarattachecl
through glycosicliclinkage may be mono-, cli-, tri-
or tetrasaccharide.
I5.7 PATHOPHYSIOTOGY Of HEAR.TFAILURE:
Accordingto the FrankStarlingmechanisms,
the degree of force of heart musclecontractionis
governed by the extent of ventricular muscle
stretching.lt does not apply to all clegreescf
muscles stretch. If the myocarclialfibre is
stretcheclbeyond critical length, insteaclof an
increase in force of contraction. a fall in
contraction force results. A failing heart cloes not
pump bloocl efficientlyenough to meet the bocly's
neeclsfor oxygen and nutrientsclue to reduced
power of contraction.Blooclstarts accumulatingin
the heart due to poor efficiencyof the heart. The
resulting progressive increase in encl-cliastolic
volume leaclsto graclualincreasein heart failure.
The bocly's compensatory mechanisms get
activateclto cause increaseclsympathetic tone,
elevationof plasmarenin and plasmaanticliuretic
hormone activi!. The manifestationsof failing
heartinclude:
(a) Stimulation of sympathetic nervcrls
system, innervatedto S. A. nocle resulting into
vasoconstriction, tachycarclia ancl sweating.
Theseare largely the compensatorybocly mecha-
nisms to counterbalancethe effects of inefficient
anclpoorly pumping heart.
( b ) A s a consequence, salt 'and water
retention results into peripheraland pulmonary
eclema.
(c) Seconclary
symetoms(nq(trde-eas1(<\l.13s
\\l\1 . \r=t\q=.:r.sss ts.\ \1pr\rsx$l1 s\
myocard\um.
The main pharmacodynamic property of
digitalis is its ability to increase the force of
myocarclialcontraction. The first proof regarding
carcliotonicactivity of ctigitaliswas given in 1938
by Cattell and Golcl. The beneficialeffects of the
drug in patientswith heart failureinclucleincreased
carcliacoutput, decreaseclpre-loacl, clecreased
 of MedicinalChemistry(Vol.ll)
Principles M DrugsActingon Cardiovascular
Sysl

heart size and venous return, increasedrenal flow
ancl diuresis: all these effects leacl to relief of
edemaanclnormal heart rate.
The clecreaseclheart size brings the heart under
the range of operation of Frank-Starling mecha-
nisms. Renalflow allows the drainage of retainecl
eclema fluicl. The renal soclium ion excretion is
increaseclclue to competitive antagonism at
mineralocorticoiclalreceptor becauseof structural
resemblance.
Chemlstry of aglycone part :
(r) ln cligitalisglycosicles: The anellationof
the A - B anclC - D ringsis cis (Z), the 3 - OH is axial
(0),anctall of thesesteroidscarrya 14p-OHgroq
The C-I 7 siclechain is an unsatu
The sugar part, binclingto the
tetrasaccharicle consisting mainly of ctigitoxo
and glucose.
(ii) Strophanthinaglyconeh
in addition to other hyclroxyls,u
6 in ouabain.The 19-CH3is repl;
1" alcohol and the sugars
rhamnoseor cymarose. I
(iii) The squill aglyconescarry a 5tx-memD
lactone ring with two double bonds. None is
becauseof high toxicity.

Aglycone structures of cardlac glycoslcles

R'

HO HO
OH

(a) Digitoxigenin:R= R = H (a) Strophanthiclin: R' = CHO;R2: H

(b ) D igoxig en in:R=OH;R=H ( b ) Ouabagenin: R' = 611rgP;R2= 611
(c) Git oxige nin :R=H;
R=O H

d
I

ococHr

OH

ScillaridinA Bufotalin Aglycone portion of Helleb

(toactpoison)
Bufaclienolicle
Droto
 -

Principles
of Medicinal (Vol.lt)
Chemistry N DrugsActingon Caidiovascular
System

(iv) The lactone ring is not essential.The Compoundswith marginalactivity:where

coplanarside-chainsinsteadof a ring have even
higheractivity.
Cooc2Hs
(v) The activity of a compounclclependsto a
great extent on the position of the 23rd-carbonyl
P=
o4ygen,which is held quite rigiclly by ring D ancl
the doublebond.
(vi) Removal of the sugar portion allows Inactivecompouncls: where
epimerizationof the 3B-OHgroup, with a clecrease
in activity and an increase in toxicity clue to
changesin potarity.
Compounclshaving cligitalisactivig fall into
four categories,depenclingupon their mocle of
action.
(I) Inotrdpfc and Na+, K+ - ATpaseInhlbftorc :
e. S, (a)Carclenolicles (ll) Inotroptc but not Na+, K+-ATpaselnhlbttors
(b) Bufaclienolicles
e.9., catecholamines.caffeine, veratrum
(c) Carclenolide-3-bromo
acetate. all<aloicls.
etc.

o
H,N

Amrinone
(lll) Na+, K+ - ATPase - Inhlbltors but not
Inotroplc :
Active compounds:w here e.g. Socliumazicle,-SH blocking reagenrs,
Mersalyl,Fattyacicls,Diisopropylfluorophosphate
CoocH.l c :N cHO and somesteroiclalallrylatingagente. g.,

R_ R- R=
CH,COOCH,X
I
C=O
Compouncls
with moderateactivity:wtrere'

R=
AcO
X=Cl,
Principles
of Medicinal (Vol.ll)
Chemistry ffi DrugsActingon Cardiovascular
System

( lV ) N a +, K+ -ATPase Inhlbltors but Inotropic

(c) The compounclshaving
acttvlty ls uncertaln : e.g., chlormaclinoneacetate.
- CH = CH - CH = NH. siclechain (A = N) ar
Structure - Acttvtty Relatlonshlp :
C-17,exhibithigheractivity.
Sincecarcliacglycosidescompriseof
(cl) lf the conjugation system in C-17 side
(a) A genin or aglyconeportionand
chainis extended(i. e. - CH = CH - CH = CH- CH =
(b ) A sugarportion,the SARstudiesof these
A), activityabolishes.
agents are based on the separateSAR investi-
(e) Since H-boncling (which takes place
gations on both these portions.
betweenthe sicle-chainanclK+-binclingsite of Na-
(l) Genln or aglycone portlon :
K+-ATPase enzyme)cleterminesthe clegreeof Na-.
(A) C-17 Sl<lechaln :
K+-ATPaseinhibition,the molecule'sclipoleis an
The substitutions at C-17 of the genin portion importantparameter.
of carcliacglycosiclesare generallyof two types
C H = CH-C(R)=A R' K

I I I
-
StenrrC CH--c =A

o-il
Where A may be oxygen or nitrogen.
(ii) A five or six-membered lactone ring. ln @r -
Na+ K+ ATPaseenzyme

H =o H- X
c-c
,'9: /

Steroid

Where,X = K+ binctingsite on Na+,K+ -ATPase

Butenolides
enzyme.
(n With the help of PROPHETcomputer
system from National Institute of Health, the mosi
stable conformationof each of varie$ of genin
w a s s u perimposed graphically wit h t he
cligitoxigenin,a cardenolicteprototype. It is found
that the clistance between the position of
particularcarbonyl oxygen ( or nitrile nitrogen
.zc:. relative to cligitoxigeninserves a nearly perfec:
Pentaclienolides inclex of its activity.
(B) Sterolclnucleus :
both these lpes of C-l7 substituent,there is a
cloublebonclconlugateclwith a carbonyloxygen. (a) Lactonering at C-17, as shown bv Thon,rs
is essentialfor activitv.
(a) Reductionof C-17 siclechaindouble bond (b) Sincesome compounds,not having C-14
results into clecreasedactivi$. hyclroxylgroup, have been shown to exhibit more
(b) In the siclechain activity, than corresponding C- 14 hyclroxy
clerivatives,C-14 hyclroxylgroup cloesnot seern
- c H = c H - ( crQ : A, to be essentialfor activitv.
where A may be a heteroatom, activity fallsif It is (ll) Sugar Portlon :
largerthan - OCH3.lt is generallya hydrogen or Thoughthe sugarsare not clirectlvinvolvedin
smallalkylgroup. cardiotonic activity, their attachment to the
Prlnclplesof MedicinalChemistryOol. ll) al
steroid (at Cg) contributes greatly to both
pharmacoclynamicand pharmacokinetic para-
meters of the cardiac glycosicles.Since the free
geninsare more rapidlyabsorbedand morewidely
distributed than the correspondingglycosides,
this leads to their rapid metabolismto give less
active 3-epimers,followed by rapid excretionvia
sulphatesanclglucuronidesformationat free C-3
OH group. The free genins therefore are quite
unstable as therapeutic agents. Pharmaco-
dynamically,the genins are usually less potent
than their glycosidic forms and show rapid onset
ancl reversalof enzyme inhibitions. In contrast to
this the glycosidesform very stable complexes
with Na+,K+-ATPase enryme. Replacement of the
sugar moietieswith nitrogen containingsiclechains
gives potent analogsof cligitalise.g. N-(4'-amino-
n-b uty l ) 3- a m in o acetvl der iv at iv e of
stroptranthiclinehas about 6O times greater
affinity towards Na+, K+-ATPaseenzyme than the
parentgenin. H-bondingis the principalinteraction
involved between sugar ancl enzyme. Particularly
3-OH ancl5-CH3groups seem to be binclinggroup
in 2, 6-deso{t/ sugars.
The compoundsgiven in table 15.2 clarifu
these points of SAR.
I5.8 MECHANISMOT ACTION :
Digitalis glycosiclesare effective in cardiac
failure, regarcllessof the etiological reason.The
positive inotropic effect of cligitalisis manifestedin
both, normal ancl failing hearts,although in the
former,the increasedoutput may be terminatedby
its clirectvasoconstrictiveeffects. Digitalis appears
to have no indirect effect on mitochondriaor on
the uptake of any energy yielclingsubstrates(i. e . ,
either ATP or creatininephosphate).Nor does it
have anv clirect effects on the contractileelements
within the sarcoplasm.It does not appear to
reverseany biochemicaldefects associatedwith
heart clisease.The intracellularconcentrationof
Na+ anclK+ are maintaineclby the activity of Na+ -
K+-ATPasepump.The hyclrolysisof ATP by Na+ -
K+ ATPasesystem provides energy necessaryfor
the operation of pump. The most probable
explanationfor the clirect positive inotropic effiect
of cardiacglycosiclesis their ability to inhibit the
membrane bound Na+- K+-ATPasepump. This
DrugsActlngon Gardiovascular
SysEm
inhibitionresultsin impairmentof activetransport
of Na+ and K+. The first well documentedproof
about the pump inhibitory activity of cardiac
glycosideswas provideclby Repkeand Portiusln
1963.
The Na+- K+-ATPase is the prominentbinding
site for cligitalis.It blocksmembraneboundNa+ K+
-ATPase\ all tissues. But since it has a high
affinity for heart muscles, it gets accumulated
mainly in the left ventricles and conductlng
system.lt binds with the externalsurfaceof the
enzyme resulting into suppressionof the active
transportof Na+ and K+ ions. As a resultthere is a
gradual increase in intracellularNa+ ions and
extracellular K+ ions. Cardiacflbres possessa
mechanismfor exchangeof intra
with extracellular Ca++ ions.
intracellular Na+ concentratior
mechanismresultinginto an increasein net influx
of extracellularCa++ ions, which in turn then
causesthe releaseof additional intracellularCa++
ions from the stores in sarcoplasmicreticulum to
activate contractileforce, An elevation in the level
of free intracellularCa++ is also due to the drugs
inclividualability to interferewith Ca++binding on
sarcoplasmic reticulum. Thus, the positive
inotropic effect of these glycosides is due to an
increase in automaticity and excitability of
myocardialmusclefibers.
The activity of Na+ -K+ -ATPasepump ts
regenerated due to the dissociative effect of
increaseclextracellular K+ ions on the drug
enzyme attachment.Even though the blockageof
Na* - K+ - ATPasepump seemsto be the main
mechanismthrough which cligitalisglycosides
exert their positive inotropic effect, many other
ATPaseinhibitors(suchas actinomycin,quinidine,
oligomycin, soclium azide, sulfhryctrylblocking
agents) fail to exhibit the expectecl positive
inotropic effect on the heart. On the other hand,
catecholamines(i.e. isoprenaline)have consi-
derable cardiotonicactions but have very short
biologicalhalf-life. l'l
Besides this, acidosis, hypoxia, cardlac
ischemiaand decreasedrenalperfusionare someof
the factorsthat bring down the efficaqyof Na+- K+
- ATPasepump.
Principles
of Medicinal (Vol.ll)
Chemistry N Systam
DrugsActingon Gardiovascular

Table 15.2
Replacement of the lactonering of Digitoxigenwith open chain moietieshaving stericand electronic
resemblance
to the lactone.
Relatlve Potency
+ve Inotroplc effect Inhlbitlon of Na+, K+
-ATPase

(1)

100 100
-c--cH

(z\ ffHr 130

-cH=c H - c =o
ocHl
(3) t- Inactive Inactive
=o
-cHzcHz-c
(4) Inactive lnactive
-cH=c H - c =o
(s) ffnE o.4 3.O
-cH: cH-cH: cH-c o =
(6) PctHt
-c H :c H - c = o
(7) -CH = CH- C= N 110

(8) fH' lnactive Inactive

-cH=N-NH-C= O
1 5 . 9 OTHER EFFECTS
OT DIGITALISGLYCO-
SIDES
Besidestheir abilig to inhibit the tunctioning
of Na+- K+-ATPase pump, digitalis exerts some of
its actions through its effect on autonomic
nervoussystem and on vascularsmooth muscles.
For example,digitalis has a vasoconstrictoraction
on the vascularsmooth muscle. The changes in
the circulationbrought about by digitalis are mainly
reflection of reflex alterations in A.N.S.
functioning.It also changesthe heart sensitivi\r
to the vagal and sympathetic neurotransmitters.
At low to moderate doses, digitalis exerts a
negative chronotropic effect mainly due to the
increased vagal activity and direct depressant
action on the concluctingtissue (A. V. node).
Digitalis also increasesrefractoryperiod of both.
atrial anclventricularmuscle.Thus the depression
of conductingtissue accompaniedwith increased
refractory period may protect ventricles from
excessivebombardmentin afrial arrhythmiasdue
to increasedfiltrationthrough A.V. node. But this
may lead to bradycardiaancl in toxic doses, even
heart block. In addition, the presenceoF delayed
afterpolarizationdue to low conduction velocitl'
canslow anclimpair impulsepropogationgiving rise
to reentrant rhythms.
 Principlesof MedicinalChemistry(Vol.ll) m DrugsActingon Cardiovascular
System
In S.A. node, the rate of generationof impulse (92-95o/o)
is decreased by mainly parasympathetic absorbed.Certain drugs tike, kaolin,
activation. The atrial myocarclium however. antacids may interferewith the absorption.These
rerriains almost unaffected at therapeutic glycosides possess relatively large volume ,of
concentrationsof cligitatis. A clecreasein atrial clistribution (VD). This accounts for their slow
action potential clurationand effective retractory clistributianin the body cornpartments.Digitoxin is
periodis mainly clueto the predominanceof vagit extensively (79.5o/olbound to plasma proteins
tone. However high concentrationof ctigitatiscln whife digoxin is also significantty(ZO-ZS%) bouncl
decreasethe excitability of all carcliai tissues. to plasma proteins. Skeletal muscles, heart,
Digitalis-induced arrhythmiasmay resultdue to an kiclneysancl RBCsare the bocly tissueswhere most
enhanced sympathetic activig from the effect of of the administereddose of carcliacglycosiclesget
digitalison medulla oblongata.Thesearrhythmias concentratecl.
can be treated by B-aclrenergicblockers.
Digoxin has fairly rapid onset of action when
At the level of A.V. node, cligitalisinclucesslow administereclintravenously while digitoxin is
conductionand increaseclrefractoryperiod. Below usually
not given by i.v. route clue to its slow
this level, the effects on ventricular myocarclial onset
of action. It has the longest cl,urationof
fibers are mainly exerteclthrough perkinje system. action,
if used orally. Intramuscularroute is not
In all myocardialregion, the only region which is preferablefor the aclministrationof these drugs
strongly influenced by sympathetic tone is His_ clue
to the induction of severe pain ancl muscle
Purkinjesystem. It is least sensitiveto the changes necrosis.
in vagal activity. In this region a clecreasein
refractoriness(i.e. shortening of action potential Other less commonly useclcarcliacglycosides
duration)is observed. inclucle ouabain,lanatosideC ancldeslan6sicle. The
latter acts as a precursorof cligoxin in the body. All
In summarylthe most importanthemodynamic
-- these drugs are poorly absorbeclfrom GIT ancl are
effect of cligitalis is its positive inotropic action
which resultsin decreasein heart size ieaclingto usuallyadministeredintravenously.Liver servesaS
increasedcardiac output with increaseclefficiJnqy the principal site of metabolism for all these
glycosicles.Digitoxin and cligoxinare metabolizecl
of the heart. Thus it is an effective clrug il
congestive carcliac tailure. tt may also leacl to to relatively inactive dihyclrocligoxinby hepatic
microsomalenymes.Hencein cale of toiiciql, the
ias clue to increasein myocarclial rate
of metabolism can be increaseclby giving
automaticity. The vagal tone metabolicen4/mes inclucerslike, phenobirbitalor
predominanceusuallyresultsinto :
phenylbutazone.
(a) Decrease in atrial refractory period
(increasedatrial concluctionvelocity may convert Other metabolicmechanismsinvolve cleavage
flutter into fibrillation). of glycosicliclinkage.The free genin portion is then
(b) Delay in conduction of impulsesthrough excreteclin the form of glucuronicle.part of the
genin portion is also reportecl to undergo
A.V. node.
(c) Bradycarclia. epoxiclation.
Thefluid in peripheraledemais clrainedout due The half-life of cligoxin is estimated to be
to diureticactionof digitalis.Thisactionis due to about 35-40 hours. tt readily crossesplacenta.lts
metabolites(i.e., dihydrodigoxine,digoxigenin,
(a) Increasedcardiac output with increased
clihydrocligoxigenin)are primarily eliriinated in
renalperfusion,and urine.The rate of eliminationof carcliacglycosicles
(b) Direct action upon the clistalrenal tubule is veryrslow which,if not takeninto coniiieration,
by exerting competitive antagonism with alclo_ may result
into drug intoxication clue to its
sterone(clueto structuralsimilarig). accumulation.Hence, the cardiacglycosidesare
I5.10 PHARMACOKINETIC PARAMETERS usually administeredorally in two stages. The
Digoxin and digitoxin are the most commonly patient is treatedwith an initial dose of thJ drug to
prescribedagents. Both are readity absorbeclfrom get therapeuticresponse.Thiscloseaclministration
GlT. However,to a considerableextent, digoxin is is known as initial cligitalizationor loading close.
inactivated (to form 2 - hydroxydigoxin) by Il. therapeutic response obtained tirough
cligitalizationis furthermaintaineclby a low dose
intestinalmicroflorawhile digitoxin is extensively schedule
which is known as maintenancedose.
Principlesof Medicinal
ChemistryPol. ll) m DrugsActingon Cardiovascular
System

I5.II THERAPEUTIC USES are quite frequent and can be severe in toxic
(A) Congestlve cardlac fallure : closes.Theseadversereactionsare mainly clue to
(i) An increasecl parasympathetic tone,
The positive inotropic effect of these
(ii) A loss of intracellularpotassium(hypo-
glycosides causes the heart to contract more
kalemia)
strongly ancl efficiently.The beneficialeffects of (iii) An increasedintracellularCa++ concen-
these drugs in patients with heart failure inclucle:
tration. The cardiaceffectsof cligitalisglycosides
increasedcarcliacoutput, clecreaseclheart size ancl are much complicateclclue to unusualcombination
venouspressure,cliuresisanclrelief of edema.The o f,
recluctionin myocardialoxygen<lemandclecreases (tt OecreasecfA.V. concluctionancl increasecl
the intensity of compensatorysympathetic refractory periocl clue to enhanceclvagal activity,
nervous system which results in a decreasein and
svstemicarterial resistanceand venous tone. (ii) Increased abnormal or ectopic auto-
However cligitalistreatment is not effectlvewhen : maticity due to drug's clirect effect.
(a) Heart failureis associatedwith very high Digitalisglycosicles are usedto treat a cliseasecl
preloaclor after loacl. In such cases the use of heart. Due to the combination of above two
cliuretics(which lower clown bloocl volume ancl effects,such a cliseasecl heart easily get attacked
ventricularfilling pressure)and/or vasoclilators by arrhythmiasor A. V. block occurreddue to an
(whichreducepreload,anclafter loac'l)is given more exaggeration of depressant action on conduction.
Digitalis in high close, is likely to incluce the
weightage. development of almost every known carcliac
(b) Chronictreatmentis requirecl. This is clue arrhythmia.The infarctedmyocarcliumservesas a
to a loss in therapeutic efficacy through clevelop- site to clevelopectopic foci which is responsible
ment of significanttoleranceto clrug action. ln for the occurrenceof both atrial and ventricular
suclr casevasodilatorsancl,/orintribitorsof angio- tachycarclia. lt is better to cliscontinuedrug
tensinconvertingenzyme (saralasin. captopril)are therapyunclersuchconditions.
the clrugs of choice useclalong with cligitalis or a 15.13 D'G'TAL'S'NTOXICATION
cliu re ti c . . The largevolume of clistribution(VD),low r.ete
(B) Atrlal arrhythmlas : of elimination (longer cluration of action), the
At therapeuticdoses,cardiacglycosicleshave concurrenteffectsof the glycosicleson A.N.S. ancl
on peripheral vascular smooth muscles (besides
a protectiveaction upon the ventricles.Thisaction
their action on Na+, K+-ATPasepump) and
is exerted by increasing the vagal tone ancl by a
hypokalemia (in patientsreceivingcliureticsalong
direct. depressantaction upon A.V. conduction. provoke the
with cligitalis) are the factors that
This results into an increased'filtering' of the sensitivity of the patient towards cligitalis
impulseswhich are generateclat relativelyhigher intoxication.The low therapeutic inclex of these
rate during atrial arrhythmias.The recluctionin drugs necessitatescareful clinical observationof
conductionveloc.itlrand an increasein refractory the patients cluring the periocl of initial
period protect the ventricular muscles from cligitalization.Hence, extreme caution is to be
excessive stimulation. Atrial 4rrhythmiaswhere observeclwhen they are given intravenously.Both
digitalis finds dinical use, inclucle-atrialflutter, atrial hypokalemia ancl hypercalcemiasensitize myo-
fibrillationand parorysmalatrial tachycarclia. carclium to the glycosicle action. ln such a
conclition, a cleclinein restingmembrane potential,
However,the glycosiclesare contrainclicated in
brings the cell quite near to their thresholdvalue
patients having hypokalemia, hypercalcemia,
for generatingan impulse.This explainsthe basis
impaired renal function or ventriculartachycardia. of digitalis-induceclextrasystoles cluring the
Quinidineor procalnamideare better clrugsto treat therapy. An adequate potassium intake should
ventriculartachycardia. always be maintainecl in the therapy when
I5.I2 ADVEN,SE EITECTS hypokalemia is reported. The hypokalemia, if
The cardiac glycosides have a low therapeutic remained uncorrected, may leacl to the
tachyarrhythmiasin digitalis overclose (due to
safetymargin. Consequentlythe adversereactions
Principlesof MedicinalChemistry(Vol.ll) 291
declinein restingmembranepotential).Hence,if a
diuretic is needed in patients receiving cligitalis,
then potassiumsparing diureticsare to be usecl.
However, in toxicig signs due to conduction
impairments(i.e.A.V. block),potassiumintakemay
provoke the cligitalis toxicity. Hence, it is
contrainclicatecl in casesof A.V. block. Unclersuch
conditionsvagolyticagentsare useful.
An enhancement of automaticityby cligitalisis
the probable reasonbehinclthe clrug induceclatrial
arrhythmias.Any antiarrhythmicclrug can be usecl
to suppress atrial arrhythmiasdue to cligitalis
toxicity.
A consiclerable fractionof orally administerecl
digoxirr is inactivatecl(to 2 -hyctroxyctigoxin) by
intestinalmicroflora.t'lencein the patient receiving
digoxin along with an antibiotic,the extent of
absorptionof active clrug suclclenlyincreases.This
leaclsto appearanceof toxic effects of cligoxin in
therapeuticcloselevel.
I5.14 TR.EATMENT OT INTOXICATION
(1 ) Dig i t a l is g ly c o s ic le s h a v e v e r y p o o r
therapeuticindex. In case of ctigitalisintoxication,
the therapy shoulclbe immecliatelycliscontinued
so as to lower clown the plasma concentrationof
the clrug.
(Z) The patient shoulcl be evaluateclto trace
out hypokalemia if cliureticsare concurrently
administerecl.The plasma potassium level may be
maintainecl-inthe upper normal level by giving
potassium either orally or intravenously. The
increasingextracellularK+ ion concentrationmay
procluce the stimulatory effect on Na+ - Kt
-ATPasepump, there by clecreasingthe binclingof
c'ligitaliswith the pump system. The suppression
of ectopic beats anclabnormal rhythms (clueto the
clrug incluced automaticity) are other beneficial
effects of potassium intake. However its
administrationis contraindicatedin the presence
of diminished carcliacconcluction(e.g., sinus
brabycarclia,A. V. block). In such conclitions
atropinelike clrugsmay improvethe functioning of
heart by suppressingthe underlying cause (i.e.,
increasecl vagal tone).
- (3) Digitalis increasesthe automaticity anct
excitability of myocardial fibres. ln toxic closes
cligitalis may induce severe atrial arrhythmias.
Many antiarrhythmic agents (e.g., propranolol,
phenytoin, liclocaine)along with potassiumsalts
can be used in suppressingctigitalisinduceclatrial
arrhythmias.
DrugsActingon Cardiovascular
System
( 4) I n s e v e r e l i f e - t h r e a t e n i n g c l i g i t a l i s
intoxication (accidentalor attempted suicides),
above treatment may not be effective to get
immediate response. In such cases, specific
glycosicleantibocliesaclministrationleaclsto rapid
recoveryof the heartfunctioning.Digitalisspecific
fab antibocly fragments were first evaluateclfor
their effectiveness in humansin 1976. Like other
antiboclies, howevertheir use is accompaniecl by
emergence of allergic reactions in sensitive
patients.This linrits their use in patientswith pre-
allergichistory.
I5.I5 ALTERNATIVES TO DIGITATISTHER,APY
The low margin of safety and inherent
toxicities associateclwith the use of cligitaiis
glycosicles,lecl to the search for development of
group of agents having positive inotropic effect.
There was an increasing tendency to use
vasodilators (hyclralazine,prazosin, nitrates),
c l i u r e ti c so r cardiac st imulant s (p-aclrenergic
agonists)to reducethe preloadancl/orafter load of
the failing heart. However. adrenergicclrugshave a
shorterclurationof action while vasoclilators mav
not be the pnmaryclrugsof choicein all the cases.
Out of availablealternativesto ctigitalis,bipyrictine
derivatives are of special interest clue to the
combination of both positive inotropic property
ancl vasodilatory effect in one compound.
Examplesfrom this class include, amrinone and
milrinone.
H
N
H ,N
Amrinone
N= C
Milrinone
Prlnclplesol MediclnalChemlstry(Vol.ll)
Chemically,amrinone is 5-amino (3',4-
bipyridine)- 6 (l H) - one,while milrinoneis a 2-
methyl,S-carbonitrile derivativeof amrinone.Both
these agents can be usecl orally as well as
intravenouslv.Mllrinone is considerablvmore
potent but has relativelyshorterdurationof action
than amrinone.Theirusein congestiveheartfailure
is mainly clue to their positive inotroplc and
vasodilatory effects. The mechanism of the
positive inotropic effect of amrinonedlffers f;oin
that of conventionalpositive inotroplc agents.
Sincetheir efficacyls not decreasedby the use of
adrenergic blockers, the direct actlvatlon of
adrenergicreceptor is not their mechanlsmof
action. Probablythe mechanismmay be relatedto
an increasein intracellular concentration of c-AMP
by inhibition of phosphodiesteraseenzymes,
(however, several agents that lnhiblt these
enzymes,do not exert a positiveinotropiceffect).
The increasein c-AMP then lowers the rate of
inffuxof Ca++ions resultinginto vasodilation.The
net effect is recluctionin the afterloacl.The
positive inotropic effect makes these agents
useful in the treatment of congestivecardiac
failure,where their inotropiceffect is aclclitiveto
that of cardiacglycosicles.
Liver serves as the principal slte for
metabolism.About six metabolitesof amrlnone
have been iclentifiecl.lts use in the chronic
treatmentis not advisabledue to seriousaclverse
effects.Amrinonecluringlong term usemay induce
immunologicabnormality.This along with long
term inhibitionof phosphodiesterase enryme may
contributefor the appearanceof adverseeffects.
Theseeffiectsincludenausea,vomiting,abdominal
cramps, diarrhea, fatigue and reversible
thrombocytopenla, headache, fatigue and
hepatotoxlclty.Hence, its clailydose should not
exceecllO mg/kg.
Milrinone ls quite a safe clrug. lts use ls not
associatedwlth most of the aclverseeffects seen
in amrinonetherapy.However efficaqyof the drug
appearsto be age dependent.
Other drugs having positive inotroplceffects
inc l ude do p a m in e ,d o b u t amin e(p 1 -a g o n ist ),
ephedrineand pirbuterol.Pirbuterolis a p-
adrenergicagonist having both, a positive
inotropic and vasodilatoryeffect. The positive
& DrugsActlngon Cardlpvascular
System
inotroplc effect of catecholamlnesls due to a
resultant lncrease in the lntracellularCa++
concentrationthat is brought about by the drug
induceclchangesin c-AMPlevel.HoweverIn many
cases,inotropic effect and c-AMP level may be
dissociated.
9. Coronary flow ls lncreased with
dobutaminein proportion to myocardialoxygen
consumption with little change in oxygen
exilirction. Dcibutamineslgnlflcantly increases
oxygen delivery by 48.5 olo and oxygen
consumptlonby 22Vo.
HO
cH,-cH2-NH-CH-CH,-CH,
Dobutamlne
Dobutaminehas a unique combinationof
positive inotropic effects,enhanclngcontractility
and arterial vasodilation,reduced afterloadand
enhancing perfusion.Thus lt acts as both,
inotropicagentand vasodilator.
Sincethe extracellularcalclumis importantin
clecidingthe force of heart contraction,attempts
were alsomadeto clesignspeclficcameramolecules
for Ca++ ions which wlll lntroduce more
Ca++ionsinto the cell.X 537-A ls such
extracellular
an agentdevelopeclby Hollandet al in 1975.Since
the pacemakeractivigl is less dependenton Ca+-
ion concentration and requlresdlffierentionic basis
than the myocardialcell, this Increasedinflux of
Ca++ ions results in posltive Inotropic effect
without associated tachycardla. However
decreaseIn apparent Ca++ sensltivity of the
contractileproteinsmay occurtn responsetq " fall
pH anclrise ln qltoplasmiclevelsof
in intracellular
inorganicphosphateand creatlnephosphate.
I5.16 ANTI-ARR,HYTHMIC AGENTS:
Normal synchronousmechanlcalactivity of
the heart depends upon a speclffcsequenceof
electricalactivationfor all myocardlalcells during
each beat, beginnlng first at the SA node and
enclingwlth depolarization of the ventricle.
Principles
of MedicinalChemistry(Vol.ll) 2S DrugsActingon Cardiovascular
System

I nu5 an arrnvtnmra mav arise because of Though the spontaneous electrical depola-
atterallon In. risation of the S.A. nocle (pacemaker)cells is
(l ) AutomaticiW inclependentof the neryous systems,these cells
(z)LOnOUC On. ano are inneryateclby both sympathetic ancl para-
(3 ) Refractoryperioclof the myocardialcells. sympatheticnerves, which may cause an irrcrease
Abnormalitiesof heart rate are inclucleclamong or decreasein the heart rate, respectively.Other
the arrhythmiaseven though the actual rhythm of specialcells in the normal heart, which possess'the
the beat is not necessarilvclisturbeclin these property of automaticig (seconclarypacemal<er)
conclitions. may influencecardiac rhythm when the normal
Orlgin of Arrhythmia : pacemal<eris suppressedor when pathological
The generation of cardiac impulses in the changesoccur in the myocarcliumto mal<ethese
normal heart is usually confineclto specialisecl cells the dominant source of cardiac rhythm
tissuesthat spontaneouslydepolarizeand initiate (ectopic pace makers),especiallywhen myocarclial
the action potential. These cells are located in the cell damageoccursbecauseof localizeclmyocarclial
right atrium and are referreclto as the sino atrial clisease (infarction) or from cligitalis toxicity,
nocle (S. A. nocle)or pacemakercells. When the excessive vagal tone, excessive catecholarh\e
impulseis releasedfrom the S.A. nocle,excitation releasefrom sympathomimeticnervesto the heart).
of the heart tissuetakes place in an orclerlymanner or even high catecholamineplasmalevels.lf the SA
by a spreacl of the impulse throughout the node is preventedfrom operating normally the AV
specialisecl automaticfibresin the atria resultingin noclewill usuallytal<eover as pacmal<eror, if both
contractionof the atria. A. V. noclefunctionsas a are inactive,the v-entricular
conductingtissueswill
clelaycircuit and concluctsthis impulse slowly to serve as pacemaker.Wheneverthe SA node is not
the bundle of His anclfinally,through the Purkinje the controllingpacemaker,the heart beat is less
fibre network in the ventricles, resulting into well coordinateclanclthis may result in inefficient
ventricular contraction. The P wave represents pumpingwith an increasein energyexpenditureto
atrial depolarization and the QRS complex maintain an aclequatecirculation or ineffective
representsventricularclepolarisation. The interval pumping with an inadequate circulation.The
between the two (PRinterval) is the time taken to clevelopmentof automatici! in these secondary
conduct the beat through the AV nocle ancl is pacemakercells(e.g.,specialatrialcells,A.V. noclal
lengthened in AV block. The T wave denotes cells, bunclleof His or / and Purkinjefibres),may
ventricularrepolarization,and the QT interval leaclto cardiacarrhvthmias.
clenotes the time between clepolarizationand In summary,SA noclecells clepolarizequickly
polarizationof the ventricles. A prolongecl QT and thus control the heart rhythm. The impulses
preclisposesto torsaclesde pointes (i.e. a fast are conducteclfrom the SA nocleacrossthe atria to
ventricular rhythm with polymorphic QRS the atrioventricular (AV) nocteand then clown the
complexes). The events are representeclin bunclleof His to the Purkinjefibres ancl the
following figure. ventricles.Thisis termedsinusrhythm.Thecardiac
+ l-5 arrhythmiasmay arise from abnormalitiesin either
impulse formationor impulse conductionor by
both. These reasonsmay be brought about in
severalways :
- -30 (1) An infarction may cause the cleath of
pacemakercellsor of conductingtissue.
E (2) A carctiactissue disorcler,e.g. fibrosisor
rheumaticfever, or a multisystemconnective
- 90 TP tissue disorder, e.g. sarcoiclosis, disrupts the
concluctionnetwork.
t00 200 300 msecrrrne (3) Sympatheticor parasympatheticcontrol
changes,e.g. stress,anxie!, exerciseor smoking.
(4) Hypothyroiclism,hyperthyroiclism,hypo
aclrenalism,hyperkalaemiaancl hypokalaemiaor

Ilg. t 5.7
Prlnciples
of Medicinal Ool.ll)
Chemistry
other electrolyte clisturbancesmay predispose to
arrhythmias.
Abnormality in an impulse formation (auto-
maticig) gives rise to changesin heart rate anclto
the cleveloprnentof ectopic (abnormal) beats,
originating in secondary pacerneker <.ells. While
disturbancesin conduction can be partial or
complete(clelayor block),can be uniclirectional or
bi-clirectionalancl can occur with or without re-
entry or circusmovement.
Thus all carcliacrhythms can be clescribedin
termsof the rate origin and pattern.
(a) Rate relateclarrhythmias: Tachycardiaand
bradycardia.
(b) Origin relateclarrhythmias:Sinus, atrial,
nodal, supraventricular, re-entrantanclventricular.
(c) Pattern relatecl arrhythmias : Ectopic,
premature contraction, paroxysmal, flutter,
fibrillationblock,ancltorsaclescle pointes.
What has been c{escribeclas "circus move-
ment" or, more recently, "macro-reentry"occurs
when a wave of excitation travels around an
anatomicalobstacle,an anatomicalloop. or along
functional athwavs. Macro-reent arrhvthmias
Premature
I nrpulse
Fig. 15.8 : Reentry ln Wolff-Parklnson-Whlte
svndrome
have been clemonstrateclin tissues with slow
responseaction potentials(i.e., A.V. nocle,S.A.
node) as well as in those with clearly separate
parallel pathways possessing different electro-
physiologicalcharacteristics(i.e. paroxysmalatrial
tachycardia associated Wolcl-Parkinson- White
preexcitationsyndromes).
Signs ancl symptoms of arrhythmias may
include clizzinessor collapse becauseof poor
bloocl supply to the brain ; shortnessof breath
*I DrugsActingon Cardiovascular
System
due to poor oxygenation;angina associatedwith a
poor coronarycirculationancl/orincreaseclcardiac
workloacl arising from a tachycarclia,and weakness
and palpitations.
Chemlstry and Classlflcation :
The rnaior antiarrhythrnic drugs were intro-
duced into medicine as either antimalarial
anticonvulsantsor local anestheticsand it was
only by chancethat their antiarrhythmicproperties
were discoverecl.
Treatment of carcliacarrhythmias has been
empiric in the past becausethe electrophysiologic
mechanisms involvecl in the initiation and
perpetuationof the maioriry of abnormalcardiac
rhythmswere unknown.This requireda l<nowledge
o f th e complet e pharmacology of t he
antiarrhythmicagents as well as complete electro-
physiologicl<nowled5le of arrhythmogenesis.
Electrophysiologicstudies on antiarrhythmic
agentsin normalanclcliseasedtissuehave revealed
effectson impulse formation (pacemakeractivity),
intramvocardialconcluction,ancl/or recovery of
electrical excitability. Most antiarrhythmicagents
suppress abnormal pacemaker activity but
proclucelittle effect on normal pacemakeractivi{
until toxic concentrationsare attainecl.
Antiarrhythmic drugs may reduce the rate of
rise of action potential as well as magnitude of
voltage charge during the upstroke (phase O) of
a c ti o n p ot ent ial. Membrane responsrveness
(change in membrane potential to applied
depolarizing current) may be climinishecland
threshold potential may be clecreased by
antiarrhythmicagents.They may slow recoveryrof
electricalexcitability and alter the relationship
betweenmembranepotentialcluringrepolarization
ancl recoveql of excitability.
Antiarrhythmic agents can be clividecl into
atleast 4 groups baseclon what is l<nownas their
elcctrophysiologicactions, as originally suggestecl
by Vaughn-Williamsand coworkers.
Class | : Local AnaestheticDrugs :
The major electrophysiologiceffect of this
classof drugs is a reductionin the maximumrate of
myocardialcell clepolarisation during phase0 of the
action potential without any effect on the resting
membranepotential.
Prlnclpbsol liledlclnalChemlctrypol. ll) * DrugsAcilngon Crdlovlscular Syrbrn

Accorclinglythe various antiarrhythmlcdrugs I actionsare quinidine, procalnamlde,lidocaine,

are classiffedas r flecainlde,encalnide,Iorcalnlde,propafenone,
(lA) Membrane- depressantdrugs (depre- phenytolnand disopyramicle.
ssant of electrophysiologicalpropertlesof myo- cHg
cardlalcells)
e.g.,Quinidine
NH- c - c H - N H 2
Procalnamide
Diisopyramlde
(lB) Drugswhich facilitateimpulseconduction CHs
and shorten refractoryperiod while depressing Tocainide
automaticity
e.9., l.lclocaine
Phenytoin cF.rH
Mexlletlne
o
ll
Tocalnlde c - NH-CH
Aprincline
(lC)Flecalnide ocH2cFj
Encainide
Lorcainlde Flecainide
Propafenone
(ll) 0-adrenerglcblockers
e.g.,Alprenolol
Atenolol, QH' - CH'
Metoprolol o
Practolol H.]CO
tl
C-NH
cHr
Propranolol,Plndolol
(lll) Amiodarone
Bretylium Encainide
D-Sotalol o
(tV)SelectiveCa++antagonlsts tl
cH,-{-N
e.g.,Nifucllplne
Verapamil
Dlltlazam
(V) Miscellaneous agents
Atroplne
Neostlgmlne cl
Lorcainide
Edrophonlum
Antlchollnerglcdrugs such as trlqycllcantl-
depressantsor atroplne may removevagal control CH"-CH.-C= O
and causetachycardla. cH'-cHoH-cH2-NHCH2CH2CH1
In the presenceof these agents,conductlon
velocitSrls decreased and the threshold for
excltablllty (current requlred for cellular
depolarizatlon)ls Increased.Repolarlzatlon and
recoveryof excltabilitymust proceedto a greater
extent before another lmpulse can be lnltlated Propafenone
becauseof drug-lnduceddecreaseln depolarizing Classll r p-adrenerglcblocklng egcnt3 s
curreRt.This resultsln an IncreaseIn the effectlve Local IncreaseIn catecholamlneactlvlt5lthat
reftactoryperlod (ERP). The maior drugswlth class accompany centralty medlated sympathetlc
 Principles
of Medicinal
Chemistry
(Vol.il) m DrugsActingon Cardiovascular
System
nervoussystem clischargeor myocardialischemia
can be associateclwith sufficient local enhance_
o
ll
ment in automaticitvso that competing rhythms c o-cHr-cH2-N(CrH.5)2
ancl ectopy emerge. B-Btockerscan suppressthis
type of automaticigr and can also procluceclirect
{( H- t - - (- - H-
_-1
clepressant efFects on the myocardial cell '- - - z'J

membrane. Amioclarone
Class III : Agents that prolong the actlon
potential cluration :
The class III anti-arrhythmic clrugs are
pharmacologicalty anclchemicallycliversegroup of
compounclsthat have ability to prolong action
potential clurationand hence refractoqrperioclof .IJ
carcliactissues.Bregrliumis a prototype. These
agentssharethe common propergl oF prolonging Bret1llium
both action potential duration ancl the effectivE Amioclaroneis a benzofuranclerivativeinitially
refractory period. Bretylium ancl amiodarone clevelopedin 1967 as antianginalagent clueto its
supresscarcliaccatecholamineeffects that result abili! to increase coronary blooct flow and to
from sympathetic nerve stimulation.The most decreasemyocarclialoxygen demancl.Increasein
impressiveactionof this classhas beentheir abilitv action potential cluration is its major electre-_
to suppressventriculartachycarcliaancl/orventri- physiologicaleffect.lt has structuralsimilaritiesto
cular fibrillation.D-solatol lacl<sthe non-selective thyroxine. Similar increasesin action potential
p-blocl<ing activity of racemicsotalol. clurationare seen in hypothyroxidism.It prolongs
the action potential cluration in atiial anC
ventricularmuscleas well as purkinjefibreswithout
?in'
NI
altering resting membrane potential or auto-
maticity. It has antifibriltatoryactivig and recluces
czH: CHr ventricularfibrillation.It also blocks calcium ion
channels resulting into adclitionalvasodilation
activity.
Clofilium Class lV : Slow Channel Blocklng Drugs :
Sodium entry into the myocardialcell during
phaseO'of the action potentialcan be suppresseo
cH., by administration of tetroclotoxin or by cle-
polarizingthe cell membraneto potentialslessthan
- 6O mV. Theseinterventionsare associatedwith a
markecldecreasein the slope for phase O of the
Melperone action potential.Theseslowly rising action poten-
OH tials have been associatecl with markeclreduction
NHCH( CH. 1) " in concluctionvelocity, uniclirectionalblock.
reentry ancl also with the appearanceof sponta_
neousautomaticigr.Clinicaluse of these clrugshas
cH3so2NH
shown them to be effectivein controlling ventri-
Sotalol cular responserates to supraventriculararrhyth_
mias, presumablyvia depressanteffect on slor,r
OH
f'nt responsepotentialsinvolved in A.V. noclalcondu_
ction. Reentrantrhythms within A.V. nocle.such
as paroxysmalatrial tachycardiaare also suppre-
cHlSO.,NH ssecl,probably by similar mechanisms.Ventiicular
arrhythmiashave not been effectively suppressed
lbutilicte
by these agents.
Principlesol MedicinalChemistry(Vot.ll) gl DrugsActingon Cardiovascular
System

New ancl experlmental antlarrhythmlc clrugs :

/ Ct H'

Aprincline
OH
I
C_CH-,CH,CH,N Phenytoin

OH

Dipheniclol
o
Airnokalant

C H,SO.N IJ
9H,

E--4031

cH,so.,Nll

OH MK-499
c Hr
Ci bcnzol i nc
OC H ,C H_ N H ,
It has an active metabolitenamely clesethyl-
amioclarone
I
CH.t
l

Mexiletine

HtN
ll OH
o
I
ocH'cHcH,NHC,H,
Procainamide

H.5C'CO Propafenone
C=O I5.I7 ANTIANGINAI DR,UGS
I ^,, ^,, ^,/'cHrcH3)2 The worcl 'angina' (from the Greek verb
meaning,to choke')is used to describethe pain or
N cliscomfortof cardiacorigin which results clue to
tl temporary ischemia of the myocardium; that
means the flow of bloocl is inadequateto maintain
the metabolic clemancisof heart for oxygen and
Disopyramide nutrients.
Principles
of Medicinal (Vol.ll)
Chemistry & DrugsActingon Cardiovascular
System

from enclogenoustriglycericlesaccumulatein the Accumulationof noxious metabolitesappears

c)atosolas acyl esters with potentially noxious to contribute to the acceleratingimpairment of
effectson myocardial membranes. myocarclial metabolism and ultrastructural
In ischemic myocarclium, contractility is integrig. Fatty acyl CoA esters inhibit activity oF
impaired virtually instantaneously,clespite the aclenine nucleotide translocase,an enzyme
relatively slower cleteriorating oF myocardial involveclin transportof ATPfrom mitochondriato
intermediarymetabolismand the comparablyslow cytosol. Increased concentrations of acyl CoA,
decline of high-energyphosphatestores.This may coupled with the increaseciconcentrationsof
be manifestedin its extreme form by production of glycerol phosphate, promote synthesis of
so called stone-heart.Prolongedischemiaresultsin triglyceridesby virtue of the mass action effect.
mitochondrial swelling with a decrease in Accumulationof neutral fat is thereforeobservecl
mitochondrialmatrix densit5land the appearance in myocarclium subjecteclto repeated ischemia.
of amorphousgranulesthought to contain lipids. The acyl esters themselves, ancl possibly other
Swelling is a reversiblefeature but clepositionof m et abolit es s u c h a s I y s o p h o s p h a t i c l e s ,
granules in the matrix is among the earliest accumulate in the ischemic tissue and ma.v
morphologicalcriteria of irreversibleinjuql. Thus, contributeto lossof membraneintegrity.
despite the persistenceof some electron transport Kallikreinis a serine protease enzyme which
function, oxidation of pyruvate coupling of acts to form the potent vasodilator,braclyl<inin. lt
respirationto synthesisof ATP and suppression has an important mediatory action in the local
of latent mitochondrial ATPase are markedly control of cardiac ancl renal function. Braclykinin
impaired. acts as an enclogenous mecliator of carclio-
Myocardium obtains energy from substrate protection. In patients, activation of the plasma
Kallikrein-kininsystem has been ictentifiedduring
catabolismand transducesit to mechanicalenergy myocardial
ischemia.
utilised in contraction, thereby fulfilling the
functionalrequirementsof heart as a pump. Under The most common symptom is chest pain
physiologicalconditions,metabolismof free fatty which occurs either at rest or with exercise.
lschemic pain may result from a sudden clecrease
acicl fulfills 60 to 9oo/oof myocardial energy
in coronaryl bloocl floW (e.g., coronaqlthrombosis
requirements.Thus; production of ATP under
aerobicconditions15dominateclby free Fattyacict or spasm) and/or from the inability to increase
oxidation.Approximately140 moles of ATPcan be coronarv blood flow sutficiently to meet an
increment in myocardial 02 clelnanclas occurs
synthesizedfrom one mole of a long chain fatgl
during exercise (e.g., severe coronary narrowrng
acid. Under physiologicalconditions, fatgr acicls
extractedby myocardiilm are metabolisedprimarily clue to atherosclerosis). Such pain may occur in the
by p-oxidation within mitochondria. However, absence of coronary occlusive disease when
coronary perfusion pressure is low (e. 9.
during brief intervals.ofischemia,uptakecontinues
b u t oxidatio n is inh ibite d; t he r es ult is hypotension) or when o{/gen clemands are greatly
elevated (e.g.,aorticstenosis)
accumulation of cytosolic fatty acids some of
which are deposited in triglyceride. CHESTPAIN
The citric acid cycle refers to a series of
reactionsthat sequentiallyoxicliseZ-carbonunits Cardiac Non+ardiac
(acerylCoA) cleriveclfrom glycolysis or fatty acid
oxidation. The qycle is responsiblefor generating Ischemia Non-ischemia Pulmonary Gastrointestinal
most of the ATP derivecl from substrate (Esophagial
spasm)
- Caronary - Pericarditis
metabolism.Under physiologic aerobiccondition, atherosclerosis- Aorticdissection
one turn oFcycle resultsin productionof 12 moles - Coronaryspasm- Cardiomyopathies
of ATPand Iiberationof 2 molesof COzper mole of PsychogenicNeuromusculo-
- Depression skeletal
ace!l CoA catabolized. Glycolysis (glucose - Anxiety
metabolism)occursin cytoplasmwhile fatg acicl
oxidationoccursin mitochondria.
Principles
of Medicinal m DrugsActingon Cardiovascular
System

inclepenclentcoronary risk factors

Establishecl Both nitrates ancl nitrites exhibit same
include increasingage, male sex, hyperchole- pharmacologicalaction. Nitrates convert them-
sterolemia,cigarettesmoking,diabe(es anclhyper- selvesinto nitrites anclhence both are coilectivelv
tenslon. termed as nitrites.
Potential risk factors include, Obesity, life- Nitrites bring about relaxatton of smooth
sgle, family history of prematurecoronaryartery muscleparticularlyof post capillaryvessels(like
disease,Type A personality,hypertriglyceridemia veins ancl venules).They do not have a direct
anclhyperuricemia. action on capillariesas capillariesclo not have
smooth muscles, but this action talies place via
relaxation of precapillary spinctures which are
Mechanicalinjury Vasoconstriction
responsiblefor inflow of blooclin capillaries.
General Measures :
cholesterol Plateletand monocyte Certain general measuresare inc'licatedin the
fLDL
adhesion,rinfiltration treatment of anginal patientsto reduce the cardiac
ENDOTHELIAL work load and to prevent further arterial
DYSFUNCTION
Growth pronotion
degeneration.
Hypenension
Smoothmusclecell The loaclon the heart can be reclucedbv,
proliferation
( 1 ) Correctingany obesity by avoiclin.gheavy
Cigarette
smoking I Arterialpermeability meals.
Alteredlipoprotein
enny/ clearance (z)Avoicling situationsthat lead to stress.
(3) Lowering of plasma levels of cholesterol
and triglycerides.
Classlffcatlon of Antlanglnal drugs :
(4) Avoicling excess of exercise and excess of
Drugs employecl for the treatment of angina work.
pectorisinclucle:
Treatment of Anglna Fectorls :
(i) Nitratesanclnitrites
(iD Xanthines (aminophyllines) (i) Etiology must be corrected first e.g.
(iii) Nicotinicacid and its derivatives anemia, syphilisetc.
(iv) Papavarine (ii) Aclministration of glycerol trinitrate
(v) p-adrenergicblockers (nitroglycerin)beForeexercise.
(vi) MAO inhibitors (iiD Disciplinecllife to prevent the chancesof
(vii) Miscellaneous attack and recluction in weight t s
Nitric oxide has been iclentifieclas a mecliatorin beneficial.
a vast array of physiological processessuch as (iv) For prophylaxis Ionger acting nitrates
endotheliumdependent relaxation.neuro trans- should be employecl.
missionanclcell mediated immune responses(i.e. (v) Short acting nitrite agents are useful in
macrophageincluceclcytotoxicity). caseof nitroglycerinetolerance.
Nitric oxicle is a potent local vasoclilator.A (vi) Use of seclativein anxious patients.
ubiquitous enzyme in enclothelium,nitric oxicle
(NO) synthetase,forms NO from the N-guanidino (vii) Reclucingsmoking habit.
terminalof L-arginineand molecularo4ygen.Nitric (viii) Prophylactic use of p-blockersin frequent
oxide stimulatesguanylatecyclaseto increasec- attacks,
GMP which in vascularsmooth muscle clilates (ix) Anticoagulantsin severe conditions of
blood vessels ancl inhibites platelets. The NO angrna.
generation by nitro-prussicleis an acceptecl (x) Surgicalprocedures.
mechanismin systemicvasoclilation.
 of MedicinalGhemistry(Vol.ll)
Principles $1 DrugsActingon Cardiovascular
System

Table 15.3
Cllnlcall used antlan lnal clru
Nltrltes and Nltrates :
(a) Nftrltes
cHcH.,cH,'oNo NaONO "a\ ./'*
NO .
+
2N a
I NC/ \.*
CHr Nitrite
Sodiurn
A myl nitrite l\ltroDrussrrle
soolum

(b) Nltrates
cHroNo, cH,oNo,
I I
CHONO,
I CHONO,
H.rPOr
cll,oNo?
I
cH,oNo,
Nitloglycerrn
tetranitrate
ErythLitol Trolnitrate
phosphatc

cH,oNo, CH,ONO, cll..'

I I IcHoNo.,
- c - cH..'oNo,
o,NoclH" o,No- CH
I I I
cHroNo, o , N o - CH CH
I I
tetranttrate
PentaerYthritol cHoNo, CH
I I
CHONO" olNocH
I ICH,,
cH)oNo,'
Mannitolhexani(rate Isosorbi
de dinitrlte
Mlscellaneous antlanglnal drugs :

ocHr

CH,CHNHCH,CH"CH
N= C - C - CH( CH{ ) ,
I
((-
Hr).,
I
Perliextlene N - cH..
Prenylamine I
( CH,)r
o
COOH
t
ocH r
ocHl
l\ rcollnlc aclo Acipimox Verapamil
Principlesof MedicinalChemistry(Vol.ll)
Cc'ntralmeclritnisms
Periphcral
adrenergic
ilcttva ll0 lt
l act or s
Balo and
chcmoreceptors
Blo o dvo lu m e
. l5.l2 : Mosalctheo of
The vascularfluctuationsin the circulationare
communicated and controlled by baro and
chemoreceptors.The baroreceptorsare pressure
sensitive receptors locatecl in the walls of heart
ancl blood vessels e.g., caroticlsinus ancl aortic
arch receptors. When there is a fall in bloocl
pressurein caroticlsinus,it stimulatessympathetic
nervous system resulting into vasoconstriction
and an increasein bloocl pressure.On the other
hand, an increasein bloocl pressureactivatesthese
baroreceptorsresulting into arterial clilationthus
opposing a tenclencyfor permanent hypertension.
The loss of this inhibitory activigrof baroreceptors
may. leacl to moclerate hypertension. While
chemoreceptorswhich are also locatecl in vessel
wall are sensitiveto changesin oxygen content of
the bloocl.Thev inclucevasoconstrictionin order
to compensateany fall in orygen concentrationin
bloocl. The effects of activation of the baro and
chemoreceptorsare mecliatedthrough the release
of renin which then initiates the activation of
qngiotensin- alclosteronesystem. Renin(molecular
weight 42,OOO)is a proteolytic enzyme that
catalyses the formation of active pressure
hormone, the angiotensin.lts presence in the
kiclneywas first discovereclin 1898. lt was named
'renin'by Bergmandue to its renalorigin. Kiclneyis
the rich sourceof renin where it is stored in the
granularjuxtaglomerular(JG)cellsin the wallsof the
afferent arterioles, in the form of prorenin (a
3CB DrugsActingon CardioVascular
Systern
Cardiac
outpul
Renin-angiotensin
system
aldosterone
Vr s cosi ty
bloocl erftrslon In tlssue
zymogenwith a molecularweight of 63,OOO). The
prorenin in turn, is obtained by intracellular
proteolysisof an inactiveprecursor,preprorenin.
Both proreninand preproreninare also presentin
plasma.
Renin - Angiotensinsystem is an important
part of the homeostaticmechanismsin the body.
It.get activateclby clecreaseclblooclvolume, low
renal pressure (baroreceptorsin renal afferent
arterioles)and low socliumion concentrationin the
plasma(chemoreceptors in renalafferentarterioles)
It regulatesthe electrolyte balanceby controlling
aldosteronesecretionby aclrenalcortex.
The componentsof renin-angiotensin system
are present in many other tissues.Prostaglandins
also are founclto stimulate the releaseof renin in
responseto inflammatorystimuli. For example,
PGt2 (prostacyclin),through its vasoclilating
action, activatesthe baroreceptorsand stimulates
the renin release.Similarlythe IG cells are directly
innervatedby central sympatheticnerves. Hence
under the conclitionsof strain and stress, the
sympathetic stimulation may lead to the
hypertension clue to the activation of renin-
angiotensinsystem.The renin-angiotensinsystem
then regulatesthe blood pressureand plasma
sodium at normal level by exerting generalized
vasoconstriction and inducingaldosteronerelease.
Principlesof MedicinalChemistry(Vol.ll) tt4 DrugsActingon CardloVascu3ar
System

Corticnlccn[ros.

Hypotlralrniua

MedullarY-''-
Vn.omotorcentro

9rh Cronial

Cnrotidrinur
(bororeceptor)

Aorticarch
(buroreceplorl

Flg. 15.13 Central control ovcl hcart fonqllonlng

The effect of sympathetic nerve stimulation is
revealedin the Fig 15.14.
Hence antihypertensiveagents which act at
adrenergicterminal, may act by various mechanism
like,
(i) Interfeiing with the synthesis of
noradrenalineand forming false neurotransmitter,
e.g., methyldopa.
(ii) Increasing the metabolism of free
noradrenaline,
(iii) Inhibiting the releaseof noradrenalineat
post ganglionic adrenergic nerve terminal e.g.,
bregrlium.
(iv) Inhibiting reentry of noradrenalineinto
storagesitese.9., reserpine.
(v) Antagonising noradrenaline at receptor
sites,e.g., o anclp adrenergicantagonist.

nerves
Sympathetic

Adrenalqland Norepinephrine

heartrate
Increased Constrictionof blood
lreartfbrce
Increased vessel(cr-response)

Adrenaline Dilatationof bloodvessel(p-response)

tlg. t5.14 : Effects of adrenerglc nculotransmltt€rs on cardlovascularsystcm

Frinciples
of Medicinal (Vol.ll)
Chemistry
The term hypertensionis generallydefineclas a
pathologicallyelevated systemicarterial pressure.
ln this disorder,the small arteriolesappearto be
uncler excessivesympathetic nervous system
stimulationwhich causesarteriolarconstriction
and increaseclperipheral resistanceto the tissue
capillariesand venous circulationresulting into
increasedblood pressure.Due to the variable
nature of the systolic bloocl pressure,the term
hypertension usually refers to an abnormal
elevation in diastolic pressure. For practical
guidance, usually the systolic/diastolicbloocl
pressureabove 160/95 is consiclereclto be a state
of hypertension.
When the hypertension is clue to the
symptoms of definable causes, such as renal
artery stenosis (i.e., pathological condition of
kidney which restrlctsthe blood flow through the
renal artery),pheochromocytoma(a hypertensive
condition causeclby the releaseof large .rmount of
catecholaminesdue to tumors in the aclrenal
meclulla)or an enclocrineclisorclerlike alclenomas
(excessivesecretion of aldosterone by the aclrenal
cortex), it is referrecl to as seconclary
hypertension. Seconclaryhypertension may be
classifiedas neurogenic, renal, endocrine and
cardiovascular.When the cause of hypertension
cannot be clearly defined, it is classified as
essential hypertension. In the presence of
essentialfiypertension,the pnmarycause In most
of the patients is inereasedvascular reststance.
Essentialhypertensionis of two !pes: graclual
accelerated(mali nant).
(beni.qn)and
Left
Heartfailure
Cardiacoverwork
tlg. 15.15 : Effect of sustalned hypertenslon on heart
gb DrugsActingon Cardiovascular
System
Along with other factors like, hyperchole-
sterolemia,diabetesand smoking,hypertensionis
an important contributory risk factor for the
development of arterioscleroticcardiovascular
diseases.Usually in men, hypertension is more
common beforethe age of 45-50 years.After this
age, it is more common in women.
Sustainedhypertension may seriously affect
the functioningof vital systemslike carcliovascular
system, central nervous system ancl renal system.
ln heart, the increaseclsystemicpressureleaclsto
an increasein the carcliacworkloacl.The resulting
cardiacoverwork then becomesa prominent cause
of left ventricularhypertrophy.
The sustainedhypertensionmay disturb the
functioning of central nervous system resulting
into vertigo, clizziness, occipit.rl heaclaches,
dimmed vision,vascularocclusionand hemorrhage
white in kiclneys,renalarterioscleroticlesion of the
afferent ancl efferent arterioles clevelop, resulting
into renalfailure.
I5.I9 ETIOLOGYOT HYPERTENSION
:
The various factorswhich contribute to lessor
more extent to the state of hypertension can be
classifiedas
(a) Neural factors
( b ) Hormonalfactors
(c, Electrolvtefactors
(d) Vesselwall factors,ancl
(e) Genetic factors.
Increased
myocardial
oxygendemand
AneinaPectoris
Principles
of Medicinal (Vol.ll)
Chemistry CD
(a) Neural factors : Stress or emotions
causing excessivesympathetic outflow from the
brain may result into an increasedcardiacouput
and elevated peripheral resistance. The
overproductionor incomplete destruction of
sympathomimeticamines may further contribute
to the elevatedperipheralresistance.The abnormal
levelsof noradrenaline, adrenaline,dopamineand
serotoninmay play a peripheralas well as a central
role in activation of vasomotor tone. Usually
agents which block the effects of syrnpatho-
mimetic amines are useful to treat hypertenslon
caused by neural factors.
(b) Hormonal factors r Renin, a proteolytlc
enzymefound primarilyin the kidney is releasedin
responseto lowered perfusion pressureand low
sodium statesof the circulatingblood. It catalyses
the conversionof angiotensinogento angiotensin
I (clecapeptide).
The latter is rapicllyconverted in
the plasma by a chloride activated enzyme
(primarily in the lungs) to angiotensin ll
(octapepticle).Angiotensin ll has three folcl action.
(i) It constricts the arterial network to
increaseperipheralresistance.
(ii) It slowly triggers the releaseof alclosterone the classification of these clrugs. They are
which in turn, increasessodium rete2tion and
plasmavolume,
(iii) lt causesan excessivereleaseof catechol-
aminesfrom adrenalmedulla and from peripheral
sympatheticnerves, resulting into an increasein
cardiacoutput. The renin-angiotensin-aldosterone
system thus affectsall three pnmaryfactorswhich
can causehypertension,like
(a) Blood vessel constriction,
(b) Increasedblooclvolume, and
(c) Increaseclcardiacoutput.
Though elevated renin-angiotensinlevels
appearto play a critical role in severehypertension, lBl Vasodllators :
other hormonesand vasopressorsubstancesmay
sometimes be important like arachidonicacicl
metabolites,prostaglandins,corticoids, kinins,
vasopressinand some yet unidentified hormones. (b) Calcium channel blocking agents e.9.,
Prostaglandins(PGA,PGE)for example, causea fall
in blood pressure and renal dilation. They also
initiate the release of renin by a central effect on
the vagus.
(c) Elcctrolyte factors : The inabiligr of the
kidneyto excretean adequatedaily amountof salt
,DrugsActingon Cardiovascular
System
and water results into abnormal retention of salt
and water in the blood which causesan increasein
the blood volume. The net result is an increasein
the workload on the heart.The blood potassium
and blood selenium level may also play an
etiological role in hypertensionalong with other
dietaryand environmentalfactors.
(d) Vesscl wall factors : The vascular
smoothmusclesare highly sensitiveto changesin
the c;rdiac output. Hence increasedperfusion
pressurqdue to lncreasedcardiacoutput leadsto
structuralchanges(like wall thickeninganclhyper-
trophy of vasculature)in the blood vessels.The
direct acting.vasodilators, hencemay be of value in
this type of hypertension.
(c) Genetlc factors : The increasedsensitivity
and susceptibility to various etiologic factors
(which are mentioned above) by offsprings of
hypertensives underlies the importance of
hereditaryFactorsin hypertension.
15.2O crAsstFtcATroN
All currentlyavailableantihypertensiveclrugs
act mainly by interferingwith normal hemostatic
mechanismsand this provides a useful basis for
classifiedas :
IAI DruSsaffectlng sympathetlctone :
(i) Drugs that alter cenrral sympathetic
activigle.g., methyldopa,clonidine.
(iD Drugs that act as adrenergic neuron
blockers,e.g.,guanethicline,reserpine.
(iii) Ganglionicblockingclrugse.g., trimetha-
phan.
(iv) a-adrenoceptorblocking agents e.9..
prazosin,phentolamine.
(v) p-adrenoceptorblocking agents e.g.
propranolol,atenolol.
(a) Direct vasodilators:
(i) Arterialdilatorse.9., hyclralazine
(iD Balancecl e.9., minoxidil.
vasoclilatores
nifedipine
ICI Agents actlng on renln-anglotenslnsystem:
(i) Renin inhibitors
(ii) Angiotensinantagonistse.g., saralasin.
(iii) Angiotensinconvertingenryme inhibitors.
e.g.,captopril,enalapril.
Principlesof MedicinalChemistry(Vol.ll) DrugsActingon Cardiovascular
System

[Dl Dluretlcs : Activation of postsynapticcr1-receptorsleads

(i) Thiazidese.9., hydrochlorothiazide to arterial vasoconstrictionresulting into an
(ii) Loopdiuretic e.9.,furosemide increasein peripheralvascularresistance.Hence
(iii) Potassiumsparingdiureticse.g.,triamterene. cr1-adrenoceptor blockingagentscan be clinically
[El Central depressants : used as antihypertensive agents. Examples
15.2I GENERALCONSIDERATIONS include,prazosin,trimazosinand indoramin.They
Thesedrugs proclucetheir hypotensiveaction appear to exert vasodilatory effect through the
by affecting the biosynthesis, storage, uptal<e, blockadeof o1-adrenoceptors. Prazosinis the first
release,metabolism ancl adrenoceptoractivation memberof this class,reporteclin 1974followedby
by sympathomimeticamines. trimazosin.Both are quinazolinederivatives.They
Agents acting at both, centralsites (reserpine, mainly affect the venous vascular becl but become
guanethicline)and at peripheral sites (carclio- more balancedduring long term treatment. They
selectivep; - antagonists) are incluclecl in this class. affect to varyrngdegree, the functioningof renin-
The adverseeffectsinclude increasedrenin secre- angiotensinsystemresultinginto socliumand fluicl
tion and clevelopmentof tolerance.Other effects retention.They tencl to proclucetoleranceif usecl
incluclesedation,dryrmouth anclclepression. chronically.They are mainly useclin the treatment
The lowering of blood pressureby drugs like of hypertensionanclheart failure.
methyldopa ancl clonidine is brought about p-aclrenoceptors are mainly present in heart,
probably by stimulation of central presynaptic pulmonarylvessels,vesselssupplying bloocl to
d2-adrenoceptors, thereby reducingthe releaseof skeletal muscles and are also involved in glyco-
efferent sympathetic traffic from CNS. genolysisand lipolysis.The p-adrenoceptorblock-
Prototype
examples fromeach cardiovascularcategory ing agents act by the competitive inhibition of the
Discovery Prototype Category effect of catecholamineson p-adrenoceptors.Pre-
1957 ChlorothiazideDiuretic viously it was proposeclthat the antihypertensive
1959 Bretylium Neuronal blocker effect of these clrugs results due to a downward
1960 Alphamethyldopa Dopadecarboxylase inhibitor suppressionof functioning of baroreceptors.But
1964 Furosemide Loopdiuretic now the antihypertensiveeffect of p-aclreno-
Propranolol Betablocker
1966 Clonidine Alpha-2 agonist ceptor blockingagentsis explainedin the following
tvod Atenolol Beta-1 blocker lines.
1971 Nitedipine Calcium channel blocker (a) Decreased renin release occurs due to
1977 Captopril ACEinhibitor inhibitionof p1-receptorswhile renal plasma flow
1978 Lovastatin HMGCoAreductase inhibitor and rate of glomerular filtration are reduced by
1981 Disopyramide Antianhythmic blockadeof p2-receptors.
1989 Losartan Angiotensinll receptor (b) Decreaseclnorepinephrinereleaseoccurs
antagonist
from the postganglionicsympathetic nerves clue
Cuanethiclinemay be consiclereclas a repre- to the blockacleof presynapticp-receptors.
sentativeexample of the drugs that depressthe (c) Centralmechanismhas been proposedfor
functioning at adrenergit neurons. Drugs in this some lipophillicp-blockers, and
classappearto act by more than one mechanism. (d) The cardioselectivep1'blockersact by
These agents mainly act by causing a gradual exerting a recluction in rate and force of heart
depletion of catecholaminestores from central and contraction.However such cardioselectivitvis of
peripheraladrenergicnerve endings resultinginto relativenatureanclis seenonly at low doses.
reduced sympathetictone. Unlike clonidine, the Due to interferencein glycogenesis,these
therapy with reserpineancl methyldopa is usually clrugs may cause hypoglycemia like symptoms
associatedwith extrapyramiclalsicle-efFects. during chronictreatment.
" Alpha aclrenoceptorsare subclassifledas post-
presynaptic Dichloroisoproterenol was the first B-blocker
synaptic d1-adrenoceptorsand o1-
introduced in 196Os.All p-aclrenoceptorblockersare
aclrenoceptor.The ot1-receptorsare predominantly
present in smooth muscle cells qf arterial walls. analoguesof aclrenoreceptor agonist,isoproterenol.
While a2- receptorsare presenton the presynaptic The B-blockerscompetewith agonist moleculesat
adrenergicneuronsand exert inhibitory influence three principle reactive sites. They are characterized
over the releaseof norepinephrine. by a substitutedaromaticring and a side-chain.
Principlesol MedicinalChemistry(Vol.ll) ilB
hyperterrsion.Hence drugs that antagonise the
effect of renin, angiotensinor alclosteronecan be
used in the, treatment of systemic hypertension,
congestivecardiac failure ancl pulmonary hyper-
tension.The drugs from this class can be sulr-
categorizeclas
(a) Renin antagonists
(b) Aldosteroneantagonists,
(c) Angiotensin-ll antagonists,ancl
(ct) Convertingenzyme inhibitors.
At present, renin antagonists clo not have
therapeutic potential while atdosterone anta-
gonistsmay principallybe used as diureticagents.
Saralasinis an example of angiotensinII compe-
titive antagonist while captopril (1977) is an
example of orally effective converting enzyrne
inhibitor.
Sodium retention and consequent fluid
retention usuallyserve as the initiating factorsin
hypertension.Certainantihypertensivedrugs (e.g.
aclrenergic.neuron blocking agents, vasoclilators)
could not retain their efficary clue to reflex acti-
vation of plasmarenin. In such casesdiureticscan
bring about impressiveresultsby suppressingrenal
tubularreabsorptionof sodium, thus reducingthe
blood volume and the cardiacoutput. They exert
antihypertensiveaction by promoting the loss of
salt and water through the kidneys.Howeverthey
too, are not free from adverse effects and may
induce reflex renin activation and metabolic
changeslike, hypokalemia,alkalosis,hyperglycemia
and hyper uricaemia.Sexual clysfunctionis also
reporteddue to long term treatmentwith diuretics.
Fror_n.theforgoingdiscussion,it becomesclear
that none of the above categories qualifies the
test for ideal antihypertensive agent. Their
efficienqyis largely paralyzeddue to emergenceof
compensatoryreflex mechanismsin the body. For
example, vasodilatorslead to reflex tachycardia
and elevation of plasma renin activity while
sympatholyticsgracluallylose their effectiveness
clue to fluid retention. The sympatholytics can
abolish reflex tachycardiaassociatedwith vaso-
dilatortherapywhile the fluid retentioncausedclue
to sympatholytics and vasodilators can be
effectively neutralized by the use of diuretics.
Such a combinationof a sympatholytic,vaso-
dilator and a diuretic agent presentsmost effective
antihypertensive treatment Whiere very low
incidencesof side-effectsresult due to compara-
tively low dosesof each of the three components.
DrugsActingon Cardiovascular
System
I5.22 DR.UGSATTECTING SYMPATHETIC TONE
(SYMPATHOTYTICS)
(l) Drugs that alter central sympathetlcactlvlty :
(a) cr- methyklopa : Tyrosineancl DOPA are
the principal intermecliatesin the biosynthesisof
catecholamines in the bocly. Drugs having
structural resemblancewith these intermediates
will then, naturally compete with the enzymes
which convert these intermediatesinto norepine-
phrine. ct-methyltyrosineand o-methyldopa are
the examples of drugs developecl through this
concept. Both get acted upon by enrymes instead
of tvrosine ancl DOPA resulting into false
neurotransmitters instead of norepinephrine,
which have lesspotenry than norepinephrine.
Since the rate of decarboxylation of
a-methyldopa is consiclerablyslower than that of
DOPA, it ties up the en4yme,DOPA decarborylase
for longer period of time and is effective inhibitor
of the biosynthesisof norepinephrine.Insteaclcf
norepinephrine,methyl norepinephrineis formed
which has weak central as well as peripheral
actions. Thus pressor response to adrenergic
stimuliis reducecl.
CH:- C- COOH
I
NH,
a-methylclopa
Sinceit is a potent agonist at presynapticA2'
receptors in the CNS, it causesan inhibitionot
further release of central sympathetic outflow.
This central mechanismis now recognizedas the
main site of action of methyldopa and the concept
of 'false neurotransmitter' responsible for
peripheral effects is considereclas a secondary
mechanismof action. Methylclopa is one of the
olclest and commonly usecl antihypertensive
agents. Its antihypertensiveeffect results from a
clecreasein peripheralvascularresistancewithout
affectingcardiacoutput. lts use is also suggested
in the treatment of malignant carcinoicland
pheochromocytomas.lt is an antihypertensive
agent of choice in pregnantwomen and children.
The plasma level of the clrug can not be correlated
with its antihypertensiveeffect since the action is
clue to its metabolite(a-methyl norepinephrine)
 pol. ll)
PrinciplesollMedicinalC hemistry 310
and not due to the drug. The drug gracluallyloses
its efficacydue to weight gain and fluid retention.
(b) Other a2-adrenoceptoragonists :
/\
CH H Introcluctionof fwo chlor!ne atoms in the Z-
Nt-tc- NHz
CI
Guanabenz
I H
cHr
Clonidine
In the beginning of 196Os, Helmut Stable,
while working on decongestiveimidazolines,(e.g.,
tolazoline, phentglamine) observed that the
imidazolinenucleusis connectedwith an aromatic
ring by a methylenebriclge.With previousresearch
works, he found out that replacementof {H2- by
- NH - group may lead to increasein decongestive
activity.The re::,rltingcompoundswhen tested by
Dr. Wolf who aclministereda few clropsof O.3 o/o
solution to Mrs. Schwandffor common colcl, it
was found far less interesting than its potent
antihypertensive activity. The compouncl
(clonidine) was then developecl for this new
indicationand was introducedin therapyin 1966.
Cardiovascularactivity ancl blood pressureare
centrallygoverneclmainly by hypothalamus,the
nucleustractus solitarii and the nucleusof vagus
nerve. Catecholamines are the principal
neurotransmittersin this region except at vagus
nerve.Clonidineis a potent igonist of,presynaftic
inhibitory o2-adrenoceptors.By activating these
receptors,it reducesthe sympathetictraffic from
the CNS.
The inhibition of sympathetic function results
in corresponding dominance of parasympathetic
tone resulting into bradycardia.Cloniclineis cr2-
agonist. It stimulates both, central and peripheral
DrugsActingon Cardiovascular
System
o(2-receptors resultinginto reducednorepinephrine
release.lt lowers clown mild to moderate hyper-
tension by reducing vasomotor tone. lt has a
number of chlorpromazinelike actions which
indicatesthe presenceof multireceptorsitesfor its
acuon.
(.rrylimine)imiclazolicline moleculeproved important
for the activity of clonidine,as
(a) two substituentsat ortho position forced
the moleculeinto a non-planarconformationwith
the two rings approximatelyperpenclicularto each
other so as to meet the steric requirementsto fit a-
aclrenoceptor.
Norepinephrinecan assume several confor-
mations in its interactionswith c,-receptor,
clonidine can alter its conformation much less
reaclily becauseof the presence of two chlorine
atoms at ortho position preventing free rotation of
2 rings" This contributes to better complimentary
fit at cr-receptor.
(b) two chlorineatoms also make the molecule
sufficiently lipophillicto crossBBB.
Norepinephrineis the prototype of agents
acting on cr-receptors. The cr-adrenergiceffectsof
clonidine may be explained on the basis of
structural overlap between clonicline and
n o r e p i n e p hrine. Accorcling t o P ullman and
Coubcils, the distance betw,eencationic N+ and
center of aromatic ring of nor-epinephrine is
between 5.1 - 5.2A", while nitrogen is situated
between 1.2 - 1.4 Ao above the plane of aromatic
nucleus.
HO
t.4A
OH i-*'
I
I
Norepinephrine
N
I 1.36A
H I
I
I
I
I
Clonidine
Prlnclpbsol Medlclnal flol. ll)
Chemlstry
It is believedto Inhibit both, nor adrenerglc
and S-HT-nergic neuronsin the braln.lt alsobrlngs
about reduction ln plasma and urlnary
catecholamlnes,renln actlvity ancl urlnary
aldosteroneln hypertenslvepatient. lt ls also
capable of actlvatlng the central Hz-receptors.
Becauseof its excellent penetratlon Into CNS,
clonldine preferentlallystimulatesbraln d,2-
adrenoceptorsthat decreasethe cardiovascular
actlvigl. In contrast norepinephrlnewhlch is
distributecl mainly perlpherally, Increases
cardlovascularactlvlty.
Other examples of drugs belonging to this
class include. guanabenz, guanfaclne and
prperoxan.
(ll) Drugs that act as adrenerglc ncuron
blockers :
(a) Cuanethldlne: A number of antlhyper-
tenslve agents exert their actlvigl by affiectlngthe
storage and release of noreplnephflne. Thls is
achievedby Inhlbltlonof Ca++- lnflux lnto the
nerve termlnal. Examples include, breglllum,
guanethidlneand rylochollne. Guanethidlnemay
be consldered as representativeof drugs that
depressthe functlonof postgangllonlcadrenergic
nerves. lt utilizes the same transport system
which ls involved In re-uptakeof norepinephrine
into the nervetermlnalsand reachesIn the nerye.
Upon accumulationIn adrenergicnervesfibers,it
induces a gradual depletion of catecholamine
intraneuronalstoragesltes and itself acts as a false
neurotransmltter and releasedby nervestlmulation
resultinginto a decreasedpressorresponse.The
effectsof guanethidineare cumulativeover long-
term treatment.
- cH2cHz- l H2S04
Cuanethldlne sulphate
NH
ll
CH2NH
- c- NHz , H2SO4
Guanadrelsulfate
3t1 DrugsAc{ngon Cardlovascular
System
(b) Reserplne:
It ls an exampleof rauwolffaalkaloldsobtalned
from the roots of Rauwolfla serpentlna from
Apocynaceaefamily. Once, reserplnewas one of
the most favouredantihypertenslveagents. Due
to its moderatepotencyand a hlgh lncidenceof
adverse effects, it is rarely used today as an
antihypertenslveagent. lts parenteraladmlni-
stration In the tment of severe
hypertensionbril >odpressurein a
smooth and graclualfashion.
(lll) Sympathetlc gangllon blocklng drugs I
In sympathetlc ganglla, the release of
noreplnephrinefrom the intemeuronactivatesthe
postganglionlccr-adrenerglcreceptors resultlng
into characteristiccatecholamlneresponse.The
gangllonlcstlmulationmay lead to the releaseof
adrenallneand noradrenaline from adrenalrnedulla
and sympathetlcnerve termlnals.The gangllonic
blocking agents can reduce the level of sympa-
thetic actlvlgl.Hencethey were oncewidely used
In the treatment of hypertenslvecarcliovascular
disease.Slncemechanisms governlngtransmission
in all autonomlcgangliaremalnssame,their non-
selectivity of action leads to numerousside-
effects. Hence they are now totally replaceclby
more selectlveand less toxlc p1 -adrenoceptor
blocklngagents.
The developmentof antlhypertensiveagents
from thls category began wlth observation that
tetraethylammoniumchlorldetranslentlylowered
bloocl pressure in hypertenslve patients by
inhibitlngtransmlssionof nerve lmpulsesthrough
sympatheticganglia.When a serlesof quatemary
ammonium compounds was deslgnecl,higher
members(e.g. decamethonlum)exert curarelike
paralysisof muscleswhlle lower members (e.g.
hexamethonlum)produced gangllon blocklng
action. The drawbacks of antlhypertenslve
gangllonlc blocking agents Include lnconsistent
fluctuatlons ln blood pressure, poor oral
absorption and side-effects assoclated wlth
sympathetlc and parasympathetlcbfockade. ft
was thought that fluctuailons In blood pressure
and severity of slde-efrectswould be due to poor
oral absorptlonof these agents.Thls led to the
development of mecamylamlne whlch is a
secondary amlne permlttlng complete oral
absorptlon.Howevermecamylamlne also failed to
improve therapeutic effiectiveness. The structures
of mecamylamine and pempldineled to the ideaof
preparingguaniclines, alkyl guanldlnesand arallyl-
alkyl guanldlnes.Guanlthidlne,bretylium and
Principldsof MedicinalChemistry(Vol.ll) 312 DrugsActingon Cardiovascular
System

bethaniclineare the outconre of these efforts.

Recentlyintroduceclexamples from this category OH
include,

NH
tl
- c - NH, N(cH2cHcH)2

Debrisoquine u-20,3B8
Both are potent peripheral vasoclilators.u-
20388 also possessesanticliureticactivig.
NH
(lv) Aclrenoceptor blocklng agents :
ll
-c - NHz The adrenoceptors are categorizecl as
postsynaptic tr 1-aclrenoceptors ancl crr -
Cuanisocluine adrenoceptors. cLl -receptors are present on
smooth muscles of Lrlooclvesselsancl glancl cells
while c2-receptors are present on pre ancl post-
N - CH: synapticsites on the nervesand are also presentir
tl
- C --- NHCH3
the CNS. The activation of postsynapticGr-
receptors leacls to vasoconstriction while the
activation of presynapticcr1-receptorspresent or
P-4746 the nerve terminals leacls to inhibition o:
neurotransmitterrelease.Thus cr1-adrenocepto
NH blockers (i.e., vasodilation results, hence alsc
tl calleclas indirect vasodilators)or u2-adrenoceptol
c r H2 - - N H - C - N H z agonists will have a potential of antihypertensive
action. For example, prazosin ancl methoxamine
Guanoxan(Pfizer) act on sl-receptors while the antihypertensive
action of clonidineand a-methyl-norepinephrineis
due to their cx2-agonisticproper!.
NH
ll clt -adrenoceptor antagonlsts :
ll
CH C H ; - C H , - N H - C- CIl2

ctBA l3:686-Si.r HrCO -R

N
NH HrCO
It
il NH:
o - cHr-cH2 -NH -NH-C-NH,

Guanoclor(Pfizer)
Cycllc guanldlnls {Trlazlnes)

- CH2)2
N(CH2CH
cH2coNHczH5
u-7zzo
 of Medicinal
Principles pol. ll)
Chemistry 313 DrugsActingon Cardiovascular
System

(a) Qulnazollne derlvatlves :

While investigating toxicity of antimalarial
o
compouncls,Moe et al. in 1949 founclthat various
tl
HrCO -C
quinolinesproduceclappreciableanti-cr-adrenergic
effects. As a result, a series of 6, 7-dimethoxy
quinolineswas synthesizedin Norwich laboratoryl. Hlco
The potent hypotensive agents inclucle.
NH'

HICO
Prozosin

HrCO OH
HrcQ I
OH -coocH,,
HrCO
u-558 cHr
N
HrCO
HiCO NHt

Trimazosin
HrCO Prazosin (1974) exerts its antihypertensive
NH.' action by btockingpostsynapticG1-adrenoceptor
resulting into vasodilation of the arterioles. In
Amiquinsin therapeutic closes it does not affect the cardiac
output and heart rate. No other pharmacological
Hr CO action is reportecl.The clecreaseclarterialvascular
resistance ancl recluction in arterial and venous
tone are the effects mainly due to vasodilation
Hr CO caused by blockage of vascular cr1-receptors.
N=CH ocHs Hence c,-blockers are also termed as indirect
vasodilators. Its use is accompanieclby moclest
Leniquinsin tachycardia (blockade of inhibito! presynaptic
dr-receptors) ancl low level of, plasma renin -
(cr1-blocking effect).
Like prazosin, trimazosin is a quinazoline
HlCO
derivative. Chemically it is Z-hydroxy-2-
methyfpropyl'4- (4 - amino -6, 7, 8 - trimetho4y-
N 2 quinazolinyl) - 1 piperazine carboxylate
Hr C O
monohyclrochloricle. It is a less potent cr1-blocker
OH
than prazosin,otherwise pharmacologicallysimilar
to prazosin. Indoramin is yet another example of
vascularc[,t-receptorblocking agent. Chemicallyit
is 1 tZ - (3 - inclolyl) ethyll derivative of 4 -
benzamido piperidine and resembles with the
H lCO - cH,cH- CH"
structureof procainamide.
(b) Fhentolamlne :
N The pharmacology of a large series of 2
H lCO
substituted imidazolines was first studied by
NH'
Hartmann ancl Isler in 1939. In addition to crl-
Quinazosin receptor blocki:':gactivity, these agents enjoy to
Principles Chemistry
of Medicinal flol. ll) 314
varying degrees, sympathomimetic, parasym-
pathomimetic,hlstarninelike, antihistaminergic,
MAC and cholinesteraseinhibitorv activities. The
dominanceof any of the above properties can be
effectecl by the structural changes in the basic
skeleton. Phentolamineancl tolazoline are the
examples of clinically employecl agents from this
class,in the managementof hypertension.
)-N -{ CH.
IC H ,
HO
H
\J
Phentolamine
\J
l'olazoline
(v) F-aelrenoceptorblocklng agents :
Mills (1958 Eli Lily Pharmaceuticals)confirmed
Ahlquist conclusion. He prepared the clichloro
analogof isoprenaline (i.e.DCI)which inhibiteclthe
relaxationof bronchialsmooth musclesalong with
the cardiac muscles elicited by isoprenaline.That
was the first p-aclrenoreceptorblocking agent (p-
blocker).lt also has a partial agonism as it causes
stimulation. But it was not clinicallv used.
Vasodilatorswere not successfulin increasingthe
o 2 supply to heart. So other possibilitieswere
needecl to be explored. The first promising
proposition to treat angina effectivelywas put by
Black.He proposeclto reducedemand of 02 of the
heart by blocking the effects of sympathetic
stimulation. Black concentrateclhis efforts in
obtaining a specific p-blocking agent without
stimulant properties of DCI and performecl
screeningtest for these gpes of activities for 18
months.But the successeludeclhim and crowhed
his colleague Stephenson who synthesised
Pronethalolwhich was the first clinicalp-blocking
agent.But in 1963 this compoundwas withclrawn
DrugsAciingon Cardiovascular
Syster
from the clinic as it exhibiteclthe toxic syrnptorr.-
(Thymic-tumours)in animals. But it generate:
ouite a lot of attention towarclsthe research::
optimize the p-antagonist activity whiclr st.
con nueS.
The concept of B-adrenergic blockade r'rai
pioneered in 1960s. Researcherswho we':
stuclying the effects of aryl ring and
substitutionin the molecule tried to moctily
ethanolamine chain itself bv Inter alia, ti :
introcluction of linkinggroup betweenaryi ring ar:
ethanolaminechain. After lots ol linking
triecl, the best linking group corne out to Lt
-€iroup
oxymethylene.It's first analog, propranolol.whi;-
is the most wiclely useclB-blockernow and is 10 r-
ZO times potent than its parent compounl
Pronethalolancl quite interestinglyBDH worker:
publishect papers regarclin.gthe anesthet:
properties of series of aryloxypropanol clmine:
before the cliscovery of DCl. This series als:
inclucleclthe N-propyl analogue of propranolc
which lateremergedas a B-aclrenergic blocl<er"
Cardlo-selective blocka<le :
Lipophilicity ensures the transfer acros!
DtoooDratnLlarfieras Dratn ls rnos v Inaoe up
lipicls.This coulcl also lbaclto CNS sicleeffectsof
blockers e.g. propranolol. Hydrophilicity ca-
minimise these CNS side effectsas first reportel
with Sotalolin 1964.ThisinspireclCrowther,Ho't:
and Smith'swork on the synthesisof oxypropan:
amine analogsanclSmith successfully synthesise:
the corresponclingacetamido compound fro-
readily available para acetamiclophenol. Th:
compound was named Proctalol.But the mcs-
important characteristicsof proctalol was foun:
little later which gave bifth to a new era of card::
selective blockacle.It was shown that proctalc,
blocksonly the carcliacB-receptors(0r) anclnot the
vascularreceptors(02).Thusproctalolgot the firs-
placein the historyof carclioselectiveB1-blockers
It also openecl the gate for treatment of patient:
with coexisting asthma (though not absolutel;.
with B,-blockers.[t also showecl minimum side
effects on CNS. It has a log P of O.79 while
propanololhas log P of 3.65 (partition coefficien:
of 45OO:1). Due to all thesevirtues practalolwas
launcheclin 197O as the first carclio select,.e
p-blocker.But it haclto be withclrawnafter severa
 Principlesof MedicinalChemisryOol. ll) 315
years of clinicaluse due as its toxic manifestation
ln some patients like skin rashes,ophthalmic
problems,some leaclingto blinclnessand severe
peritonitis.
Hull anct his coworkers came with the next
major break through by introducing a methylene
group between amiclefunctionanclaromaticring.
The first compouncl atenolol is as potent as
propranolol ancl it is also a carclio selective p-
blocker.
Metaprolol was next to come when Carlson
independently prepareclthis paramethoxy ethyl
compound"
Acebutotol is yet another p-blocker. Its
nonselectivity of action is attributecl to the
generation of an active but nonselective
metabolite. Tolamolol was recently developed
selective p1-blocker. Like pronethalol, it was
withdrawn from the clinical use because of its
ability to induce tumor in animaltestings.Naclolol
is yet anotherexample of long-actingp-blockers.
Like atenolol, it is excretecllargely in unchangecl
form through urine.
I All thesecardioselectivecompoundsare more
hydrophilic than propranolol and their cardio
selectivigrcan be attributed to the fact that B,,
receptors are hydrophilic while p2-receptoxsare
lipophillic.Another explanation for this cart(io
selectivity according to other researcheris the
additional interaction of a para substituent
possibly via H-boncl formation with a
complimentarysite on 0r anclnot on the B2-
receptors.
Unlikes-adrenoceptorblockingagents,the B-
adrenoceptorblockersexhibit structuralsimilarity
with isoprenalineor norepinephrine.Hence
structuralrequirementsof these agentshave been
fairly well defined. This structuralsimilarigrof p,
adrenoceptorblockerswith isoprenaline(agonist)
lmpans:
(i) A greater specificity of action. These
agentsact more selectivelyon p-receptorsand clo
not interferewith cholinergic,histaminergicor
serotonergicresponsesand
(ii) Somedegreeof sympathomimeticintrinsic
activity.Theseagents with some exceptions,still
retain sympathomimetic properties and can be
termed as partial adrenergicagonists.Due to their
DrugsActingon Cardiovascular
Sysien
partial agonist nature, they have less abiligr to
induce bradycardia,pulmonaryrobstruction and
rebound hypertension,in comparisonto other
antihypertensiveagents.
It is important to note that the p-blocking
effect and intrinsic sympathetic activig clo not
run opposite to each other. A potent p-blocking
agent(e.g.,pinclolol)may still retaina high intrinsic
sympatheticactivity.This is probably becausethe
functional groups involved in receptor blockacle
may in certain cases be quite different Frornthe
functionalgroups involveclin receptoractivation.
Similarlytheir structuralresemblance with local
anesthetics, enable these agents to exert a
membranestabilizingeffect or a quinidirrelike
action e.g., propranolol.This property justifies
their use to treat cardiacarrhythmias.
p-receptorresponsesare largely of relaxant
nature.The major exceptionto this generalization
is the cardiacp1-receptors,stimulation of which
increasesthe rate ancl force of heart contraction.
Therefore,selective p1-adrenoceptor blocking
agents gainecl high clinical importance as
antihypertensiveclrugs. The cardioselectivep1-
blockers act through the following postulatecl
mechanism:
l. Inhibitionof reninrelease.
Z. Reductionof carcliacoutput.
3. Inhibition of synaptic norepinephrine
release,ancl
4. Restoration of vascular relaxation
responses.
On the basis of their relative affini! for p-
receptor sub-types, these agents can be
categorizedinto three classes.
(a) Non selectlve p-blockers :
e.9., propranolol,pindolol,alprenolol,nadolol,
bunolol, sotalol, timolol, oxprenolol,penbutolol
etc.
(b) SelectlveB,-blockers :
e. g. Ac eb u t o l o l , a t e n o l o l , m e t o p r o l o l ,
practolol,tolamolol,pafenolol,etc.
(c) SelectlveB"-blockers :
These agents do not fincl any clinical utility.
Butoxamine is a somewhat selective Fz-
antagonist.
Prlnclplcsol liledlclnalChemistryOol. ll) 316 Syrten
DrugsActingon Cardiovascular

Table 15.4
p-blocklng agcnts

OH
NCH.t
Hlc
'Ieoprolol

NH-q-cHr
OH
I
ococ6Hs cHr
o
t1 Hlc
H.]C- C
(Boots)
Befunolol Bopindolol(Sandoz)

ocH.
OH OH
cHl

Bunolol(Warner) (Boehringer)
Carazolol

ocHs
OH cH.r
OH

Procinolol(Diamant)
sorNH, OH
OH
I
Sulfinalol CH orN cH-cH2-
/r""3
o-cH.-cH - C H , _NH- CH\
I \a",, INPEA
OH
OH
II
ocH2-cH-cH
CH.CONH,'
Atenolol OCH.CH= CH"
CIBA
HrCQ
o-cH"-cH-cH, -NH-CH"CH.-O CH.,
I I
OH cH-cH-l
tl CH,
OC
Tolamolol Butoxamine
(selectivc
Fr-blocker)
Prlficlplesof ftledlclnalChemlstry{VoLll)
r5.23 VASODTLATOnS
The elevated perlpheralvascularreslstancels
the maln causebehlnd most of the hypertenslve
conditlons. Vasodllatorsact by dllating the
arteriolesby whlch there ls a fall_lnblood pressure
wlthout interferlng wlth tlre functlonlng of
sympathetlc nervous system. The o 1-
adrenoceptor blocklng aggnts (lndlrect vaso-
dllators) bring about vasodllatlonby Interferlng
wlth sympathetlcfunctionlng.The vasodilators
are sub-dasslfred as :
(a) Dh€ct vasodlLators:
(i) Arterlalvasodllatorse.g., hydralazlne,and
(iD Arterlal and venous vrcsdflators : e.9.,
sodlum nltroprusslde.
(b) Indlrcct vasodllatorc :
e.g., c1-adrenoreceptor blocklngagents.
When heart fallure ls absent, vasodllator
therapyusuallyresultsIn a drop In cardlacoutput,
whereasIn the presenceof left ventrlcularfallure,
cardiacoutput ls lmproved.Thls responserelates
not only to more favourableafterloadconditlons
on failing (heart)left ventrlclebut to the hlghly
important circ.ulatoryactlons of vasodllatorson
the venousbed as well. Afterloadmay be deffned
as the force,or stressdevelopedIn the ventricular
wall durlngcardlaceJegtlon.
lf the restlng muscle length (preload)is held
constant increaslngthe afterload (welght) will
decreaseboth the extent and veloclgl of muscle
shortenlng,whereasreduclngthe afterloadwill
decrease the extent and speed of rnuscle
shortening.lf the preload and Inotroplcstate are
held constant,lncreaslngthe afterloadwlll Increase
both the speed and extent of left ventrical wall
Table 15.5 Cllnlcally used antlhypeilenslve agents
N
cl
I NC
N
NHNH2
Hydralazine
NH"
Nr,
NHz
Minoxidil
317 DrugsActlngon Cardlovasculsr
System
shortenlng,whereasreduclngthe afterloadwill be
both of thesevarlables.
Agents used for afterload reductlon (vaso-
dllators) :
Commonlyemployedvasodllatorsinclude:
(a) Intravenous I Sodlum nitroprusside,
phentolmlne,nltroglycerine
(b) Oral : lsosorbidedlnltrate, hydralazine,
prazosln.Thesedrugs tend to have little or no
direct effect on myocardlalcontractllity.
(c) Calclum channel blockers : Voltage-
dependent calclum channels malnly regulate
transmltter releaseor muscle contraction.They
are structurallyrelated to sodlum channelsand
includeL-(longlasting),T-(translent), N-(neuronal),
P-(Purklngjecells), Q-, and R-ty
exists In neuronaltlssueas well a
cardlac muscle. Thls type ls sensitive to
dihydropyrldlnes.The L-type Ca++ channelsare
hetero-oligomeric anclcomposedof o1-,c[2-,p-, 6-
and y-subunlts.The o1-subunlt provides the
bindlng slte for the L-channelblockers.Examples
lnclude,verapamll,nifediplne,dlltlazam,etc. The
calciumchannelblockers,unlikedlrect vasodilator
cause dilatlon of coronary arterles and markedly
affiectthe automatlclty,conductlonveloclgl and
refractoryperiod In myocardlalcells. Whlle direct
vasodllatorshave little direct effect on the heart
functloning in therapeutic doses. Like antl-
spasmodic agents they prlnclpally act through
direct musculotropiceffect resulting into the
relaxationof peripheralvascularsmooth muscles.
The cllnicallyused vasodilatorsIn the treatmentof
hypertenslon are shownln table 15.5.
CN
o
N- Na
Fe CN 2Na
cHl
Sodium CN
Diazoxide SodiumNitroprusside
o
ll
C -.NH'
NHNH2
Hydracarbazine
Principles flol. ll)
Chemistry
offiedicinal 318 Sysl
DrugsActingon Cardiovascular

C"alclumchannel blocklng agents : H

HrCO N ocHl

H3CO ocH.3
R R= H
Verapamil;
R = OCHr
Gallopmil;

ocH.1
Noz
o o
ll ll
oc2Hs
H5C2O- C - CH.,
N
H,c NI CH: IH2
C - CH' N(CH.r)z
H
Nit'edipine Diltiazem Perhexiline

Nivaldipine
H3 ETOOC COOEr

Bepr i dil MeO

CN CH, N Mc
I I I
c - (cH,)lN - CH,CH) H
t- PY I08- 068
( cH? ) ilcHr
OMe Noz
Anipam il

RsOOC COOR,
co2cH3
tlMo
Hrc N cuHd
I CHs
CoHi
l, 4-dlhydroPYrldlnes S-niguldipine
Rl R2 R4
1. Nimodipine 3-NO2C6H4 -{H(CH3)z cHr H
z. Nisolclipine 2-NOZC6H4 CHr CHr H cH2cH(cH
CzHs CHa H CzHs
3. Laciclipine Cll= Cl' l - CO O- t B u

Nicardipine 3 - NOzC{H4 QHr cHr

-(cHz)r N CH2C6H5
Felodipine 3-dichlorophenyl - CzHs CHr CH:
Principles (Vol.ll)
of MediclnrlChemistry 319 DrugsActlngon Cardiovascular
System

Nitrenclipine, a cfihyclropyriclinecalcium 15.24 AGENTS ACTING ON R,ENIN-ANGIO

channelblockerstructurallyrelateclto nifedipine, TENSINSYSTEM
Inhibits the movement of calcium through the Renin (molecular welght = 42,000) is a
"slow channel"of cardiacand vascularsmooth proteolyticenzyme,which is producecland stored
muscles,thus Induclng peripheralvasodilation in the granulesof the juxtaglomerular cellsin the
with consequentreductionsin elevated bloocl walls of the afferentarteriolesof the kiclney.Upon
pressure.The high affinitybinclingsitesfor t, 4 - releaseinto the renalarterialblooclstream,renin
clihyclropyriclines
havebeeniclentifiecl in the region catalysesthe conversion of angiotensinogen
of the slow channelIn the sarcolemmaof carcliac (lnactive precursor)into anglotensin-1.Angio-
tissues and braln. Binclingto these sites ls tensinogenis a circulatingalpha- 2 - globulinwith
stereospecific,saturable,reversibleancl compe- 14 - amino-acicls. lt is syntheslzedin liver and is
titive with other clihyclropyricli
ne derivatlves. circulatedln the plasma.
Some renin inhibitorshave reachedclinical
NOt trials,but furtherdevelopmenthasbeenlimiteclby
poor bloavailability.
Anglotensin- I (clecapeptlcle), which has less
intrinsicactivity is converteclto more active form,
H5C'OOC coocHs angiotensin- ll (octapeptlcle)by angiotensin
convertingenzyme.Angiotensln- ll is one of the
I{.rC cHl most potent vasoconstrictoragent. The renin
angiotensln system is an lmportant part of
homeostatlcmechanismsin the bocly.lt works to
Nitrendipine maintalnthe blooclpressureat'the normallevel.lt
SAR of l, 4 - cllhydropyrldlnes: alsoregulatesthe electrolytebalanceby controlling
The followlng features are essentlal for alclosterone biosynthesis anclreleasefrom aclrenal
activity. cgrtex. Slmilarly the juxtaglomerularcells are
(a) 1,4 - clihyclr( n directlylnnErvatecl by centralsympatheticnerves.
(b) aseconclary ropyricllnerlng, Hence under the-conditionsjf strain and stress,
(c) an aromaticor heteroaromaticCa-substltuent the sympathetic stimulatlon may leacl to
ln this aro matic su bs t it uent . f ur t her hypertensiondue to the actlvation of renin
substitutionat ortho position is more effective angiotensinsystem.
than at meta position,whilepara substltution The potential beneflt of angiotensin ll
results in inactive compouncl. The electron antagonlstshas been clemonstratedusing the
withclrawing groups are more favourecl than pepticle saralasin,which is a speclficangiotension
ll inhibltor. However the poor bloavailabilityof
electron-releasing groups. this agent has clriven a search for orally active
Certainsteric hlndrancein ortho posltlon is n o n p e p t lcle.compounds. In consequence,
requireclto fix the dlhyclropyridinestructurein losartanwas recentlymarketedfor the treatment
favourableconformationin which the aromatic of hypertension.
group is approximatelyperpenclicular to clihyclro- Angiotensinsare the potent vasoconstrictors.
pyriclinering. They tencl to increasethe perlpheralvascular
Calcium channel blocl<ershave negative resistance.The angiotensin-lnduced releaseof
inotropic effects. Therefore the conclltlons of alclosterone increasesthe sodlum lon retentionin
many patientswith CHFdeteriorateswhen treated plasma,resultinginto an Increasein plasma
with these agents. volume.The overall resultof all these effectsis
Amloclipinels a calcium influx inhlbltor and hypertenslon.Hence one can expect that angio-
inhibitsthe transmembrane influx of calclumions tensin antagonistswould be effectiveantihyper-
into the carcliacmusclesancl smooth muscles.lt tensiveagents.Thisexpectationwas provedto be
has a direct relaxant effect on vascular smooth correct by the developmentof saralasin(1971)
musclesancl reducesthe total ischemicburdenon ancl captopril (1977), each belng the member of
the heart. This clilatationincreasesmyocardial two distinct classes.Saralasln, losartan,valsartan,
oxygen cleliveryin patientswith coronaryartery eprosartan ancl saprisartanare the example
sPasm. of competitive antagonlst of angiotensln
Princlplesol MedicinalChemistryffd. ll) 340 Systerl
DrugsActlngon Cardlovascular

- ll, while captopril is inhibitor of angiotensin effectivnesswas overcome by introductionc'

convertingenzyme(ACE)which leadsto decrease
rate of angiotensin- ll synthesis.
(a) $rralasln :
It is a substitutedanalogof angiotensin- ll,
designeclby Palset al in 1971, which acts by
competitivetyblocking th€ angiotensinreceptor
sites.
Sar- Arg- Val - Tyr - Val - His - Pro-Ala
Saralasin
ln the structure of angiotensin - ll, the
phenylalanineat position8, is replaceclby alanine
(results into decreased intrinsic activigl) and
sarcosylis substitutedat NH2- terminal(in orclerto
increasethe resistanceto enrymatic hydrolysisby
amlnopeptidases) to yield saralasinmolecule.lt
does not crossblood brainbarrierand is retainedin
the vascularand extracellularfluid compartments
to block angiotensin receptor sites. This results
into clecreasedperipheralvascularresistanceand
blood pressure.An increasein bloocl pressureat
initial stage of therapy may be due to the partial
agonistic nature of the clrug. ln some cases a
rebound hypertensionafter clrug withclrawalmay
be seenwhich is due to suddenincreasein plasma
renin activity.
(b) C-aptoprll:
Angiotensin converting enzyme (ACE) ls
known to be inhibited by a nonapeptideBPF9a
(braclykininpotentiating factors)present in the
venom of pit viperus.This nonapeptideis termed
as teprotide and has quiek onset of action but
lacks oral effectiveness. This lack of oral
captoprilat the Squibblaboratorles by Cushman
Ondettiand co-workersln 1977whlchis structura
relative of teprotlde. It was marKeteo a-(
antihypertensiveagent in l98O ln the treatmentor
severehypertension.
HS -CH 2 - CH- CO - cooH
(mer)captopril
(c) Endaprlllc acld (enalaprll) :
Enalaprilwas developedby Merck Sharpanc
Dohme and lntroduceclin 1984. lt has simila:
pharmacological effects,mechanlsmof actionanc
therapeuticusesas that of captopril.Likecaptopn
it does containa "prolinesurrogate."
HOOC
c
I
c o H s - c H 2-cH lH-CO -N
cooc2Hs
Enalapril (monoethylesterof enalaprilic
acid)
Lisinopril,a lysinederlvativeof enalaprilate
an oral long acting ACE-inhibitor.Followingore-
administration,lt does not appearto be boundtc
other serum protelns. lt cloes not undergc
metabolismand is excretedunchangedentirely1-
the urine. lts plasma half life 'ls about twelre
hours.

.N : frl cooH
N: N
COOH
/ INH \
N
(I{ofl'nran
Cilazapril n-LaRoche)
NHz
COOH Losartan Valsartan
N
ll cooH coNH2
(fv!erck)
Lisinopril
HSOzCF

cool
cozH ph N
H
Saprisartan
(Bristol- MyersSquibb)
Fosinopril (Ciba-Geigy)
Benzapril
Principles Chemistryryol.ll)
of Medicinal 321
EtOoC
COOH
Spirapril(Schering-Plough
Sandoz)
ErOOC Htu,.
..rtf
H H
cooH
(Servier)
Perindopril
ETOOC Hn,,.
.,,,tH
COOH
(Hoechst)
Ramipril
It acts by suppressing renin-angiotensin-
alclosterone system. lt is inclicatecl in the
treatmentof all gradesof hypertensionin clifferent
age groups. lt is used alone as initial therapy or
concomitantly with other classes of anti
hypertensiveagents.
ACE-inhibitorsare generallyconsidereclas the
first step in drug therapy for congestive heart
tailure. lf these can not be tolerated becauseof
side-effects,then a combination of hyclralazine
ancl nitrates should be. triecl. lf this combination
fails to yield favourableresults, then cligitalis is
started followed by diuretics.
(d)- Aldosterone ant gonlsts :
Antagonistsof renin and aldosteronehave
also been dweloped to causedeactivationof renin
] angiotensin system. However renin antagonists
possess poor therapeutic applicabiligr while
aldostero\e antagonistsare clinically used as
diurelic agents.
Aldosterone,deo4ycorticosteroneand hydro-
cortisone are potent antidiuretic mineralo-
corticoids. Spiranolactonean aldosterone anta-
gonist is a steroidalderivative having a lactonering
in the spiro .urangementat | 7th position,
DrugsActingon Cardiovascular
System
Due to the structuralsimilari$t,it competitive!
inhibits the binding of alclosteronewith its
receptors.
Q H:
o
lt
--rs - c - CH,,
Spironolactone
l s.25 D|URETICS
Diuretic agents are usually effective in the
treatment of eclemasof carcliac,hepatic, renal or
pulmonary origin. Some of these agents also
possessmild antihypertensiveactivi\i ancl may be
usecl in the treatment of hypertension with or
without edema.The mean arterialpressttrefallsclue
to reductionin plasmavolume ancl cardiacoutput.
While a modest rise in plasma renin activi$l and
renal vascular resistance occurs through reflex
activation. Out of several classesof cliuretics,
agentsfrom
(a) thiazidediuretics
(b) loop diuretics,and
(c) potassiumsparingcliuretics
classesare usually used to increase effectiveness
of primary antihypertensiveagents.Thiaziclesare
more effectiveantihypertensiveagents than loop
diuretics,while potassiumsparingagentsare often
used as an adjunct (acljunctto long term thiazlcle
therapy where they potentiate the diuresis and
reclucethe loss of potassium.)The loop diuretics
(e.g., furosemide,ethacrynicacicl)are reserved
when thiaziclesfail to give expecteclresults.
The novel successors of loop diuretic
furosemideinclude piretanicleancl etozolin which
possess high specificity for NaCl transport,
minimum potassiumion excretiondnd prolonged
clurationof action.
c@H
Piretanide
Prlnciplesof MediclnalChemistryOol. l!) g2 DrugsActingon Cardiovascular
System

Atrial natriureticpeptide(ANP)was isolatedin

1981 by De Bolcl,Sonnenberg, et al and was
o characterizedas a factor for the control of
HsC'o- C
tl hemostasls.
Thephysiological functionsof ANP include,
N
I (a) vasodilation,
CH3 (b) increaseclGFRand salt-waterexcretion
(+) Etozolln (dluretlc)and
Loop cliureticssuchas furosemideare the first {c) Inhlbrilonof the releaseof angiotensln'll,
choice in therapy of CHF.The dose should be aldosteroneq{rcJvasopression.
graduallyincreasedto llmit symptomsand physkal ANP ls derlved from a precursor protein
slgns of edema. An alternatlvestrategy ls to producedby catdlacatrlum and at lower levels by
occasionallyuse supplemental agents such as other tissues.Slnce ANP receptorswere found to
metolazoneto maintalncontrolof symptoms. be located in smooth musclesof vascular,renal
Chronic excessivecloses of cliureticscan and other tissues,ANP may be consicleredas a
worsen cardiacfailureand contributeto symptoms potentlal lead to develop drugs useful in the
of fatigue through electrolyte disturbancesand treatment of heart fallure, renal failure ancl
clehydratlon. oedematousconditions.The effects are expectecl
Electrolyteimbalancessuch as hypokalemla, to be mediateclthroughguanylateqyclase.
anclhypomagnesemia can predisposethe patient
The parent precursor,ANP preprohormone
to arrhythmias.
consistsof l5l amino acids. ANP molecule
Symptomsof faintingor dizzinesson standing
consistingof 28 aminoacid resiclues with numbers
may inclicate a need to review cliuretic or
99 to 126, is cleaved from the precursor.A | 7
vasodilatortherapy.
memberedring structure,necessaryfor biological
I5.26 CENTR,AL DEPR,ESSANTS activity is formed due to a clisulficlelinkage
A meprobamateanalogue,mebutamate,lowers betweencysteinelO5 and cysteine122.
blood pressureby exerting depressanteffect on
the vasomotorcentersof brainstem. 15.28 PIOTASSIUM CHANNELMODUTAIOR,S
A number of clrugs seems to modulate
o membrane K+ - channels.Potassiumchannel
tl activatorscausean outward movementof K+ ions.
,cH2oc- NHz
The lnside membrane potential becomes
negative resulting into hyperpolarization.Since
o clepolarization is not possiblein suchcase,Ca++-
cFt3 and Na+ - ion channelsdo not open. Thusthe
contractilemachineryof cardiacsmooth muscles
15.27 ATN,IALNAIN.ruRETIC (ANP)
PEPTIDE remainsrelaxed resultinginto antihypertensive
Blood pressureand fluid volume homeostasis effect. Relaxationof vascular smooth muscles
are criticallydependenton regulatorypeptides, leaclingto vasodilationalso occurs by the same
such as anglotenslnll which has vasoconstrictive mechanism.
properties, and atrlal natriuretic peptide (ANP) Nicorandilproducesa marked increasein
whlch inducesdiuresis,natrluresisand a sllght coronaD/blood flow. A negativeinotropic effiectis
vasoclilation.ANP is inactivated by neutral
( NEP) . observed at therapeutic concentrations. Besides
endopepti d a s e s Th e slmu lt a n e o u s
increasing outward membrane K+ conductance ln
inhibitionof ACE and NEPmay prove to be an
efficient way of treating various cardiovascular vascularsmooth muscles, nicorandilactivates
diseases.Mixanpril is an exampleof such a clual guanylate cyclase, resulting into recluced
inhlbitor. intracellularCa++concentration.
Princlplcrol l/bdlclnal Chemistry(Vol.ll) g DrugsAc.tlngon Gardiovascular
Syrtem

NC
s
ll
c\*/M"
H

Aprikalim
BRr349t5
All the above examples do not share thg
commonparentsketeton.Forexample,the parent
skeletonin BRL 34915 is p-ethanolamine,in
nicorandillt is nicotinicacid and aminopyridlnein
pinacidil.
Nicorandil
Cromakalim, nicorandil and pinacidil relax
bronchial smooth muscles. Hence, these clrugs
may have potential as novel anti-asthmatic
./cN
N agents.

Cromakalimis the first antihypertensiveagent

HH
Pinacidil shown to act exclusively through potassium
channel activation. lt increases the outwarcl
movement of potassiumions through channelsin
the membranesof vascularsmooth muscle cells,
leadingto its relaxation.Cromakalimis an outcome
of an effiortto clissociatep-blockade activig from
NC antihypertensive activity. The molecule was
Me clesignedto put conformation restriction in the
Me
flexibleopen chainp-blockingagents.
Cromakalim

NH NH

B-blocklng agent Rlgtd analog Cromakallm

Principlesof MedicinalChemlstryOol. ll) AA DrugsActlngon Cardlovascular
Sysiem

Tablc 15.6
Slde effects of commonl uscd catesorlesof antlh cilcnslvc a ents
Slde effects Slde effccts
Diuretics Incontinence,muscle weakness,Digitalis Anorexia, nausea, visual
confusion,clizziness, gout glycosides disturbances,diarrhoea,confu-
ACE Hypotension, dizziness, cough, sion, deterioratlon or social
inhibitors taste disturbance, sore throat, withdrawal
rashes,tinglingin hands,joint pains Potasslum Gastrolntestlnaldisturbances,
Nitrates Headache,hypotension,dlzzlness, salts swallowlngdifficulty,diarrhoea,
flushing of face/neckGl upset tlredness,limb weakness.
cvh
cvh
!u
H-*
I -sI HrN
I
CH1 cHr
cP - 108,671
Enalkiren
cvh
o
tBUSO JL
N-Bu
H
s OH
N IcHr
cGP38560A Terlakiren
Cvh
tBuSO

Boc-Pro-Phe(N-a-Me)His
N Ile-NHCHT(2-Pyr)
H
NH
utl
Remikiren
Ditekiren

cvh
o
tl
S
I
o

N
Za*iren (A-72517)
Cyh= cyclohexyl;
Z-Pyr- 2-pyridinyl;3-pyr= 3-pyridinyl

Structureof Renln lnhlbltors

ooc
 r6.r TNTRODUCTTON
16.1 INTRODUCTION
Spasticityis a condition which is characterizecl
by exaggerateclresting tone of a muscle. Muscle
162 TRANSMISSION
NEUROMUSCULAR hypertonus is usually accompanied by an
increased resistance to passive stretch. The
15.3 NICOTINIC RECEPTOR
CHOLINERGIC skeletal muscle relaxants are used to relieve
muscular spasticig. Spasticity may be causeclby
musculoskeletal or spinalcorcltrauma, brainlesions
16.4 CLASS|F|CAT|ON or brain diseases.Regardlessof the cause,spinal
cord region is the site for the mechanismsinvolved
16.5 STRUCTURE
- ACTIVITY- RELATIONSHIP in the expressionof spasticig.
Neuromuscular blocking agents may find
clinicalutilig in :
16.6 ABSORPTION, ANDEXCRETION
DISTRIBUTION (a) Surgery ancl in intensive therapy units
where they are usecl to provicle muscul.tr
16.7 THERAPEUTIC
USES relaxation.
(b) Convulsions e.g. electroconvulsion
16.8 TOX|CEFFECTS therapy,where they are used to prevent injury due
to the violence of the fit. For example, in status
epilepticus, tetanus or in the case of convulsant
16.9 COMPETITIVE
VERSUS
DEPOLARIZING
AGENTS drug poisoning,neuromuscularblocking agentsare
usecl with mechanical respiration when other
16.10 CENTRALLY
ACT]NGMUSCLERELAXANTS means are insufficient.
(c) Variousorthopeclicprocedureswhere they
help in correctionof dislocationsand the alignment
16.11 THERAPEUTIC
USES of fractures.
(d) Neuromuscularblockersof short duration
of action, are used to facilitateintubationwith an
enclotracheal tube and have been useclto facilitate
laryngoscopy,bronchoscopyand esophagoscopy
in combinationwith a generalanaesthetic agent.

(32s)
Principlerol MedicinalChemisryflol. ll)
Acegllcholine producesits spectrum of bio-
logical activities by acting either on muscarinic
cholinergic receptors or nicotinic cholinergic
receptors.The actions of ACh on autonomic
ganglia and skeletal muscles are thus clue to
activationof nicotinic receptors.Thesestructures
are stimulated by small doses of ACh ancl get
clepresseclif ACh is aclministereclin larger doses.
Sincenicotinealso evokessame responseon these
systems,this action is referredto as the ganglionic
or nicotinicaction of acetylcholine.
The main source of nicotine is the plant,
Nicotiana tabacum from potato family. The alkaloid
is presentin varying quantities(l-80/o)in the clried
tobacco leaves, in combination with malic and
citric acicls.
Pharmacology of nlcotlne :
(a) ln GIT,the alkaloiclstimulatesmusculature
anclthe activitSlof secretory glands.
(b) lt depressescardiac activigr. Small closes
of alkaloid cause an increase in blood pressure
while in larger closes,it causesdecreasein blood
pressure.
myelin sheath
.axon
L,roove Ol nCurOmuSCuElUnCUOn
flg. 16.l : An lnnervatedmuscle flber
&6 Neuromuscular
Blockers
(c) Both, autonomic ganglia ancl skeletal
musclesare stimulateclby small closesancl para-
lysecl due to larger closes of nicotine. Nicotine
leads to repetitive excitation (fasciculation)
followe( by block of transmissionin the neuro-
muscularjunction.This resultsin neuromuscular
paralysis.
16.2 NEUROMUSCUTAR
TRANSMISSION
The skeletalmusclesare supplieclwith somatic
efferent nerves. Depenclingupon the skill ancl
clelicatenessof function assignecl to skeletal
muscle,the main nerve is linkeclwith other nerves.
For example,the nerve controlingthe functioning
of largermusclesof limb is interconnectedwith less
numberof other nerveswhile the nerve controlling
a clelicate function needs interconnectionswith
several nerves to exercisefine control.
The axon loses its myelin sheath when the
nerve comes in closecontactwith the musclefiber
and gets bifercated into several fine branches
which penetrate the muscle cell membrane. The
region of contact of the terminals of these
brancheswith the muscle membrane is known as
neuromuscular junction.
It
. t\. .'-
,
musclecell
mcmbrane
Principlesof MediclnalChemlstry(Vol.ll) gl Nsuromuscular
Blockers

The surfaceof musclefiber that is near to the outwardK+ conductances.When their summation
nerveterminalscrndis encircllngthe nervetermlnal attainsadequateintensity,it can leaclto excitation
is known as 'encl-plate'regionwhich carriesthe of the musclewhich is followeclby contractionof
sites for nicotinic receptorsand chollnesterase the skeletal muscle. The bound ACh is then
enryme.The gap betweenthe nervetermlnalancl hyclrqlysedby cholinesterase enzymespresentin
end-plateregionls about 50 mm wide and may be junctionalfolclsto cholineand acetate.Thisentire
termed as synapticcleft" processof musclecontractlonls completectwithin
2-3 m sec. and maintains its unlformityif repeatecl
The process is just similar to neurotrans-
many times per seconcl.
missionin other synapses.When the motor nerve
is stimulatecl,an action potential is generateclby I6.3 NICOTINICCHOLINER,GIC RECEPTORS
the exchangeof potassiumand sodium lons. lt In vertebrateskeletalmuscle,the end-plate
travels along the length of t[e axon ancl reachesto region comprisesof about O.1 % of the total cell-
nerve terminals.The activationof Ca+a-lonophore surface.The encl-platereglon bears the sites for
leaclsto influx of extracellularcalcium Into the nicotinic cholinergic receptors. Recent studies
nerve-terminal. In responseto Ca++-lnflux, many revealedthe structureof a nlcotlnicreceptor.lt
storagevesiclesget ruptured ancl releaseACh into consistsof five subunits ln the ratio of o,zI y 6.
the synaptic cleft. The ruptured vesicles Only cr-subunitsare foundl to possessbincling
imrnecliately reform ancl store the newly sites for ACh" Theseq,-subunltshave molecular
biosynthesiz.ed acetylcoline. weight of 4O.OOO claltonseach while B, y ancl6
The releasedACh then reacts with nicotinic subunitsare 5O,OOO; 60,000 ancl 65,OOOclaltons.
receptor sites present in the Junctionalfolds of These subunitsare arrangeclln the cylinclrical
end-plate region ancl causes opening of ion- fashion(with a cliameterof about 8 nnr) Ieaving
channels resulting lnto development of local, somespacewithin them, to form an open,ch.rnnel
gradeclcurrentsin the rnembraneof muscle-fiber. like interior.Thenicotinicreceptorsusuallyoccurin
These are termed as encl-platecurrents.They are pairslinkeclby a clisulfidebrldgebetweenthe clelta
generatecl clue to increased inwarcl Na+ and sub units.

Nervetermlnal

foldsof
Junctional
endplatercgion

Sitcsfor cholincsicrase
enzymc
oo
0
!o
Ca# I Onophore
th4

Storage for ACh

vescicles receptor
Nicotiniccholin:rgic

Ilc. 16.2 r Groove of a neuromuscular lunctlon

Principles
of Medicinal
Chemistry
flol. ll)
The receptor concentrationin the end-plate
region appearsto be 8-lO thousand/pmz.The
binding of ACh to the receptor surfaceresults into
the opening of the ion-channel.The channel life-
time depenclsmainly on the intrinsicpropertiesof
the drug usecl.Forexample,ACh-induceclreceptor
activation leads to opening of ion-channel for
about I rn sec. Anticholinesterasedrugs prevent
85 A"
channel
tlg. 16.3 : Arrangementof subunlts In nlcotlnlc
receptors
the degradationof ACh anctextends its biological
lifu. This resultsinto increasein survivalperiod of
ACh. ln such case ACh will repetitively bincl with
the receptorand will causerepetitive ion-channel
opening. Tetraethylammoniumand 4-amino-
pyridine are the example of clrugswhich increase
the neuronalACh releaseby prolonging clurationof
action potentialat nerve terminal.Due to this, the
number of vesicles which undergo rupture,
increases,resulting into more ACh releaseinto
neuromuscular junction.The bursts of miniature
encl-platecurrentscauserepetitivecontractionsof
the skeletalmuscle.
16.4 ctAsstflcATtoN
Variousneuromuscularblocking agents act by
interferringwith
H,c g,/CH,
o
(c,Hs).]
- N - cH,cH,oH
Trrcthylcholine
ffi Neuromuscular
Blockers
(a) synthesisor releaseof ACh
(b) ACh-receptorinteraction.
Hencethey can be classifiedaccorc'linglyinto
I . Drugs that depress ACh junctional
concentration
(a) by inhibitionof its synthesisor
(b) by inhibitionof release.
II. Drugs that prevent the action of released
ACh on receptors.
(a) by depolarizing the muscle end-plate
regionor
(b) by inhibitingdepolarizingactionof ACh.
lll. Centrallyacting muscle-relaxants.
l. (a) Drugs whlch Inhlbtt the blosynthesls of
ACh:
Choline. an aminoalcohol is neecleclfor ACh
biosynthesis.It is transporteclto the site of
synthesisby intracellulartransportmechanisnrs.
Triethylcholine and hemicholiniums, due to their
structuralresemblance with choline,competewith
the transportmechanismsancl thus decreasethe
rate of synthesisof ACh.
/zn
IP
(CzHs)r- N - cHzcH2oH
Triethylcholine
Hemicholinium, a series of cornpouncls
synthesizedby Schuelerin 1955 compete with
choline. Their inhibitory action is reverseclby
increasingthe concentrationof choline.The most
extensivelystudied member of this seriesis HC-3.
Both, triethylcholine ancl HC-3 coulcl not be
employeclclinicallyclue to their lack of selectivig.
They impair the procluction of ACh in other
cholinergicnervesand in braintissuesas well.
H,C\ e cHr
N N
o o
ot-l
HCml c l t olt nlu m - HL - - 1
Prlnclplerol MedlclnalChcmlstry(Vol.ll) 329
(b) Drugs whlch Inhlbft thc release of ACh :
(t) The influx of extracellularCa++ ions in
'nerve terminal leads to rupture of synaptic
vesicleswhich releaseACh. Hence there exists a
quantitative relationship between the concen:
tration of C-a++ions and arnount of ACh released.
Naturally neuromuscular block can easily be
obtained if ACh enough to generate post-
junctionalend-platepotential,is not releaseddue
to reduction in the amount of Ca++ ions.
Potassium ions facilitate transmission by
enhancingACh releasewhile magnesiumions have
exactly opposite effects.
(ll) lon-channel blockers : Many categories
of drugs including, atropine, .amino-glycoside
antibiotics. local anaesthetics.barbituratesand
some psychotropic clrugs interfere with ACh-
induceclopening of an ion-channel.They bind to
these receptor sites and cause narrowing of ion-
channel passagewhich results into reduction in
the muscle tone. They do not interfere in the
release of ACh from prejunctionalsites. The
anaestheticagents specificallystabilize the post
junctional membrane with weak to moclerate
potenciesand reducethe intensi! of currentflow.
This activity of anaestheticagents is synergistic
with the action of competitive (non-depolarizing)
neuromuscularblockingagents.
(lll) Botullnum toxln : Clostridiumbotulinum,
an anaerobicorganism releasestoxins which are
categorisedinto eight antigenicallydistinct types.
Of these, the type A has been iclentifiedas the
neurotoxiccomponentof botulinum toxin. It has
a molecularweight of about 9OO,OOO claltons,of
which the two polypepticle chains of about
15O.OOO daltons have been characterisecl. lt is a
botent inhibitor of the ACh releasefrom the nerve
terminals.This inhibitory action is effecteclby
lockingof the moleculargates through which ACh
moleculesare releasedfrom the nerve terrninal into
the synapticcleft. The clepressionof the releaseof
Ncuronrurcular
Blockers
ACh from the motor nerve terminal results into
neuromuscular paralysis.The botulinum toxin can
cross blood-brainbarrierand exerts its effiectson
CNS.However, it lacksthe abilit5lto cross placental
barrier. In the persons affected by botulinum
toxin, treatmentwith anticholine-sterasesmay
improve and restorethe strengthand functioning
of the muscles.
I l. Drugs that prevent the actlon of rcleased
ACh on thc receptor sftes :
(a) Both depolarizing blocking agents and
competitive (non-depolarizing)blocking agents
cause neuromuscularblockade by acting on the
nicotinic receptorsites present in post-junctional
membrane.The depolarizingagents are weak
agonists of ACh having greater affinity ancl
weaker intrinsicactivigr at the receptor sites. They
binclto nicotinicreceptorand depolarisethe post-
junctional membraneby opening the ion-channel.
Due to their greater affinigl, they may cause
prolonged depolarizationby repeatedopening of
ion-channelsand make further depolarizationby
enclogenous ACh impossible. This repeated
excitation leads to muscularfasciculationand the
loss of significantquantities of K+ ions from the
muscle cell. The continuoustriggering of muscle
excitation then causes a block of .transmission
followed by neuromuscular paralysis. These
events can also be seen with very high doses of
aceglcholine. Due to prolongeclancl repeateclend-
plate depolarization,a'time comes when the
depolarizedarea can not generate muscle action
potentialsufficientto causemusclecontraction.
The action of depolarizingmuscle is mani-
fested at an early stage by transient muscular
fasciculation.This is followeclby the paralysisof
musclesof fingersancleyes.The largermusclesof
limb ancltrunk are affectecl.Ultimately respiration
ceases clue to paralysisof diaphragm. During
recovery the muscles regain their strength anci
functionin the reverseorder to that of paralysis.
Prlnciplesol MedlcinalChemlsfi (Vol.ll) 3f) Neuromuscular
Blockerr

(cH3)2N
- CHz-CHz-O- -cHz-cHz- - o - cHz- cHz-N - (cH)z,z Br

bromide;R = CHs
Succinylcholine
bromide;R = CzHs
Suxethonium
Succ.inylcholine
is the only agent from this pressuredue to its contractile action on extra-
categorywhich is useclclinically.lt has more side- occularmuscles.
effectsthan competitive neuromuscularblockers. Aclverseeffects include muscle fasciculation.
tl) Succlnylchollne : lt was synthesizedby muscle ache and pain, hyperkalemia,increasein
Bovet et al in 1949 in order to create synthetic intraoccularpressureancl rise in bloocl pressure.
alternatives or substitutes for d-tubocurarine, a The latter effect is due to stimulationof autonomic
natural competitive neuromuscularblocker. As ganglia and not clue to histamine liberation.
shown in the structure, succinylcholineis a twin Diazepammay be useclto reducemusclepain and
structurecomprisingof two ACh molecules.lt has spasmassociatecl with the use of succinylcholine.
a rapid onset and a short clurationof action. lt acts Succinylchoiineis mainly usecl to prevenr
on the nicotinic receptors ancl initiates repeatedtetanic muscle contraction ancl for providing
clepolarizationof the encl-plate region resulting general muscle relaxation neecleclto carry oui
into a brief perioclof musclefasciculations. This is
surgery. lts ethyl analog, suxethoniumbromide
phase I which is followed by phase II, inducing has similar properties as that of succinylcholine
neuromuscular blockadeif the clrugis aclministerecl
except that it gets hydrolyzed more rapidly than
repeateclly. succinylcholine.
Succinylcholine has a very short duration of (ll) Decamethonlum : lt is an exampleof a
action(5-10 minutes).lts actionis terminatecldue series of compounclsin which a polymethylene
to its rapicl hyclrolysisby butvrocholinesterases chain briclgestwo quaternary nitrogens. Such a
presentin plasmaancl liver. The main metabolite, series is known as methonium series and is
succinylmonocholinestill retains a weak compe- representeclas
titive neuromuscularblocking activigl. The clrug
unclergoesa two step metabolism as shown in the
Fig.16.4.
The action of succinylcholine can be
prolonged by administrationof local anaesthetics
cHr cHr
which block butyrocholinesteraseenzymes. The
clrugcloesnot reachthe CNS.lts prolongeclaclmini- Methoniumseries
stration ma lead to an increasein intraoccular
Bu-ChE
Succ iny lc hloline onocholine.t choline
Succinylm
Hydrolysis

acid+ choline
Succinic
. 16.4: Metabollsm of succln lchollne
 Principleool ModicinalChembtry(Vol.fl) 331 Neuromuscu
larBlockers

Decamethoniumis an effectiveneuromuscular When the summationoi end-platecurrentsattain

blockingagent. In usualdoses,it neither releases aclequate level (post-junctional end plate
histaminenor it blocks autonomic ganglia. Its potential),it leadsto the excitationof the muscle.
effectivenessas a clepolarizingagent is clue to the followed by contraction.
clistanceof separation between two quaternary
If the end-plate receptor sites are alreacly
nitrogenswhich is about 1.4 mm. This distance
blockeclby clrugs having affinitlr but not intrinsic
correlatesclosely with the clistancecovering two
activigl, endogenous ACh cannot bincl to the
acljacentACh receptorsat the enel-plateregion.
receptor ancl hence can not clepolarizethe encl_
(cHrh N - (cHz)ro-N (CH3)3 ; 2 Br- platC region. This witl result into muscle relaxation
Decamethonium bromicle clue to neuromuscularblock. Since these agents
It is longer acting and more stable molecule than act competitively with endogenous ACh to
succinylcholine.lt is not employed clinically. occupy receptor sites, such drugs are known as
competitive or non-depolarizing or anti-clepola_
(lll) Carbolonlum bromlde : It clepolarizesthe
rizing or membranestabilizingagents. Sincethey
motor end-plate region mainly due to its
anticholinesteraseactivity. Presently, it is not block competitivelythe transmitter'saction on the
under clinicaluse. receptor sites, the post-junctional membrane
o remains insensitive to the propa.gated nerve
tl.- (CH2),, impulse and contractioncloesnot occur. Exampies
[cH.,1., fi - tctl'r'
- o - e ng -J2 ; 2Br'
of this category inclucle,cl-tubocurarine,Alcuro_
Carboloniumbromicle
nium, Pancuronium,Gailamine,Atracuriumancl
(b) Drugs that act t--- lnhlbltlng depolarlzlng p-erythroicline,
etc. Action of all thesecompounds
actlon of acctylchollne
can be reverseclby increasingthe concentrationof
Acetylcholinereleasedlion.rthe nerueterminal. ACh at receptor sites. This can
be achievecl bv
binds to c-subunits of the nicotinic-cholinergic anticholinesterases.
feceptor and causesopening of an ion-channel.
Table l6.t : Competltlve neuromuscularblocklng agents

H.r)r
ocHs
.N
CH,,

HrC
\+
N-
HiCO
R L- H r

d-Tubocurarlnechlorlde : R = [l
Metocurlne chlorlde : R = CH
Prlnclplo qt llcdclnel Cfrinlrtry (Vol.ll) & ItlromtncsbEbCcn

o
il
o-c - cHl
(ii)

o
2Br

Pancuronlumbronrlde ; l - C H r
Vecuronlum brcmldc; l - H

(i i i )

H3CO

f-erythroldlnc

oo ocH3
ltll
-c*o-(cH")s-o-c-cH2
HlCO ocHl
H:C Hzc

H.rCO ocHj
ocHr Attrcurlun ocHl

(v)
cH,cH= CHr
@
e
o -c H"cH,N (CrHs)1
(c,'Hs)l
o cH,lcH"u
CH CH.CH"OH
HO- H,,C- H C ;3P
I
N
o cH?cH2$(c"H.)r
2CP
e

H.CCH= CH ' Gallamine

triethiodide
Alcuronium
chloride
Principlesot MedicinalChernistrygol. ll) gl
(|) d-Tubocurerlne : lt is an exampleof
varlouscurarealkaloldswhlch are found In plants
of genera Menispermaceae and Strychnos.The
term 'Curare'is used to describevarlousSouth
American arrow polsons which possegsneuro-
muscular blocking alkalolds. Currently cl-
tubocurarineis obtaineclmaln[ from the bark of
Chondodendrontomentosum.Sinceat that tlme.
the natlvewere using bamboo'tubesto store the
crude preparation,the alkalold was named as
tubocurarine.The ftrst clinicaluse of thls crude
alkaloidwas done in | 932 by Westto treat spastlc
disorders.The isolation.structuralelucidationand
determinatlon of optlcal activity of the ingredient
of the crude preparatlonwas carried out in 1935
by King. Since | 942, its us€ for promoting muscle
relaxationin generalanaesthesia was continuedon
ever-increasingscale. Soon after, metocurine,a
syntheticclimethylanalogueof tubocurarlnewas
clevelopedwhich was founcl to be three times
more potent as muscle relaxant than cl-
tubocurarine.
d-Tubocurarinehas a rapicl onset of action, if
given intravenously.lt competitively bincls to the
encl-plateregion and reduces the frequencyof
channel-opening events resulting into flaccicl
paralysis.At therapeutic doses, it partially blocks
the gangllonic transmlssion.Some of the sicle-
effects of the drug can be explainecl by its
capacityto liberatehistaminefrom the mast cells.
{Theseside-effectsinclucle bronchospasm,hypo-
tension, excessivebronchialand salivarysecre-
tion, etc.). ln larger doses, cl-tubocurarinebloc(s
the transmissionboth at autonomic ganglia ancl at
adrenal meclulla resulting into a fall in bloocl
pressureancl tachycardia.Histamine releasefs
partly responsible for this hypotensive response.
It also clecreasesthe tone ancl motility of GITand
leadsto an increasein intraoccularpressure.
d-Tubocurarineand all other quaternary the ester group or by disconnecting both
neuromuscularblockerslack an ability to enter the
CNS. Hence thev clo not exert central effects in
man. They are usecl as muscle-relaxantsin
anesthesiamainly clue to their peripheraleffiectsat
Neuromuscular
Blockenr
neuromusculariunction. For this purpose,
d-tubocurarinechloride ls administered0.2 to
O.7 mg/kg of body weight for an adult either by
i.v., or i. m. route. lt is commonly used to relax
muscles and thus to prevent dislocation ancl
fracture associatecl with electroconvulsive
therapy.
(ll) Grllemlnc : lt is one of the memberof a
serles, synthesizedby Bovet and co-workers in
| 946 in hope to avail synthetic substitutesfior
curarealkaloicl.lt is widely used as competitive
neuromuscularblocking agent. lt containsthree
quaternarynitrogens and block the muscarinlc
receptors of cardiac branchesof vagus through
atropinelike action.This resultsinto an increasein
heart rate, blood pressureand developsoccasional
arrhythmias.
(lll) Pancuronlum : This compounclfirst
synthesizedin 1964 consists of a steroidal
.nucleusin which acegdcholinepart is incorpo-
rated. lt does not have steroiclalactivity. lt is
about five tlmes more potent than d-tubocurarine
as a blocker of neuromuscularjunction. This
activigris potentiatedby ether. lt has quite less
abilityto causehistamineliberation.
Vecuroniumis a mocleratelyshort-actingancla
bit potent analog of pancuronium.The structure
of vecuronium cloes lack the 2p methyl group
presentin pancuronium.lt does not lead to release
of histamine.lt neither affectsautonomicganglia
nor the vagal neuroeffiectorjunctions.
(lv) Atracurlum : lt is another new synthetic
clerivativeof curareancl has intermecliatecluration
of action. It is 3-4 times less potent than
pancuronium and its neuromuscularblocking
activity is potentiatecl by halothane. lt is
metabolizedin plasma primarily by hyclrolysisof
quaternary nitrogens from each other. lt
possessesa half-lifeof about twenty minutesancl
has,lessability to causeliberationof histamine.
Princlples Chemistryffol. ll)
ol Medicinal 34
(v) Dlhydro-p-crythroldlne: lt is a semi-
syntheticderivativeof p-erythroidine, an alkaloid
obtainedfrom E. americana.From varioussemi-
synthetic clerivativesof p-erythroidine, the
clihyclrocompounclwas founcl to be clinically
usefulmusclerelaxant.
(vl) Baclofen : lt is a newly introduced
muscle relaxantused in the treatment of spasms
associatedwith disorclersthat affect spinal cord.
H2NHZC-CH -CHz COOH
QHs
Baclofen
Its structure is closely related to that of GABA, an visual disturbances,hallucinationand a dose-
inhibitory neurotransmitterpresent in CNS. After
oral administration,the clrug is rapidly absorbecl inclicatedin pStientswith liver diseaseor weakness
and enters into the CNS where it may inhibit of respiratorymuscle.
monosynapticancl polysynaptic spinal reflexes.
About 35o/oof the aclministeredclrug appears
unchangedin urine. It can be usedorally in a ctaily
dose of 15 mg to treat spinal spasticity ancl
spasticig associateclwith multiple sclerosis.lf
clesireclthe closecan be progressivelyincreased
upto 5Omg.
(vll) Dantrolene sodlum : This agent is of
specialinterest mainly cfue to its unique mecha-
nism of action. It causesmuscle relaxationby
clirectly blocking the contractile mechanism of
skeletalmuscle fiber. It prevents both, the influx
of extracellularcalcium ions and the release of
intracellular Ca++ ions from the sarcoplasmic
reticulum.This resultsinto blocking of excitation,
OrN CH = N- N
Dantrol ne sodlum
Blockerr
Nduromuscular
contractionand couplingof skeletalmuscles.lt is
not used as an adjuventto anaesthesia due to its
slow onset and longer duration of actlon. lt has a
half-fifeof 7-9 hours. Generallythe drug action is
more pronounceclon fast muscle fibers than slow
musclefibers.lt is metabolisedby liver microsomal
enzymesand excretedmainly through urine ancl
blle.
It is usedorally in a dose of I 2-25 mg, once 1
day, for the treatmentof chronlc spasticitydue to
spinal cord inJuryor multiple sclerosis.ln the
treatmentof malignanthyperthermia,it is usually
given intravenously.
Sicle-effectsinclucle drowsiness, diarrhoea,
clependentmuscle weakness.Hence it is contra-
(vlll) Benzodlazeplnes, Beside having
anxiolytic and anticonvulsantactivities, some of
the benzocliazepines possess muscle relaxant
activity. Diazepam,chlorcliazepoxideancl clona-
zepam are the most useful agents for the control
of flexor ancl extensor spasms,spinal spasticigr
anclmultiple sclerosis.They are usuallyemployed
in the doserangeof l5-6O mg.
(ix) Some antipsychoticclrugs like chlorpro-
mazine and fonazine are also of value in the
therapy of muscle relaxation. Fonazine, a
phenothiazineclerivativecausesa non-specific
arrestof histaminerelease.
oe
N
 Principlesof MedicinalChemistryffol. ll)
16.5 STnUCTURE-ACT|VrY
nEtATtONSHtp
(i) The quaternarynitrogenmoiety maintains
cationic charge in minimally hydrated conclition
and confersgoocl neuromuscular blockingactivit5r.
(ii) The neuromuscularblockaclecan also be
obtainecf with non-guaternerizecl compounds )ike
nicotine.
(iii) Larger alkyl substituents at quarernary tetanus.
nitrogenhinder the attackof the clrugmoleculeat
receptor-sites.
(iv) Lipophilicity plays an important role in
governing the accessof molecule to the muscle
membrane. More bulky ancl rigicl molecules clisorclers
generallyexhibit competitive type of activig while to imbalancebetween the central and spinal
simple ancl flexible structure is founcl to be
necessaryror depolarizingtype of muscle-relaxant
activity.
(v) The distance between two quaternary symbolizedby immobilitlrof joints.
nitrogens in the clrug governs the activity. lt
should be near about 1.2 - 1.4 nm for optimal
activity. Gallamine ancl p -erythoicline are
exceptions to this rule. Quaternerizationof
nitrogenatom in p-erythoidineresultsin declineof
activigr.
(vi) The quaternarynitrogen atom can be
substituteclby arsenium, osmium, sulfonium,
phosphonium and platinum with retention of
muscle-relaxantactivity.
I6.6 ABSOR.PTION,DISTRIBUTIONAND
T,XCR.ETION
In general, the quaternary ammoni0m
compounds,clue to their ionic nature are poorly
absorbeclafter oral aclministration.From intra-
muscular sites, absorption is rapid and regular.
Major amount of clrug is eliminatedthrough urine.
Pattemof metabolism is not uniform in each type.
lnsignificantamount of the drug administereclmay
be excretedthrough bile.
cls Neuromuseular,
Blockers
I6.7 THERAPEUTIC
USES
(i) Muscle-relaxants
are employed as an
aclluvantin surgicalanaesthesia in order to carry
out operationswith ease.They are aclministered
after the patient is anaesthesizecl.
lii) TheSt are used in te trea nent af status
epilepticusand to reclucepainfulmusclespasmsof
(iii) They can be usecl in various orthopeclic
operations.
(iv) Some of these agents are used in the
treatment of spastic muscle clisorclers.These
involve an increasecl tone of muscledue
controlof muscletone.
(v) cl-Tubocurarine is particularlyusefulin the
cliagnosisof myastheniagravis ancl conditions
t6.8 TOXTCEIIECTS
Respiratorymuscles,musclesof the eyes ancl
cligits may be attacked by these neuromuscular
blockers. lf these muscles get paralyzecl,the
patient may be exposed to fatal effects.
The ability of some competitive muscle
relaxantto liberatehistaminefrom the mast ceils
may lead to prolongeclapnea, bronchoconstrictlon
and cardiovascular side-effectsof these clrugs.
The acute toxicity by these clrugs can be
overcome by the aclministrationof anticholine-
sterases,adrenaline,potassium chloride or anti-
histarninics.Artificial respirationproves to be
beneficial in recovering the condition of the
patient.
r6.9 COMPETITTVE
VEnSUSDEPOLAR|S|NG
AGENTS
The following.table summarisessome of the
important points of differences between
depolarizlng and competitive types of
neuromuscularblockingagents.
Prlnciples
ot Medlclnal (Vol.11)
Chemistry 3g/ Neuromuscular
Blockers

Table 16.3 : Somecentrellyactlng muscle-relaxant

cH,- oR
CH_OH
I ocoNH2 cH 2 - o
cH2-o
H.rCO
R= H
Mephenesin; Emylc arbamate Methocarbamol
carbamate;
Mephenesin
R = CONHz
cl

cH"ocoNH, cHrocoNHcH(cH,).,
Meorobamate Carisoprodal Phenaglycodol

OH CH OH
I_
ocoNrtr H,,C NII

Styramate Phenyramidol

--CH',
NH
CI

Chlorozoxazone Chlormezanone

Nefopamhasa benzoxazocine structureanclis relieve musclemuscletenslonand pain in stress

developeclas cyclizeclanalogue of diphen-
hyciramine.lt lacks antihistaminicactlvify. lts
muscle relaxant actlvity may be due to its
interference
with serotonergictransmisslon.
16.I I THER.APEUTIC USES
(i) Due to thelr centrally locateclslte of
action, these agents can be used to treat
spasticity in spinal cord injury ancl mu lt ip le
sclerosis.
(ii) As peripheral neuromuscularblockers,
these agentscan be employeclas an adjunct for
incluctionof anaesthesia.
(iii) Drugshaving prominentanxiolytlcaction
(e.g., cliazepamand lorazepam)can be useclto
and anxiety.
The usual close of centrallyacting muscle
relaxantsvariesaccordingto the disorclersancithe
agent chosen for its treatment. Generallyfor
relaxlngthe muscles,the dose for followingagents
can be used
Diazepam lO mg l.v.
Chlordiazepoxide - 50 to l0O mg i.v./i.m.
Mephenesin 1.2g per dayorally
Meprobamate l.2g- 1.6g perclayorally
ln these doses, these agents produce thera-
peutic effectswhich are assoclateclwith certain
minor slde-effectslike, drowslness,heaclache,
blurreclvlslon,generalweaknessand seclation.
aoo
 I7.T INTRODUCTION
INTRODUCTION
The steroicls form a group of structurally
172 NOMENCLATURE
NUMBERING
AND
relateclcompounclswhich are wiclely clistributedin
STEREOCHEMISTRY animals and plants. The structuresof the steroicls
are basedon the t, Z-cyclopentenophenanthrene
17'3 ADRENALCORTEXHORMONES
OR skeleton.
ADRENOCORTICO!DS 3!7

17.4 SEXHORMONES ffi

175, ANTIOESTROGENS
OROVULATION
STIMULANTS 373

17.6 PROGESTINS 375

l, 2-cyclopentenophenanthrene
17,7 ANDROGENS
ANDANABOLICAGENTS
Steroids consist of four fusecl rings. A
perhyclrophenanthrene(rings A, B ancl C) is the
17.8 ANTIANDROGENS 384
complet'elysaturateclclerivativeof phenanthrene
17.9 oVULATION 384 while D is a five-memberecl qyclopentanering.
The major therapeutic classesof steroids are :
17.10 GYNECOLOGICAL
DISEASES (l ) Antl-lnflemmetoly egents : e.g. Cortisone.
(2) Scx honnones: e.9., Estrogen,progesterone
17.11 ORALCONTRACEPTIVES and testosterone.
( 3 ) Oral contraceptlvcs : e.g. Nor-ethisterone.
17.12 PEARLINDEX (4) Carclhcsterolcls: e.g. Digitoxigenin.
17.13 MECHANISM
OF ACTION
(s)Dluretlcs : e.g. Spiranolactone.
(6) Antlblotlcs : e.g. Fusiclic
acicl.
17.14 ADVERSEEFFECTS (7 1Neuromuscularblockers : e.g. Pancuronium
bromicle.
(8) Vttamln D precursor : Ergosterol

(33e)
Principles
of Medicinal
ChemistryPol. ll) Sieroids

cH'oH
C=O OH OH

Eslrogen
Cortisone { l7p - cstradir:l) Testosterone

OH
= CH

Progesterone Digitoxigenin Norethister0ne

cHr
o\.io *
ooH

OAc

HO
I
CH,
Spiranolactone K-Prorenoate Fusidicacid
(Aldostcrone
antagonist) (Aldosterone
antagonist)

cHr
-at, CH,
--'ococH.,

H.,C-

Pancuronium
bromide Ergosterol
Spiranolactone
and K - prorenoateare usefulhypotensivediureticagents.Latteris 3 - 5 times moreactive
than s iranolactoneancl cloesnot cause otassiumloss.
Princld.. ot toCclnal Chcnlruy (Vol'll) 3f1 Sterolds

I7.Z NOIIENCLATUTT'NUMIT,IING AND

26
sTf REOCII[tllsTtY
( 1) Nearlyall steroiclsare named as clerivatives ?.1
of any one of the following basicsteroiclalrings.

H
v
5 a -Cholestane (C = 27)
The ring junctureor backbonecarbonsare
shown in the structureof 5a-cholestanewith a
t hearrydark line.
(C= 17) (2) Solicllinesclenotegroups above the plane
5 (cror F)- C.pnane
of the nucleus(p-configuration)and dottecl or
brokenlinesc{enotegrouPsbelow the plane (a). If
the configurationof substituent is unknown, its
bond to the nucleusis d rawn as a wavy line.
(3) The configurationof the H at C-5 is
alwaysindicateclin the name.
(4) Circleswere sometimesused to indicate
c -hydrogens ancl dArk clots to indicate
p-hydrogens.
(5) Compoundswith 5 cx-cholestane, belong
ll
to allo-series while compouncls derivecl from
5(aor0)- Estfane(C = lE) 5p-cholestane,belong to the normal series.
(6) lf the double boncl is not between
l8 sequentiallynumbered carbons, in such cases
both carbonsare indicatedin the narre.
(7) When a methyl group is missingfrom the
side-chain,this is inclicatedby the preftx 'nor' with
the numberof the C-atom,which hasdisappeared.
(E) The symbol A is often used to designatea
C = C bond in a steroid. lf C = C is in between
carbons5 and 4, the compounclis referrecl to as a
ill Aa - steroid; ancl if the C = C bonct is between
(C = te)
5 (a or F) - Anclroctane positions5 and lO, the compound is clesignated
as A5(1o) e.g.,
steroic.l.
:r CH. OH

20CH.'
raCH,
l9
QHr
HO 6
I
I
l7 p-estradiol
H 17 p-diol)
(Estra- l, 3, 5 (1o)-triene-3,
tv Sincel7 p-estradiolcontains18 carbonatoms,
= ztl it is considereclas a clerivativeof Estrane,a basic
5 a - Pr e g n a n e(C nucleus.
Prlnclplcr of lrriledicina
I Ghemiatry(Vol.lt) w2 Steroids

c 2l l r

A ndrost-5-eneorA - Androstcne l7 (r-E rh y|l 7- -p-hydroxy- | 9'iroraDdrosl-4ctl-3

()tlc

19nor
l7-a.cthyl, | 7-p-hydnrxy-
| 7 c-nrethyl- androst-
l, 4-diene-3-one
l7 p-or
androst-4'en-

cll3

l? c-metlryl-anclrrlsl
- 5-enc
Testosterone
( l 7-p-hydroxy-4-androsten-3-one) -3p,l7 p-diol

cllr clll
I
c =o
CH

OH
| 7-p-dihydroxpartdrost-4-cnc--1-ttnc
I 7 cr-nrcthyl-4,
or .
Progcstcmnc
20-dione
Pregn-4-ene-3,

cHr
cHr

l7 a-methyl:lI P, l7-P-dihydroxy-9
Cholesterol c-fl uoroandrost-4-en-3-one
(Cholesr-5-en-3-0-0
I)
czHt

l3 p, t7 c-diethyl-
l7 p hydrorygon-4-en-3-one
5p, l9-nor-androst-3-one
Prhclplooof liloc$clnalChanblry (Vol.il) 33

Stercochcml
(t) The absolute stereochemlstry of the
moleculeand any substituentls shown with solid
(F) ana dashed'(a) bonds, a (axial)bond is Cortex
perpendicularto the plane of molecule whlle
(equatorialbond) is horizontalto the plane of the Medulld
molecule.

Ilg. l7.l : Adrenal gland

Both the steroid hormonessynthesizeclby the
cortex and the catecholaminessynthesizedby the
q,a
p,e medulla mecliateadaptive responsesof the body
to a changing environment. The adult adrenal
5 c-androstane cortex, which makesup approximately9096of the
(2) The aliphaticside chain at position 17 is gland, is composed of three zones. The outer
alwaysassumedto be of p configuration. subcapsularglomerulosazone synthesizesaldo-
(3) The terms cis and trans are occasionally sterone while the middle fasciculataand inner
usecl to indicate the backbone stereochemistry reticulariszones synthesizecortisol and androgen,
between rings. For example, 5 q-steroids are A/B precursors,
trans ; and 5 p-steroidsare A/B cis. The terms syn The adrenocorticoidsecretion is under the
and anti are used analogous! to transand cis. influence of adrenocorticotropichotmone (ACIH)
(Confometlons: (or adrenocorticotropinor corticotropin);which ls
Cholestane,androstane and pregnane can released by the anterior lobe of pitultary gland
exist into two conformatlonsi.e. (i) Chairform and (adenohypophysls). lt is a pepeticleof 39 amino
(ii) Boatform. acids whose structurewas finally establishedin
1991.The adenohypophysis, in turn, is under the
influence of the nervous system negativefeed-
back control exerted by corticosteroicls.
p,e
Extemalor internalstimuli
It
5 c-Cholestane(ln chair form) Highercentres
Chair confiormationls more stable than boat I
t
conbrmatlon due to less angle straln and hence all Hlw
qyclohexanerlngs ln the sterold nucleus exlst in . . _+
r
the chalr conbrmation.
r7.3 ADnEN/UCOTTEX
rK}|mONIS Or
ADIT,NOCORTICOIDS: I
The adrenal glands are flattened, cap like I \

I I
structures located on the top of the kidneys. The I t
inner core of lt, is known as medulla, which Aldosterone
Hydrocortisone
Corticosterone
s€cretescatecholamines.e.g. adrenallne,whlle the
shell of the gland is known as cortex, whlch
synthesizessteroid hormones known as adreno- c .R .f.: It is a corticotropin releasingfactor.
cortlcolds or adrenal cortex hormones. Llke most An lnhibitoryr
responseis inclicatedby dotted line.
endocrine glands, adrenal cortex is regulated by
Ilg. 17.2
the hypothalamo-pituitaryglands.
Principlesof MedicinalChemisrry(Vol.il)
In 195O,the only iclentifieclnaturallyoccurring
steroid (other than the aclrenalcortex themseives),
with' an oxygen function at C- l 1 was sarmen-
togenin (a), which had been isolated from the
seeds of a poorly ictentified African plant. The
British expeclition sent to Africa to trace the
sourceof (a), found hecogenin (b), forrnerlya rare
steroicl,as a constituent of the wictely cultivatecl
Agave sisalana,the sisal plant (b) ancl it has C-12
ketonic orygen. Furtherwork at Glaxo Laboratories
Ltd, resultedinto its conversioninto cortisonein a
l8-step process(scheme I )
(a)
A particularlyclifficultaspect of the synthesis
was the need to introduce the stericallyhindered
ketonic oxygen at C-i l. Desoxycholic acid,
$ 3.solg.
availablefrom oxbile, has an a-hvclro rouD at
SchemeI r Syntheslsof cortlsone
6 stages
AcO
w Steroids
the neighbouringC-12 ancl was useclas starting
material in the initial methods of synthesis;
improvementsin the method by Sarett et al. at
Merck were accompaniedby a reduction in the
price from $ ZOOIgin 1949 to $ 1Olg in 1951.
However,this methoclstill entailedmore than 20
chemicalstages.
There was no easy chemical method for the
introcluctionof 11-oxygenfunction into the more
freelyavailablesterolssuchas cholesterol,stigma-
sterol and cliosgenin so the Upjohn company
mounted an effort to fincl a microorganismthat
would perform this conversionwhich was already
known to occur in the adrenal cortex. Success
came quickly using a strain of Rhizopusarrhizus.
This mould converted (3) into (4). Subsequent
improvements involved different microbes and
controllecl conditions of growth. Higher
concentration of (3) could then be 1la-hydroxy-
lated in almostquantitativeyielct.The substrate(3)
could be obtainedfrom (5), a che4p byproductof
processingthe soyabeanor from diosgenin,at that
time readilyavailablefrom Mexicanyams. A route
from (4) to cortisone was quickly cleveloped
(scheme 2) ancl the price clroppecl further to
cHroAc
co
-oH
Cortisone
4 stages
 Principhsol MedicinatChemirtry(Vol.ll) 345 Steroids

CH. cH,
i t' H:C
c- C=O
HO...

Progesterone
(3) nyqroxyprogesterone
(4) Stigmasterol
(5)

H3C.=

(3) I stage
(4) --+-+--
stages microbial J Stages
bioconversion

Diosgenin

CH.OAc
H I
CO

6 stages

Classlllcatlon :
The adrenal cortex Syntheslzestwo classesof
steroids.
(d Glucocortlcolds :
These steroicls regulate the carbohydrate,
protein and fat metabollsm and are intimately
involved In the operation of the processesthat
enable the body to reslst the infection and stress
e.g., hydrocortisoneand cortisone.
(b) Mlnerelocortlcolds :
Thesesteroids mainly influence salt and water
balance (and hence the control of blood volume
ald blood pressure) by maintaining proper
electrolyte balancee.g. alclosterone,I T-d.ro*y-
corticosterone.
Small amounts of sex steroicls such as
dehydroepiandrosterone, testosterone, proge-
steroneand estracliolare also secretd by cortex.
Though hydrocortisone and cortisone are
categorised as glucocorticoicls,they. possess too
much salt-retaining(mineraiocrticoiclal) activigr in
the closes needecl for therapeutic purposes.
Similarly,a potent mineralocorticoid,aldosteroneis
a very costly drug and not a practicalclrug procluct.
Consideringthe above two facts, efforts were
made to clevelopnew potent and low cost adreno_
corticoiclshavingminimum side-effiects.
Prhdphr of llcdlcinal Ct rblry (Vol.ll) 3fi Sb?d&

llfructurc-Actlvlty Rcletlonthlp : The glucocorticoiclactivity parallelsto anti-

In 1951, when hydrocortisoneand cortisone inflammatory effects. Glucocorticoids have the
were used in doses necessaryfor the treatment of capacigl to prevent or suppressthe clevelopment
rheumatoid arthrltis, they were founcl to affect
of local heat, redness,swelling ancltendernessby
other metabolic processes.
ln hope to develop a compound with high which inflammationis recognisedat the gross level
glucocorticoid and low mineralocorticoidactivity, of observation,Edema,fibrin cleposition,capillary
the following major fuatureswere recognised. dilation, migration of leukocytes into the
(t) Substlhrcnts whlch slgnlflcantly lncrelsc inflammed areas are the early signs of
antl-lnflammetory and glucocortlcold ectlvfry ere inflammation:They are also indicated in some
l-dehydro(Ar) allergicdiseases,e.g., bronchialasthma,urticaria
6cr-fluoro anclother types of dermatitis.
(2) Substltucnts whlch rlgnlflcently
decrcase mlnerdocortlcold actlvlty arc : Mechanlsm of actlon :
16ct- hydrory (l ) Thesedrugs reclucethe increasedpermeabili$r
164-and 16 p-methyland of capillaries.
164. l Tcr-ketals (z\They inhibit the leakage of inflammation
producing lysosomal enzymes into the
cH2oR surrounclingtissues by stabilizingthe lyso-
C. =O somalmembrane.
CH ----oH ( 3 ) These damaging lysosomal enzymes are
releasedwhen antigen-antibodycomplexes
9Hr are engulfedby white blood cells anclcortisone
inhibitssuchan engulfingProcess.
(4) The reclucedpermeabili$ of capillariesinhibits
the migration of white cells out of blood
stream,which in tum, decreasesthe numberof
Co rtiso n e : R= H such cells able to permit leakage of their
Cortisoneacetate: R = COCH3 lysosomal enzymes into the surrouncling
(3) Substltuents whlch markedly lncrclrc tlssues.
both glucocortlcold and mlnerelocortlcold
(5) Thesedrugs maintainthe integri$rof the cell
actlvltles are :
9c-fluoro membraneeven in the presenceof toxins and
2'l-hydroxy thusinhibitthe cellularswelling.
Zcr-methyl and (6) They interfere with prostaglandins and
9cr-chloro collagenase synthesis and the clrculatory
distribution of leucocytes in lnflammed
tissues.
(7) The optimum glucocorticoiclstructureshows a
C=O
CH ----oH lc,Zp-half chairconformationfor ring A, with
ring D, a l3-envelope(C-13is bent up ) or a
CH-r half-chair.Halogenationis most effective in
positions6, 7,9 ancl12.The compouncls bind
on th.eirp-face by hyclrophobicbincling
forces.Among newer clrugs,the [3, Z-c) -
[Z-aryl pyrazolo)clerivative(l).shows high
or Cortisol
Hyclrocortisone activigr(20OOtimes that of cortisol).
 Prlnclplesof McdlclnatChemlctry(Vol.ll)
Steroids

This.increasein potenqy by the introduction

ot- the Ar doublebond may be due to the resultant
C= O changein the shapeof ring A from a chairform to a
---oH half-chairand to a flattenedboat,conformation.
i]-CH: (b) Between 1953 to 1960, many derivatives
of A-corticoicls ancl the halogen_containing
analogs (especiallyfluorinateclcompouncls)were
synthesizecland some became..useful clinical
agents.The 9 a-fluoro group increa3esthe anti_
inflammatory activity but mineralocorticoicl
potency is also increased.An adclitional 16 cx_
hyc{ro.4rgroup is helpful,to reclucethe undesirable
mineralqcorticoidactivigr.
(a) A-Corrtlcolds,
: . . I'
It was obseived tl
vatives of cortisone-anc CH?OH
preclnisoneand prednis I =Q
C
antirheumaticancl anti-i r---OH
parentcompoundsand p --oH
side-effects.These compounclsare known as
A-corticoids, since they contain an additional
doublebonclbetween,poslfidni1,ancl2 (i.e.Al).

CH]OH Triamcinolone
C= O (c, uunng same periocl, in 1956, methyl-
prednisijlohbwas synthesizedancl introduced into
----oH
the ctinicat,practice;
QH, triamcinolone.

. C= O '
r-reontsone

iH'?oH
C:=O
-oH
HO.

QH:
, :, Methylprednisolone..
(d) To stabilizethe 17
B-ketol side chain to
metabolism.in vivo, researchwith l6-methyl
substitutedcorticoidsled to the,development;f
rreclntsolone
dexamethasone in 1957.
Prhdphl ef }ledldnal Chomi.try (Vol. ll) 3S g.rcb

C= O
C= O HO ---oH
HO ---oH CH
---cHi
CH

Dexamethasone Fluprednirclone
It has 5 tlmes anti-inflammatoryactlvigl of
prednisolone. Soon after, betamethasone,a
C= O
slightly more active analog,was introclucecl. CH
HO ---oH
----oH
CH

C= O
CH ---oH
HO
CH,r
CH I
F
Fluandrenolone

cH1
I
Betamethasone c =Q
CH OH
A slightly moclified analog of clexamethasone,
synthesizedin 196O and introclucedfor clinical
trials was paramethasone.

C =O CH.
*-oH
- - CHl Fluorornetholone

fH'?oH
9= o
.l
---oH
---oH
t
Paramethasone
(e) The newer analogs,fluprednisolone,fluan-
drenolone, fluorometholoneancl fluocinolone, I
I
were synthesizedand are found to be potent antl- F-
inflammatoryagents. fluoclnolone
 Pilnclplesol liedlcinalChemistry
ryol.ll) 349 Steroids

t bfe tt.t r f,nh.ncclncnt hctor for verlousfrrnctlonelglouPs

functlonrf gmup Glycogcndcporftlon Anal-lnf,emmeaory
ictlYlty Elfiecton Urlnary Ne+
l. 9c-fluoro to + ++
2. 9s-chloro o5 ++
3. 9c-bromo o.4 +
4 . t 2a-fluoro 6 -8 +
5 . l -Dehydro 3 -4 3 -4
6. 6-Dehydro o.5- 0.7 +
7 . 2a-methyl 3-6 l -4 ++
8 . 6a-methyl 2-3 t -2
9. l6cr-hydroxy o.4- o.5 o.r- o.2
to. | 7a-hyclroxy | -2 4
I t . 2l -hyclroly 4-7 z5
lz. 2 | -fluoro 2 2
+=M+ retentlon
- =N a + excretlon
Frieclancl Borman were annongthe flrst to TIOLOGICATACTIONS:
recognisethat certainmocliffcations of the steroid Corticosteroids influence carbohyclrate,
skeleton hacl predlctable effects on corticol<l protein,anclfat metabolism;electrolyteanclwater
activlgr ancl asslgned 'enhancementfactors' to balance;ancl the functionsof the cardiovascular
varlous modiffcatlons found to Increase gluco- system, skeletal muscle. nervous system ancl
cortlcoldanclantl-lnflammatoryactivitles.later. an kidney.
l. Gerbohydretc,proteln encl fet mctabollsn :
ever increaslngnumber of flncllngsrevealedthe
Corticosteroicltherapy leaclsto an increasein
lnvalldltyof applylnganlmil test resultsto man. So
liver glycogencleposition,resultingdue to,
baseclon the observatlonthat a meesureof antl- (a) Increas4in glucoseformation,
inflammatorypotency of a sterolclmanlfustsltself (b) reductionof glucoseperipheralutillzation,
irt eosinopenicresponsesIn man, whlch can be (c) conversionof glucoseto glycogen.
easilymeasurecl.Ringlerand his associatesshowecl Proteinsare also brokendown to aminoacicls
that eoslnopenk and hyperglycemlccllnlcal assay whlch, In liver. s€rye as substratesfor enzymes
correlated closely wlth the antl-lnflammatory Involveclln procluctlonof glucoseanclglycogen,
efficacyof clinlcallyused glucocortlcoldsIn man. , Cortlcosteroicls stimulate the mobilizationof
In comparlsonwlth Frleclancl Bormanenhance- fat from the peripheralfat clepots.Thereis a gain of
ment factors, these new values are in general, fat in the back of the neck (buffalohump), super
cfivicular areaanclface (moon face).
sllghtlylower.
Irblc t7.t r Cllnlcd ALlrhcumrtlc Enhenccment Jectors
functlonel ;loup Iector functlonel group factor
L l -clehydro 2.8 7. t6a-methyl t.6
2. 6-clehyciro o.9 8. 6p-methyl t.3
3. 6c-methyl o.9 9. t 64, | 7c-lsopropyliclenedioxy o.6
4. 6cr-fluoro 1.9 to . | 7 a-acetoxy o.3
5. 9o-fluoro 4.9 t t. 2l -deoxy o.z
6 . | 6c-hyclroxy o.3 t7 . 2l -methyl o.3
Principles Chemistry(Vol.ll)
of Medicinal 351 Steroids

7. Antl-allerglc and lmmunosuppresilve it is nof surprisingthat they inhibit a braclykinin

lctlons r inducedinflammationthat depenclson arachidonic
aciclproductionand metabolism.
Glucocorticoids inhibit phagocytosis of
antigens and their subsequent intracellular Glucocorticoicls are reported to be the only
digestionby the microphages.They modifo the availablechemotherapeuticagentsthat reverseall
clinical course of a variegl of cliseasesin which the clinical manifestationsof inflammation,
rportant. lt has been i..e., pain, rednessheatanclswelling.Theseclrugs
increasein bloocl glucose are usefulclinicallyfor treatment of a wide range of
ancl glycogen deposition is the biological expre- inflammatory processesranging from pruritls.
ssionof the hormone'sfunction. contactclermatitisand localizeclpsoriasis.
Mechenlsmof ectlon :
The introducecl substituents and double
The principal targets of glucocorticoidsare bonds often slow clown metabolism to inactive
liver, musclesand brain.They increasethe rate of
steroids (metabolic inactivation may occur by
enzyme synthesisln the nucleusof target cells
and achieve their effect on overall protein recluction of ring A, 6p-hydro4ylation or oxiclation
synthesis. They promote gluconeogenesis by or reduction of the clihydrolq/acetoneside-chain).
increasingthe' pyruvate carboxylaseconcentration Contrelndlcetlonr :
ancl thus increase the concentrationof oxalo- The aclrenocorticoidsare contraindicatedor
acetate in the mitochondrial pathway of pyruvate should be used wlth great caution in patient
phosphoenolpyruvatesynthesis. Another effect having,
appearsto be the inhibition of pyrtrvateoxidation. (l) peptic ulcer
Lipolysis is stimulated primarily through the (zl
activationof adenylatecyclase.The overall meta- heart disease
bolic result is increased glycogen storage ancl (3) infections
hyperglycemia. (41 psychoses
Glucocorticoids appear to exert their anti- (s)cliabetes
inflammatory actions in the m icrocirculation of (6) glaucoma
inflammedtissueby inhibiting: fopkel lntl-lnflemmatory steroldal agcnts :
The production and/or activity of vasoactive The original indication for treatment with
agents : vascular permeability is enhanced and cortisone and the subsequently synthesizeci
fluid accumulates in the tissues. These initial analogues was rheumatoid arthritis ancl this
vascular changes are largely. .caused by many continues to be an lmportant field of use despite
vasoactiveagents, which include prostaglandins, the side-effiects attended upon chronic(long term)
kinins,histamine,anclSRS-A. therapy. However, it was soon discoveredthat the
Blackwell et al characterized a specific compounds had antiallergic activity and given
glucocorticoidinduced.protein with a molecular systemically, alleviated the symptoms of asthma
weight of I5,OOOwhich'they namecl "macro- (e.g., beclomethasonedipropionate ancl beta-
cortin", that inhibits phospholipaseA2 activigr. methasonel7-valerate).They were equal! useful
Glucocorticoidsappear initially to stimulate the in hay-fever ancl in various disease conditions of
release of macrocortin already present in the cell the skin, such as eczema and psoriasis, but here
anclthen its synthesis. the secondary effucts of systemic corticosteroid
Bradykininis consideredas a potent infla- therapy (deposltion of fat, loss of Ca++from the
mmatory agent becauseof its effects on smooth bones,suppressionof the adrenalglands, suppre-
musclesand the vascularsystem, its analgesic ssion of the immune system)were too severeto
properties,its abiligr to attack leukoqytesand the warrant thelr generaluse, especiallyin children.
interactionof the kinin systemwith other vascular One way of minimizing side-effectsinvolves
regulatoryprocesscs(coagulation,fibrinolysis,and applicationof steroid locally to the inflammed
complement cascade). lt causes vasodllation, tissue, thus allowing smaller systemlc concen-
increas€dvascularpermeabllityand hypotension. trationsof the hormone,the skln being the easiet
Glucocorticoidsdecreasel€-synthesis and hence, target.
Principles
of MedicinalChemistry(Vol.ll) 352 Steroids

Numerouspreparationscontaining either
glucocorticoids
aloneor in combinationwith anti-
bacterial,or antifungalagents are availablefor
topical therapy. C= O
Topicalapplicationsinclude, ______oH
(l ) Dermalointments,creamsand lotions.
(Z) Ophthalmicointmentsancl solutions.
(3) Respiratory
aerosols.
(4) Eardrops,and
(5) Enemas.
Dichlorisone

fH'zoH
C= O C= O

---CH..

I
I
F
Desonicle
Diflucortolone
CH' OH
I
C=O C H .C I
I
C=O
HC)

9H,
I
I
F
Fluclorolone Clobetasol
Maibach and Stoughton identifiecl ZO clerma-
tological disorclerswhich respond to topica
corticosteroid5.Exceptcortisoneand preclnisone
CH.CI most other glucocorticoicls exhibit,goocl topical
I activity.Someof theseare Halcinonide,Flumetha-
C=O
sone, Flu'ocinolone, Fluorometholone,Fluanclre-
------oH nolone, Desonicle,Dichlorisone,fluclorolone,
---cHr Diflucortolone, Clobetasone,Clobetasol,etc. are
9Hr ienrs. ,
ressof glucocorticoicls
in
allergyanclasthmais assumeclto be due at leastin
part, to inhibitionof histaminerelease.Sincean
incremenfin mast cell cyclic AMp.resultsin a
Clobetasone decreaseof histaminerele4seanclsince in human
leukocyteglucocorticoidsincreasecyclicAMp and
Princlples
of Medicinal (Vol.ll)
Chemistry 3tr1 Steroids

potentiatethe increasein qyclic AMP induceclby

PGE1,it has been suggestedthat gluqocorticoicl
effectson qyclic AMP contributeto a recluctionirt
histamine release. lnhibition of cyclic AMP
phosphodiesterasehas been suggested for
mechanism of cyclic AMP increase incluceclby
glucocorticoids.
SinceSRS-Ahas recentlybeen identifiedwith
arachidonic aciclmetabolites(leukotrienesC anclD)
produced by mast cells and polymorphonuclear
leukocytes,glucocorticoidsmay inhibit SRS-A
through
(i) stimulationof a polypeptide (macrocortin
perhaps)that blocks phospholipictmetabolism.
(ii) the movement of leukocytesto inflammed
area,and
(iii) the capability of immunocompetentcells
to function once theyr'enter the site of infla'
mmation.
Mlneralocorrtlcolds:
Sodium retention, hepatic cleposition of
glycogen and anti-inflammatoryeffect, these are
three basic propertiesof corticoiclswhich are used
to estimatetheir potencies.A corticoid havin.ga
properg of predominant liver glycogen cleposition
(whichparallelswith its anti-inflammatory effiect)is
known as glucocorticoicl,while a corticoid with
preclominantly socliumretainingeffectsis calledas
a mineralocorticoicle.g. alclosterone,1I -desoxy
corticosterone,fluclrocortisone acetate.
Structure -Actlvtty Relatlonshlp :
(l ) Naturallyoccurring,highly active mineralo-
corticoicls have no OH function at positions I I
ancl | 7. In fact, OH groups in any position reduce
the soclium retaining activity of adrenocorticoicl.
Alclosterone
(not used clinically)
CH)OH
I
c =Q
I | -desoxycorticosterone
cH,ococHl
C= O
----OH
Fluclrocortisoneacetate
(2) According to the hormone-receptor
binding studies, the C and D rings, involving
positions11, 12, 13 16, 17, ZOand 21 are more
important for binclingthan the rings A and B. More
specifically,the c-surface of rings A, C ancl D, as
well as the l7 p-ketol side chain, is essentialfor
socliumretainingactivigl.
(3) Generally9u-F, 9a-Cl ancl9s-Br substi-
tuents cause increasedm ineralocorticoiciactivigr
where order of activigris F>Cl >B r.
(4) lnsertionof a 16 c- OH group results in
reverse effect i.e. soclium excretion rather than
Na+ retention.
(5) A ctoubleboncl between positions l ancl2
(Al-corticoicls), also decreasesthe activitv.
(6) Zl-F, 16 a -CH3,16 p-CHr, 16 o.-CHrO,
6 cr-Cl,and 17 a-OH groupsare reporteclto inhibit
the sodium retention property.
( 7 ) 1 L s .- t, Zcr-CH3 ancl 21-oH groups
moderatelyelevatethe mineralocorticoicl activity.
Principles
of Medicinal (Vol.ll)
Chemistry 3Al Steroids

Pharmacologlcal actions : Table 17.3

(l) Electrolyteand watel bdance : Mlncralo end Glucocordcostcrrold Actlvlty
They act on the distal tubulesof the kidney to
enhancethe reabsorption of sodiumionsfrom the llinenlo Ghce l
tubularfluid into the plasma;they increasethe cortico3teroldcorticortroid i
urinaqlexcretionof both potassiumand H+ ions. activlty ectavlty ,
In mineralocorticoicldeficiency, proportio- Aldosterone 100 0.1
nately more socliumthan water is excreted through Cortisone 0.8 0,8
the kidney with resultantdecreasein extracellular
sodium concentration; extracellular
fluid becomes
Hydrocortisone 1 1
hypo-osmotic,ancl water shifts from the extre- Fludrocorticnne 100 12
cellular into the intracellularcompartments.The Plednisone 0.6 5
shift resultsin a markedrecluctionin the volume of Prednisolone 0.6 6
the extracellularfluicll cells are hyclratedand
erythrocytesalso swell. Mehylprednisolon€ 0 6
The shrinkageof extracellularfluiclvolume, the Tdamcinolone 0 6
cellular hyclration and the hypoclynamicstate of Dexame 0 25
the cardiovascular system combine to cause Parame 0 12
circulatory collapse, renal failure and death
e.g. Aclclison'sdisease.Hyperkalemia,acidosisancl T7.4 SEXHORMONES
muscular weakness are the manifestations of Hormones are substanceswhich are secreted
aldosteronecleficiency. by the ductlessglancis(enclocrineglancls)in very
Alclosteroneexerts similar effectson kiclney, minute amounts and exert important functiona
salivaryglapcls,the sweat glancls,pancreasand effectsupon other tissues.They clo not relate to
the mucosa of GIT.
(2) Hypertenslon : each other chemically.Physiologicalactivigr of
Excess mineralocorticoicl leacls to excessive these hormonesserve as a basis for their classi-
retention of Na+ ions in plasma which results in fication. The sex hormones possessa steroidal
hypertension. nucleusanclare produced in the gonads (i.e. testes
Mechanlsm of actlon : in the male and ovariesin the female).Theiractivig'
Like other steroicls,aldosteroneprobably acts appearsto be controlleclby the following three
to initiate transcription of RNA that serves as gonadotropichormones.
template for the synthesis of carrier protein or (l ) Follicalstimulatinghormoneof FSH.
proteins that subsequently facilitate the crossing
of Na+ ions through the rate limiting permeabilitlr (2) Lutenizinghormoneor LH or interstitialcell
barrierof the mucosalsurface. stimulatinghormone(ICSH)ancl
Progesterone,the cliuretic agent spiranol- (3) Luteotropinor prolactin.
actone, actinomycin ancl puromycin block the
alclosteronestimulated transport of Na+. Such
The amino acid sequencein human LHRHis as
inhibitors have no effects on the non-hormonal
basaltransportsystemof Na+ . follows :
-Trp3-Sera'Tyrs
pGlut-His2 7-Arg8
-Gly6'Leu -Proe
-Glyr0'NH2
Agnists and antagonistsof LHRHhave been used
to impair fertility. Nafarelin[(D-3-(2-naphthy
alanine)61LHRHby nasalroute has been shown to
be the most potent LHRH agonist. While the
replacementof Hisz residue in LHRHby D-amino
acicls leads to antagonist activity. LHRH anta-
cHr gonists alone or in combination with prosta-
Spironolactone glandins have been succesfully used as inter-
ceptives.
Principles
of Medicinal
Chemistry(Vol,ll) 355 Sterolds

- - - - - - - - {t
<F----------
Hypothalarnus
.. 1 r ,i
I |.|

l1eed-DacK t,
LH_RH Feed-back
tnecnantstns I mechanisms
I
^tlf
l\ -
i _
it
tl
\r------r-
| Anteriorl-obe -------------------' i
Feed-back ,' of pituitarygland+----- Feed-back
mechanisms mechanisms
It
I FSH LH
-tI \/

Breast
S I
I
\/
\. /
I
I Ovarics
I Brcasts
Skin I
Estrogens Progesteronc

Utcrus Placenta
Vlginr Cervixsecretlons

fSH: IOLICAL STIMULATING HORMONE

'J.',,'i :
LH : LUTENIZINGHORMONT
.- IH:NH I IUTENIZINGHORMONE. NEIEASINGHOIMONE
tls. | 7.3
These three distinct gonadotropic hormones the clevelopmentof seconclarysex cnaractensUcs
are secreted by the adenohypophysis.The main in women at puberty.
function of sex hofmones: is to regulate the Anteriorlobe
ovulationin women.anclSpermatogenesis in men. l-

They are also responsiblefor the clevelopmentof I Mature

! Feed-back FSII& LII
seconclarysex characteristicsjn both. inhibition
- Follicle
I
The sex hormones are of three $rpes. The N
I
I Sudden rise
anclrogens(male sex hormones),the oestrogens I
I rnoestrogen
(femalesex hofmorfesor follicularhqrmones)ancl LH & FSH
.
gestogens (the F.orpus luteum,' hormone)
on l4thDay
Ruptured+ Mature
e.g. progesterone. Empty Ovum
Oestrogens : Folliclc
,J Menstruation
Though ovary is the main site of oestrogen on 28thDay
secretionin the female, placenta,testes,adrenal
corpusleutcum
cortex, liver, fat, skeletalmuscleanclhair follicles
readyt'orreceiving
can ,f9lmsignrfican!quintities of ,oestrogensfrom a fertilizedovum
steroidprecursors,,
Theyare large\r.responsiblefor : Eventsln mcnstrud c CIG
Principles Chemistry(Vol.il)
of Medicinal s6 S!.rolds

Classlflcatlon :
Chemicallyoestrogenicsubstances are dlvided
into threeclasses.
(e) Hunrenocstrogens rnd dcrlvetlvcs :
These compounrls are naturally occurring
oestrogensin humananclare regarcleclas cleriva-
tives of estranee.g. Estrone,Ethinylestradloland
Estriol.
R= H
Equllln:
Equlllnsodlumrulphate: R - - SO-rM*

Estrone

OH Equilenin
9H..
:---R (c) Synthctlc or nor-glcloldel ociirtrotcnt :
As the name indlcates,these are the synthetic
compouncls having a considerableoestrogenic
activitv.
HO

l7 B-Estracliol : R= H
C =C
:Rl =- C =C H
EthinylEs t r a d io
I
c
OH Diethvlstilbestrol

---oH

ct{.ro C= /\ ocH.r
HO

Estriol
Humanestrogensanclclerivatives ocHl
(b) Stalllon ocstrogcns :
Chlorotrianisene
Human urine of pregnancy is an abunclant
source of natural oestrogens but stallion excretes It is hlghly nonpolar. lt ls storecl in body fat
more estrogen than any other living form. Oestro- ancl llberated slowly, probably as an active meta-
gens excreteclare equileninanclequilin. bollte. lt is therebre, a proclrug.
tthdpb. ol lrdehd Gfnnbtry (Vo[ f) (lil Stt'roidt

OH

CH
ll
c-c
tlH
HO
cH 3
Hexestrol
A non steroidal synthetic oestrogen of yet
Dienestrol anotherclassis methallenestrilwhich is 10 times
Diproplonate and clipalmitateesters are used les potent than cliethylstilbestrol.It is obtained by
to give prolonged activit5l. removal of ring C from the structureof doisynolic
acicl.

o
lr
Cr.
OH
OH

HO H3CO

Dehzestrol Methallenestril
The cterold nuderls k not requlrcd for oestro- Stucnrrc- Acdvhy lclrtlonrhlp :
genk actlvigr. (t) t7p-oestradlol ls a potent oestrogenic
agcnt. Many structural modlficatlons of l7p-
estradlol were carrled out slnce it rapidly gets
oxldlsed to estrone,In liver and hence ineftctive
H orally.Adding a | 7 cr-allrylgroup (particularly17c-
=C
/
ethinyl derlvatlve) to oestradiol blocks thfts
oxidation and makes the compound orally active.
H Another o€strogen, syntheslzedby thls similar
route ls mestranol which is used ln oral
contraceptives.
(2) The esterlflcatlonof,17 p-hydroxy and
Trans-stllbcne 3-hydroxy functlons also prolong3 the duration
Marry derlvatlves of stllbchd whlch arc where slorr rate of abrcrptlon ls due to low water
consldcrablymorc stabh ai tftc trans lsorner, are solublllty. 3-benzoate; 3, l7-dlpropionate;
potcnt ocrtrogenlc aubstancG and ane us€d t 7-valerateand l7-qyclopengdproplonateare the
thcrapalkally e.g. most common! used ester brms.
OH
: Cr CH

KCT CH
LiquidNH,

17p+rtradiol:R=H EthinylEstradiol":
R H
Mestranol: R= Q -l{ ,
 of MedicinalCh€mictry(Vol.ll)
Prlnciplee
SIow hydrolysisof these esters releasesthe
free oestrogenover a prolonged period of time,
henceesterformsare termed as prodrugs.
(3) Steroidal nucleus is not 'an essential
featureof oestrogenicactivity. e.g. Plant oestro-
gens like genisteinand coumestrol.
OH
Genistein
OH o
Zearalenone
Allenolicacid OH
HO
Coumestrol
(4) The intensigrof activity changes if route
of administrationis changede.g. for oral route:
Estriol> Estradiol> Estrone
For subcutaneousroute :
Estradiol> Estrone> Estriol
(5) Substitutions on oestrone nucleus
significantlymodiff the oestrogenicactivi$,
(a) Insertion of hydroxyl groups at 6, 7 and
11 positionsreducesthe activity.
(b) Removalof oxgyen functionat 3 ancl 17
positions or epimerisationto cr configu-
ration resultsin less active compounds.
35S Stcrot
(c) Introduction of unsaturation in ring :
reducesthe activitY'
(d) Expansionof ring D in both' oestradiolarrd
oestrone,greatly reduces the qqstroSentr
activit1l.
e.g.
OH
'. D-homoestradiol
D-homoestradiolis;lessactirle than tlle oestradio
(e) lf ring D is removed, in oestrone cr
oestradiol, acfivity rehnain's!he sarr,e
e.g. oestradiol on treatment with strortg
base gives doisynolic acid which has sanr'
, , activibr aF that of oe5tr.adiol.t{ence ring D
is not necessarylfor the activitlt.: '' '
HO
Doisynolicacicl
(6) According to Schueler,hypothesisto hare
optirnalioestrogenic actfvi$, a molecule should
have a distance,of abouti 8:55 Ao behrVeenthc
groups that can form Hfboncls '(e:g. ketones
phenolic, and alcoholfc h,,ydroxy-lgroups)' The
activigl of non-steroiclal-synthetic oestrogens can
be explained on this hypothesis. ln dieth;''l
stilbestrol.this ctitical.clistancels 12.1 Ao and in
oestracliolit is 1O.9Ao;
ffiny other potent steroidal;,Ancl non-steroida
oestrogensconfirm this hypothesis.
( 7 ) numberof heteroqyclicanalogu€sof the
oestrogens (steroidal) are being prepared and
evaluatedbiologlca[ly.Among the most common
are the az.ranalogs.The - NH - group ls lsosterrc
to a metnyrenegroup.
' fthcpbr of llcdiclnal Chornlltry (Vol.ll) G) Steroids

(O)
l7-p-oestradiol > Oestrone

OH

Hrc

2-methoxy
metabolite 2-hvdroxvmetabolite Estriol

Metabollsm : RNA in the target cells.This RNA is thought to be

The three primary oestrogensin women are responsiblefor severaluterineeffectsthat are seen
l7 p-oestracliol,oestrone and oestriol. These with normal oestrogenstimulation,The increasecl
hormonesare metabolizedmainly in liver and are RNA synthesiseventually leads to an increasein
largely excreted as water-soluble glucuronicle the synthesisof specificproteins which affect the
conjugates.Other tissues such as kidney ancl activig of variousenzyme systems.
OH Therapeutlc Uses :
--o Estrogensare used therapeuticallyto replaceor
+
CO0Na augment hormones whose natural procluctionis
insufficientcluring menopause, in menstrual
OH
clisorclers,or as a result of insufficinetclevelop-
RO ment of female reprocluctivetract. In androgen
HOH dependent prostate carcinoma estrogensare used
SodiumGlucuronide of Estriol therapeuticallyto suppressandrogen and tumour
growth.
intestine may also act as sites of metabolism. The following are some of the important
I 7-p-oestradlol first gets oxlclised to oestrone, therapeuticusesof oestrogens.
which upon further oxidation, gives oestriol, the
found in human urine. Z-Hyclroxy ( 1 ) Or a l cont racept ives (alongwit h
major oestrogen
and 2-methoxy metabolites are also founcl in progestins).
considerableamounts. Blle also servesas the route (2) In the caseof menopause.
of excretion but oestrogens and their various (3) ln abnormaluterinebleecling.
metabolites, excreted through bile, may be (4) ln failureof ovariandevelopment.
reabrcrbed so that several days are required for
complete excretlonof a glven dose. t7.5 ANTTOtlirnoGr,Ns on ovutATtoN
Modc of ecdon : STIMUTANTS
Cellularcomponents of uterus are responsible These compouncls may De useq ror two
for the bindlng of oestrogens.At the subcellular purposes :
level, oestradiol binds wlth both the qytoplasmic (l) as turtilitydrugsand
portion and nucleus of the -cell. The uptake and (2) as anti-tumoragents.
transportation of oestrogens ls governed by These compounds have a clirect effect for
extranuclear receptors whlle oestrogen retention increasing FSH and LH production by the
and growth inltiation is controlled by nuclear hypothalamusthrough the blocking of feedback
receptor. Oestrogen Increasesthe synthesisof inhibitlon of ovary produced oestrogens.As a
Principlesol MedlcinalChemistry(Vol.ll) ffi Steroi.l

result, there is increasein levels of FSHand LH,
which causes stimulation of ovulation. These
agents, therefore, are used in treatment of
infertilityin women.
An antloestrogen, clomiphene, which is
structurallyrelated with chlortrianisene,acts by
increasingthe gonadotropin secretion.
o-cH
Clomiphene
It has
i.
a number of side-ef6ectslike enlarge-
ment 6f ovaries, nausea, depression, visual
disturbances,etc. A related compouncl, etham-
orytriphetol is also strongly anti-oestrogenic.
Q- cH,cHz
Alternatively,ovulation can be stimulated b1l
aclministrationof LH and FSH. However, animd
preparations of gonadotropins either have not
been effective (due to speciesdifferences)or may
have caused antigen-antibody reactions-
Therefore,a limiteclamount of human LH and FSH
extracis which is known as human menopausd
gonadotropin (HMG) is tested and found to
stimulate ovulation effectively. Patients with
Kallmann'ssynclrome(a genetic disorclerchara-
cterized by defective hypothalamic Gn-RH
production) have been effectively treatecl wi
Gn-RHreplacementtherapy. HMG shoulclbe used
with caution becauseovary enlargementis quirc
common.
Other important anti-oestrogensa.reTamo
xifen ancl Nafoxidine.Both tamoxifen ancl clomF
phene are aminoetherderivativesof stilbene.The
cis-isomerof tamoxifen is estrogenicrather than
anti-estrogenic.
cHr
CHt
I
o C c
I
c,,

Tamoxifen

HO C

HrCO Centchromr.r:

Ethamo>,gAriphetol
o- cHz-cH2_N
Another antl-oestrongen with weak andro-
genic actlvity ls Danazol,which is used to treat
endometrlosis.

OH
9H, :--c =CH

Nafoxidine
N
I Anti-estrogens block the estrogen ind
o fuedbackinhlbition in women who are in
bpcauseof anovulationresulting from excess
Danazol estradiol production. Therefore,multiple p
Principles Chemistry(Vol.ll)
ot Medacinal
nanciesare rathercommonin women treateclwith
anti-estrogens.Anti-estrogensare also active as
mammary
antitumoragentsin estrogen-clepenclent
(breast)carcinoma,a neoplasm having estrogen
receptors.
17.6 PROGESTINS (Gestag€ns):
The corpus luteum which is formecl from the
repturecl follicle after ovulation, starts the
secretionof progesterone,which is responsiblefor
the maintenanceof vascularityof uterine endo-
metrium. The corpus luteum continues the
secretionof progesteroneto suppressthe secre-
tions of FSHanctLH by feeclbackinhibitorymecha-
nism ancl thus prevents further ovulation during
pregnancy.It also inhibits the releaseof oxytocin
which causesuterine contractions,thus avoicling
disloclgement of the fertilizeclegg or embryo.
The progestinsare a class of compounds
having progestationalactivi$ e.g. progesterone
and 19-nortestosterones. Though 19-nortesto-
steronemay exhibit androgenicside-effects,their
main activigl remainsprogestationalonly.
2l
l8
CH
6
rrogesterone
OH
I 9-nortestosterone
Progesteroneis naturally secreted by corpus
luteum and placenta. lt is also synthesizedby the
adrenalsand testes,where it acts as a precursorof
s1 Steroids
varioussteroiclalhormones.The placentalproge-
sterone besicleshaving its physiological effiectson
maternal organs also acts as an important
precursorfor foetal corticosteroidsand anclrogens.
Progesterone is rapidly metabolisecl to
5p-pregnanecliol glucuronicle.The measurementof
urinary excretion of this metabolite can be us'eclas
an inclex of corpus luteum and placentaactivigr
and a prematureclrop in its urine level of a pregant
woman may be a warningfor possibleabortion.
HC- O
COOH
OH
O HH
H OH
5 B-pregnanediol glucuronide
The l9-nortestosterone derivatives have
markeclovulation-inhibitingactivity and thus can
be usecl as oral contraceptive alongwith
progestins.The weak androgenicproperty can be
recluceclby the structuralmodifications.
Classlflcatlon :
(l) Progesterone
(ll) Derlvatlves of progesterone.
(a) Esters of l7-alpha hydroiy proge-
sterone derlvatlves :
Sincethe na ogesterone,has a
very low poten( ;tered orally, its
ester clerivativeswere prepared which have gcod
oral activigre.g.
C= O
---.oR
(i) I 7 cr -Acetoxyprogesterone;
R = CH3CO-
(ii) I 7 a-hydroxyprogesterone-17 caproate;
R= CsHuCO-
 frnch|rl ot t$nat Chanbtsy(yot.[) c $rold!
(b) Cc-rubrtltutcd t?-elphe hydroxy
plotc3tcronc dcrlvetlvcc :
Further structural modifications of
l.7c-hydrory progesteroneat sixth carbon,hinder
C= o
the catabolismof the compounds and increase
thelr lipid solubiligr, resuliing in an enhanced
Diological e.9., medroxy progesterone cH_r
.effect.
acetateand megestrolacetate. I
I

C=O
q---oCoCH., Dehyclrogesteroneor Duphaston
(lll) Dertvatlvcs of testosterone
9Hr
The first syntheticprogestin,ethisterone,was
preparedby lnhoffenet al in 1937 in an attempt to
lnd "! orally active androgenbut later proved to
Uean'emective oral progestin.
Lt-tr
OH
rvreqroryprogesteroneacetate :---C = CH
cH_1
I
I
C= o
a'---OCOCH,
9Hr Ethisterone
Ethisteronebecame the first orally effective
progestogen.However, its oral activigl is stilt low.
FurtherSARsrucliesled to :
ln cllmethisteronewhich is a modified
CH. structure of ethisterone, introcluction of CH3
Megestrolacetate groups in the C-6 c, anclC-Zl positions,enhance
(c) Dchydrogcstcroncs : progestationalactivitlr.
Progestational activigr is further enhancedby
introducinga double bond betweencarbons6 ancl OH
7 in 6-substituteclt 7 c-hydro*y prog"rterone
derivatlvese.g. chlormadinoneacitaie. "
cH.1
Ic = Q
CH I

cHi
QH.' Dimethisterone
(lV) Derlvatlvcs of l9-noftcstosterone :
Ethrenstein in l g44 founcl that the c- 19
meflVl group is not essential for pro-qestational
activlty, which teclto this new seriei of-progestins
e.g. t 9-nortestosterone,noretl
Chlormadinqneacetate strel,lynestrenolanclethinocliol.cl
Principl$ of MedlclnalChemlstry(Vol.ll) GI Sterolds
o
tl
OH o-c-cHl
CH
=
i\:=c CH

o
tl
cH3co Ethlnocliolcliacetate
Structure-ActtvltyRelatlonshlpr
19-Nortestosterone (l) Progestationalactlvlty appears to be
OH restricteclto moleculeswith a steroid nucleus.
Progesterone is not effectlveorallyprobablyowing
to its completedegradationduringlts one passage
through llver. Further,relatlvely, it has a short
biologicalhalf-life(5 minutes).Therefore,attempts
were made to preparesynthetlcprogestins.The
syntheticproges-tins can generallybe divicleclinto
two main classes.-
Norethynoclrel (a) 174-hydroxyprogesterone clerivatives
(b) 19-nortestosterone derivatives.
(2) Modlflcatlons at t7a-hydroxyprogesterone :

C=O
:----OH

9H,
Norgestrel
I 7 c-hydroxyprogesterone
(i) Actlvity of l7 ct'hydroxyprogesterone is
ehhanceclby
(a) Unsaturation at posltlons6 ancl7.
(b) Substitution of a methyl group or a
halogenatom at sixth carbonand
H O- N (c) Introclucing a methylgroup at positionI 1.
Norgestimate The above modifications probably prevent
OH metabolicrecluctionof the two carbonylgroups
C=CH anclmetabolicoxidationat position6.
HzC (ii) Substitutionof a fluoro group at position
Zl prevents hydroxylationat this point and
enhancesthe oral effectiveness.
(iii) Inversionof the conffguratlonat positions
1O and 19 in progesteroneleads to retroproge-
Desogestrel steronewhlch is more activeparenterallyanclorally

OH
9H, :---C = CH C=O

C
I
H.i
I

Retroprogesterone
Lynestrenol
Principles (Vol.ll)
of MediciiplChemiatry 3l Stsrold!

than progesterone. Further unsaturation at

positions6 and 7 gives clydrogesterone
which ts OH
orally active.

C =O

Ethisterone
(iD Removalof 19-CH3group (19-noranalog)
further decreases its anclrogenic activity.
e.g. norethisterone.
Dyclrogesterone OH
(iv) A progestinwith a prolonged duration of
actionis 16 a, 17-clihydroryprogesterone aceto-
phenide, which is clevoid of androgenicand
oestrogenicactivitieswhen given parenterally.

C =O
Norethisterone (19-noranalog)
(iii) Following moclificationsof t9-nortesto-
steroneleadsto even more effective progestins.
(a) Substituting a chlorine atom at C-21or
adclinga methylgroupat C-18.e.g.

l6 a, 17-dihydroxyprogesterone acetophenide
(3) Modlflcetlons of t9-nortestostcronc
nucleus :
(i) lntroductionof an alkyl group at C-17 of
19-nortestosteroneblocks its oxidation to
inactive compounds and increasesits proge-
stationalactivity.
OH
OH
Norgestrel
(b) Unsaturationof the rings B or C.
(c) Introcluctionof halogenor methyl at 6 a
or 7crpositions,e.g. Dimethlsterone.
(d) Acetytationof the 17 P -OH results in
longerdurationof action e.g. Ethlnodloldiacetate.
(e) Removal of the keto function at C-3
e.g. Lynestrenol.

OH

| 9-nortestosterone
As in l7 a-ethinyl analog, increasingits
electron clensigl (- C = CH -) at C-17, one can
simultaneously decrease its anabolic activity
and promote good progestational activity
e.g. ethisterone.Ethisteroneis an orally effective
progestin,with slight androgenicactivig. Lynestrenol
Itmciltcs of MedicinalChemistry(Vol.ll) s5
Thishormoneis usedas a contraceptiveqgent
h combinationwith an estrogen.
SAt of ll-subrtftutcd enelogues: Many
analogues have been synthesized to study the
effect of substitution on the potency and
selectivityof action of lynestrenol.The most
promisingline of investigationfollowed | | p-sub-
stitution, the two effectsof which are -
( | ) Bulky 1I p-substituentsinduce through l,
3-diaxialinteractionwith the l8-methyl group, a
changein the shapeof the steroid skeletonleading
to better binding to the progesteronereceptorand
clecreaseclbincling to serum proteins. This
enhancesthe potenqyof the compound.
(Z) By contrast, long substituentsinterfere
wittr the receptorbinclingand so decreasethe
potency. The potent I l -substituted analogues
were studied for their selectivig of action and this
led to the selection of clesogestrelfor further
development.lt reachedthe marketin | 981.
i---C = CH
Desogestrel
Mode of actlon :
(l) Progesteronehas a biphasic feedback
effect on ovulation i.e. first it stimulates
ovulation process and effects of oestrogens.
Followingthis initial phase, however, ovulatign and
oestrogeniceffectsare inhibited.
(2) lt has blocking effect on the rhythmic
contractionsof mvometrium.
(3) It,potentiatesthe synthesisof only one
specificovicluctprotein, aviclin.
To induce above effects, progesterone may
require gene activation and transcription of
chromosomalinformation through the stimulated
m-RNA synthesis.
Steroids
Pharmacologlcalectlons : .
It acts.on both, the endometrium(inner
mucouslining of uterus)and the myometrium
(musclemassof uterus).lt Incluces the secretory
phase in endometrium during which the
endometrialglandsgrow and secretelargeamount
of carbohydratethat will possiblybe utilised by
the fertilisedovum as a source of energy. On
myometrium, progesteronestops the sponta-
neous rhythmic contractionsof the uterus to
prevent abortion.
Therepcutlc Uscs :
(1) Preventshabitualabortion.
(2) For treatment of functional uterine
bleedingresultingdue to the lack of oestrogens
ancl progesterone.
- (3) Fortreatmentof dysmenorrhoea or palnful
menstruation: In order to reproducemore closely
conditions which are seen in normal M.C,.
oestrogensused in the treatment of clysmeno-
rrhoea may be supplemented with progestins
during the last four days of each period.
(4) Pregnanqy diagnosis.
(s)Oral contraceptives.
(6) Fortreatmentof an advancedcarcinomaof
breasts.
(71To treat premature discomfort in the
breasts.
Sldc-cffects :
The commonly associatedside-effectswith
progestin therapy are : nausea, vomiting,
drowsiness,edema,irregularbleeding,etc.
T7.7 ANDROGENS AND ANABOLTCAGEMS
Androgens or male sex hormones are
synthesizeclfrom cholesterol in the testes and
aclrenalcortex. In the liver, androgensare formed
from C-21 steroids. Small amounts are also
secretedby the ovary.
The growth and development proceduresof
male gonads are similar to those in female.The
hypothalamuscontrols the adenohypophysis
Principlesof MedicinalChemistry(Vol.ll) s6 St rdld!

through the same releasingfactorsas for fumales,

namely, FSH' RF and LH-M. Thesefactorsthen
bringaboutthe release of FSHanclLH [LH in maleis
called as interstitialcell stimulatinghormone
(ICSH)],from the adenohypophysis.
FSHpromotesspeffn developmentor sperma-
togenesis, by stimulating the seminiferous
tubules.On the other hand, ICSHstimulatesthe
interstitialleydig cells to secreteandrogens.
The active androgenicprinciple of testes is
Testosterone.lt has two main activities. Dihydrotestosterone
( I ) A steroidalskeletonis minimum structural
requirementto haveandrogenicactiviry.
OH (2) The basicnucleus5 o-anclrostanehas
androgenicactivity.

9Hr

QHr
Testosterone
(l) Androgenlc or male sex characterlstlc I
promotlng actlvlty : lt includes normal develop- I
H
ment, functioning ancl maintenance of the male
sex orgqns and sexual characteristics. 5 cr-androstane
(2) Aiiabollc or muscle bulldlng actlvlty : lt (3) Ring expansion, ring contraction and
causesnitrogen retention by increasingthe rate of change in configurationat C-5 (i.e. 5 B-series),
protein synthesis,clecreasingthe rate of protein significantlyreduceor clestroythe androgenicand
catabolismand thus promotes laying down of new anabolicactivig.
tissues. lt also stimulates the thickness rise and (4) Testosterone is not effective orally,
lineargrowth of the bonesto son'reextent. Hence becausemetabolicchangesoccur at 17-p oxygen
it helps in the developmentof skeletalmusculature which is important for the attachment to the
anclemotionalget up of male type. The distinction receptorsite. Hence 17 a-allqylgroups are incorpo-
of anabolicfrom androgenicaction is important in rated to prevent these metabolic changesand to
anabolictherapy of such wasting conditions as renderthe compoundsorally activee.g.
cancer, trauma, osteroporosis and effects of
immobilizations. These conditions necessiate
nitrogen anclmineral retention. O H
Classlffcatlon : t---CH-r
(1) Compoundswith androgenicactivity are
calleclas anclrogensand 9Hr
(2) Compounclswith anabolic activity are
calleclas anabolicagents.
It would be highly desirable but may be
impossibleto separatethesetwo activitiestotally.
Structure Acttvlty Relatlonshlps : I 7 ct-methyl testosterone
Increasing the length of the alkyl side chain at
Androgensare regardedas the derivativesof
17 u-position resultsin reducedactivity.
androstane.
(5) Esterificationof testosteroneat C-17 with
Testosteroneexerts its physiological activity
after its conversionto dihydrotestosterone. a number of acicls resultsinto in .r long clurationof
actionwhen useclparenterally.
 of MedicinalChemistry(Vol.ll)
Principlee $7 Sroids

OH
QH.'
OR t--CHr
9Hr
HOHC

Oxymetholone
Introductionof an spz hybridizedcarbonatom
Testosteronepropionate into the ring A renders the ring more planar
R = - COCHzCHT resulting,in greateranabolicactivity.
(8) Generally,halogen clerivativesof testo-
Testosterone Enanthate sterone produce compouncls with decreased
R = COCHzCHzCHzCHzCH3 activity except when inserted into positlon
4 or9 e.g.
Testosteronecyclopentylpropionate
OH
R = - COCH.CH" HO QHr
{-'cHr
(6) A hyclroxylgroup at 17 c-position does
9Hr
not increaseor clecrease anclrogenicor anabolic
activity.
(7) Several modificationsof l7 c-methyl-
testosteroneled to potent, orally active anabolic
Fluoxymesterone
agentse.g.
(Halotestin)

OH OH
9Hr
t--CH.r
9Hr

Methandrostenolone 4-chlorotestosterone
(9) Introducingan s-methyl group at C-2 or
replacement of C-2 atom by orygen results tn
potent anabolicagents.
OH
9H.t OH
T:CH.I
QHr
9Hr
QHr
H3Cr

OH
Orymesterone Dromostanolone
Principlesof MedicinalChemistryffol. ll) 368 Steroids

OH
OH QHr
QHr t--CHr
t-'CH.r
H 9Hr
9Hr c
o\-z
N

Oxandrolone 9tlr
9Hr = - - ' Cllr
The following compound preparecl by Htc--z
WiechertanclCasaris alsoa good anabolicagent. 9H.r 9Hr
OH
QHr
{-CH.r

(l l) Using Birch reduction,l9-noranclrogens

were synthesized,some of which were founcl to
be effiectiveanabolicagents.e.9.,

Methenolone ot-r
One more compouncl of interest having a
substitutionat C-1 anclC-7 is,

Q= o ct H1
I
S
9Hr 19-nortestosterone

o
OH

From the above structures,it appears that

certain substitutionsat positions l, Z, 4, 7,
ancl 17 result in compounclsof clinical
importance.
(10) Heteroqyclicrings are also incorporateclto
yielclgood anabolicagents,e.g. Norethanclrolone

OH OH
9Hr
t--CHr {-'CrHs
9H,

Stanazolol Ethylestrenol
nncites ol MedicinalChemistry(Vol.ll) 35S
, 12)T heonly compounclwith purely anabolic
D,,.[mlnrmum anclrogenicactivityis Testolactone.
Testolactone
It is used in the treatmentof breastcancer.
It has an oral anaboliceffect 2O times ancl
':rdrogenic activity 9.5 times that of I 7a-methyl-
:estosterone.
The hormone iS thought to pass through the
:ell membrane, apparently by diffilsion ancl then
)ind non-covalentlyto soluble protein receptors
:q form cytoplasmichormone-receptorcomplex.
lrese complexesrapidly get "activatecl" or "trans-
lormed",acquiringaffinity for nuclearstructuresto
which they bind almost instantaneously. Acti-
vation involves an irreversible conformational
rearrangement,accompaniedby reclistributionof
charge.
The nuclear hormone-receptor comPlex
initiatesa burst of transcriptionin specificmRNA
rhat after about 15 min is translatedto an effector
protein.
Metabollsm ;
Most of the hormone.is metabolizedln the
l i v e r. A t this prin cip al site of m et abolis m ,
restosteroneis Inactlvateclby oxictationof | 7 p-
hyclroxygroup to give androstenedionewhich
upon further reductionof 3-ketonefunctionand
double bond gives androsterone.
Testosteroneis rapiclly convertecl to 5cr-
clihyclrotestosterone in many tissues which in
fact,acts as in vlvo active anclrogen.
OH
Testosterone
Steroids
Metabolftes :
Androsterone
Androstenedione
Slde-effects :
(l ) During long term treatment, musculi-
nization in women occurs.This leads to growth of
facialhair, deepeningof the voice, and menstrual
irregularities (if gonadotropin secretion is
clisturbed).
(2) ln both sexes, retention of water
associatedwith electrolytesleads to gain in weight
in short-term treatment but may cause edema if
therapyis extencledfor long time. Edemabecomes
troublesome especially in the treatment of
neoplaticcliseases.
(3) 17 a-alkyl anclrogensmay causeaccumu-
lation of bile in the biliarylcapillariesof the central
portion of the hepatic lobules without any
obstructionin the larger ducts. Hence,if possible,
their use should be avoided in patients with
hepatic dysfunction.
(4) On long term treatment,anabolicsteroids
can suppress endogenous production of testo-
sterone and may lead to impotence after their
withclrawal.
(5) Theyare incompatiblewith many drugs.
Principles
of Medicinal
Ghemistry
Nol.ll) 3t0

Pharmacologlcelectlons and therapeutlc uscs s Anti-androgensreact through the follo

(l) Replacemcnttherapy I Given to patlents mecha-nisms:
sufferingfrom lmproper functioningof testes, (a) compete with androgens.for its recep
faulty spermatogenesisand to restore ancl sitesin the tissues;e.g., q/proterone.
PI
l
maintainsecondarysexualcharacteristics l
In those (b) inhibit the releaseof gonadotropins,e.
who haveunclergonesurgical.gastration.
oestrogens,progestins,and testosterone itself.
(Z) As an anabollcor muscle-buildlng agent, (c) exhibit pharmacologicalactions on
they increaseprotelnsynthesisand thus promote target tlssuesjust opposite of those exerted
layingdown of the new tissues. the androgense.9., oestrogens.
(3) In the treatmentof clysmenorrhoea and Clinlcalconsiderationof such compou
breastcancer. starts urlth a searchfor I
I7.8 ANTIANDN,OGENS (l) effectiveagent for the treatmentof
Compoundswhich are capableof antagonising of prostateand
the androgenicaction are known as antiandrogens. (2) mde contraceptives.
e.g., cyproterone, BOMT or non-steroidalflut- ' Spiranolactone also has been found to h
amide. They do not prevent DFil formation but some anti-androgenicactions.
inhibit nuclear retention of DHT in the prostate. r7.9 ovuLATroN
They cause feminization in male faetus. Cypro- The problem of severe concern is an e
terone is also extremely active progestin. increasingrate of populationwhich is increasing
the exponential way. Every past second
OH
associatedwith hundreds of new arrivals in
<--'CHl world. On the other hand, due to sev
advancementsin science and availability of
many life saving drugs, the death rate
comparativelynegligible.The resultingpopul
explosion severely clamagesour economi
environmentaland social aspects.The realiza
I
I about possible consequencesqf popula
Br explosionis reflectedin the develgpmentof
BOMT fielclwhich can be called ashnfi-bttility rese
The need of birth control was first realized
Margaret Sanger who started working on
F.C subjectfrom l9lo to 195O,during which she
to generate awareness about this problem
medical profession.Shewas later honouredfor
OrN work by the title 'Mother of Birth Control'.
govemmentstartedfinancingthe researchprc{
Flutamide on family planning. As a result, intravagi
CH-1 spermic\da\agentswere designedduring 1
a 2e zzar/ deazde -*ztt. /z)e z/et e)aVzzez/ d
c:o contraceptive pilk. At the same ilme
QHt fi
i---o-{-cH3 inclepenclentwork on anti-fertiligr agents r
in the designingof a number of postcoitalc
ceptives and abortifacients.The introcluction
safeand efficaciousoral contraceptiveagents
made during l97Os. This was then followed
designing of hormone-releasing, intrauteri
devices. The events of 'normal mammali
reproductive process serve as the basis
Cyproteroneacetate developmentof all these anti-fertility
 Principles
of MedicinalChemistry(Vol.ll)
Thesemeasureswere found to be usefulnot only cycle. lt is characterizedby increaseclreleaseof
to avoid conceptionbut also in the terminationof estrogen from the clevelopinggraffian follicle.
unwantedpregnancies; Thus in summary,FSH inclucesthe growth of
In order to unclerstancl the clesigningancl primaryfolliclesand initiatesthe formatircnof LH-
mechanismof action of all these anti-fertitity receptorsites in the thecacellsand the granulosa
agents, the knowleclge about the key events in the
female reproductive process is necessary.
Estrogens, progesterone ancl testosterone are the
human sex hormones whose activities appear to
be controllecl by the following gonaclotropic
hormones.
(i) Folliclestimulatinghormone(FSH),and
(ii) Luteinizinghormone(LH).
FSH ancl LH are secretecl by the actenohypo-
physis under the control of FSH-RF ancl LH-M
hormones releaseclfrom hypothalamus.The key
event in the female reprocluctiveprocess is
ovulation.
There are about 5OO.OOO p nmary follicles
present in both the ovaries of the newborn.
However, about 4OO ova are releaseclcluring a
woman's reproductivecareer.At the start of the
menstrual cycle, plasma concentrations of
estrogensand progesteroneare low. Uncler the
influence of LH-RH, FSH-RHor Gn-RH, the
adenohypophysesreleasesFSH ancl LH. As a
result,severalgraffiantollicleseach containingan
oocyte, start enlarging ancl begin clevelolringmore
rapicllythan each others. Th.uspnmaryfollicle may
get convertedto secondaryand then to tertia4r
follicleduring this follicularproliferativestage.
(a) Folllcular phase :
However, after a few days, only one follicle
continuesthe developmentprocessresultinginto
simultaneoussuppressionof growth of other
follicles. The secretion' of estrogen by the
granulosacellsof major folliclemay be responsible
for suppressionof FSH releaseand inhibition of
growth of other tollicles.The secretionof FSHis
further suppresseclby the releaseof inhibin from
the major follicle.Inhibinwas found to be pepticle
of rnolecular weight of about 2O,OOO.Other
folliclesof retarcleclgrowth then unclergoatresia.
Further growth of the major tertiary follicle
cbnverts it into a mature graffian follicle, which
secretesprogressivelyincreasingconcentrationof
estrogens that are responsiblefor causing an
increase in thickening and vascularity of the
enclometrium.This phase which is known as
follicular phase or proliferative phase thus
continuesfrom day 1 to day 14 of the menstrual
371 Steroids
layer of the cleveloping follicle. The er..ogen
secretion in the granulosa layer oF the folticta is
then initiatecl through the activation of these
receptor sites by the circulating LH. The secreted
estrogensthen leaclto
(a) Suppression of releaseof FSH.
(b) Suppression of the growth of other
follicles,ancl
(c) Proliferationanclvascularizationof uterine
endometrium and development of estrogen and
progesterone receptorsites in it.
Sccondary 'fertiary
folliclc folliclc
I)rimnry It,tature
folliclc graffian folliclc.
B listcr hke
btrlgc
stig,rna)
)
flg. 17.5 : folllcular phase
During follicularphase, the tertiary follicle
steaclilyincreasesin its size. At one point of the
follicle, bllster like bulge appears.Unclerthe
influenceof estrogens,thin ancl watery vaginal
and cervicalsecretionsincreasewhich facilitatethe
spermmigrationat the time of ovulationancltotal
endometrial reconstructionbeglns. Estrogens
inclucea markeclmitotlc actlvlty causingan
increasein the numberof cell-layersof the vaginal
epithelium.
(b) Ovulatory phase :
Furtherthinning of the stigma wall occursdue
to ever increasing size of the mature graffian
follicle. On about 14th clay of the cycle, the
increasingconcentrationof estrogens in the blood
exerts action upon hypothalamus to cause a
suclclen but shor\-lived increase in plasma
concentrationsof LH ancl FSH.This associated
with an increasein follicular pressure due to
increasedcontractionof smooth musclesin ovary
causesgraffian follicle to rupture. The released
matureclovum then begins its journey along the
oviduct to the uterus.
 cn
of Medicinal
Principles Ool. ll)
Chemistry
<-- M afurcdovurn
Rupturedfolliclc
Dcvelopittg
corpusluteum
llg.,17.6 : Ovulatory phasc
After the ovum is released,the ruptureclfiollicle
undergoes structural changes. The cyst collapses
and the lining cells undergo lutenization'The cells
get arranged in a compact way through which
furtherenlargementof the cells is inhibited.Under
.the influenceof LH, the empty follicle changesto
corpus luteum which secretesprogesteroneand
smalleramountsof estrogens.Life span of corpus
luteum during non-pregnant cycle averages to
about 1 I days. lf fertilization occurs, the
clevelopingplacenta releaseshuman chorionic
gonadotropin(HCG)which helps to maintainthe
functioningof corpus luteum (i.e., secretionof
progesterone)till placentatakesover the charge.
The placental protein, human chorionic
gonadotrophin, is a glycoprotein having two
subunitsa and p, the former shared in common
with LH and thyroid stimulating hormone.The p
unit, although itself inert, determinesthe unique
biologicaland imrnunologicalpropertiesof human
chorionicgonadotropin(HCG).During pregnancy,
HCC helps in maintenanceof corpus luteum and
steroid procluction by corpus luteum (luteotropic
activity). In vivo, exogenous HCG given to
support the luteal phase raises hormone levels,
,prolongsthe lifu of the corpusluteum and exhibits
a placentotrophic effiect.lt can be recommendecl
as the safu treatment of choice for women with a
history of habitual abortion.
(c)' Luteal phasc:
This phase is characterizedby the formation of
the corpusluteumwhich continuesthe secretion
of progesteroneUnder the combinedinfluenceof
estrogensand progesterone,the uterine endo-
Steroids
metrium develops further. Glands become
elongateci,tortous and full of mucous. Other cells
of endometriumincreasein size and number.The
blood vesselsbecome dilatectand there is some
exudationof fluid into the uterine cavity. At this
time, the ovum reachesto the uterus. Thus the
phase preparesendometrium to receive ancl to
imbecl a fertilized ovum. Estrogen ancl
progesterone act at the level of uterus ancl
endometriumin sequentialfashionto stimulate the
growth and differentiationof the endometriumin
preparationfor embryo implantation.
lf fertillzatlonof ovum does not take place
upto about 26th clay of the cYcle,corpus luteum
degeneratesdue to the action of prostaglanclin
F261, which is secreted by the uterine endometrium.
This resultsinto decreasedprogesteronesecretion
which causes the superficiallayers of the
endometrium to break dolyn' Four to five days
before menstruation, endometrial growth ceases.
The bloocl flow decreases and dehydration of
stroma occurs. On about Z8th clay.,the concen-
tration of estrogens anclprogesteronebecometoo
low to maintain the vascularisationof the endo-
metrium. The necrotic endometrium gets
fragmentedand the surfaceepithelium breaks.The
shed endometrium then leaves the body together
with mucous and bloocl from the ruptured
enclometrialglands and blood vesselsin the form
of menstrualflow. Menstrualqycle variesfrom 19
days to 38 days in normal women' However in all
the cases, a fairly constant interval of about
14 days can be seen betiveen ovulation and
menstruation. The menstrual volume usually
rangesfrom 25-30 ml per q/cle. F{owever,in some
casesit may vary from 5 to 60 ml' Menstruationis
usuallyaccompaniedby pain, headache,nausea,
vomiting abdominalpain and diarrhoea.
lf fertilization occurs before the 26th day of
the cycle, the corpus luteum persists,grows and
continuesto secreteprogesteronewhich helps the
endometrium to remain in favourablecondition'
The increased plasma level of progesterone
suppressesthe secretion of FSH and LH through
feedback inhibition and thus prevents further'
ovulation during pregnanqy.The corpus luteum c.,f
pregnancypersists for about six months'but its
secretions reduce gradually as the placenta
develops to its own caPacitY.
Principlecof MedicinalChemldryffol. ll) 373 Sterc*b

h0
F

1 0t, '= Jv
Y t(
()

o+U y tJ

q)
o
Uzo o<
o t).,
rr'1

0
l4 l8 22 2g Days Days

tlg. 17.7 : Plasma levels of sex hormonesdurlng menstrual cycle

r7.ro GYNECOLOG|CAT
DTSEASES (e) Ollgomenorrhea : ln normal cases, the
Various clisordersaffecting the functioning of time gap betweentwo successivemenstrualflows
normal female reprocluctive system have been is of about 28 days.lf this time gap is increasedto
ictentifiecl.These are mainly clue.to either altera- 35 claysor more, it is known as oligomenorrhea.
tions in the hormonallevelsduring menstrualqycle When the intervalis largerthan six months,the
or due to microbial colonization in the female term, amenorrhea is used.
genital tract. (0 Polymenorrhea : When the interval
(a) Menopause : The term is useclto inclicate between two successivemenstrual flows is less
a cleclinein the function of the ovariesusually than 21 days, it is known as polymenorrhea.The
cluringthe age of early 5Osof the woman. This is bleeclingvolume may or may not be normal.This
the encl of female reproductivecareer. No ovu- situation mainly arises due to the failure of
lation takes place. Menstruationceases.Thereafter ovulation.
a graclualcleclinein the secretionof estrogenby (g) Metrorrhagla : In this conclition,besicles
the ovaryloccur over a prolongeclperiocl of time menstrual flow at stipulated time, abnormal
(b) Dysmenorrhea : The term is used to bleeclingoccursat any time cluringmenstrualqycle.
describe painful menstrual periocls. The main The bleecling may range from spotting to
symptoms include nausea, vomiting, fatigue, haemorrhagicflow. The common causeis uterine
cliarrhoea,heaclache,ancl spasmoclicpains in the malignancy.
lower abclomen ancl in the thighs. The (l) Enclometrlosls: The main symptoms
prostaglanclins(PGE2anct PGF2s)released in the incluclepelvic pain, dysmenorrhea,infertiligrancl
enclometriumduring menstrual cycle are respon- relatecl menstrual problems. Some enclometrial
sible for most of these symptoms. Hence most of tissues migrate to ovary, blaclcter, uterus,
the cases of clysmenorrheacan be relievecl by the appendix,gall baclcler,lungs ancl other unusual
use of ibuprofen or naproxen-likenon-steroiclal placeswhere they proliferateanclgive responses
anti-inflammatoryclrugs.ln few cases,clonidine to sex hormones.Thus enclometriosisis chara-
may become effective especially when etiology cterizeclby the growth of clisplaceclendometrial
involves excessive stimulation of the uterus bv t issues.
aorenergtcnerves. (l) Premenstrual syndrome (PMS) :ltis
(c) Hypomenorrhea (spottlng) : The term characterizedby anxiety, irritability, headache,
refers to scanty flow during regular flow. The abclominal distention, constipation, urination,
bleeclingmay be so slight that it is called as insomnia, confusion ancl depression. The
spottrng. conclitionmay be treateclby drugs like spirano-
(d) Hypermenorrhea (menorrheagla) : lt is lactone, pyridoxine ancl progesterone. In
just an oppositeto spotting. lt describesabnormal refractorycases, clonidine, alprazolamor GnRH
profuseflow cluringregularperiocls. agonistscan be usecl.
 Principlcaof MedlcinalChemistry(Vol.ll) c74
(k) Vaglnhls : In normal woman, the vaginal
pH rangesbetween4.5 to 5.5 clueto the presence
of various aerobicand anaerobicmicroorganisms
which catalyzesthe conversionof glycogen to the
lactic acid. The thick vaginal epithelium consistsof
various species of bacteria including Clostridia,
Streptococci,Coliform bacteriaand Lactobacillus.
Normally cervicalmucuos,possessesantibacterial
activigr and contaifi3'lyso4yme.
in conditions(e.9., menopause).
aginal epithelium occursalongwith
i change of pH from acid to alkaline range. The
lactobacilli count clecreasesand the cervical
mucous secretion declines. ln usual cases,
vaginitis is characterizeclby itching, burning,
physical cliscomfortancl changes in the vaginal
clischarges.
(l) Atrophlc (senlle)vaglnltls : The alkaline
vaginalpH alongwith decreasedcervicalsecretions,
leacl to increased vaginal infections. In senile
vaginitis, atrophic changesoccur due to chronic
infection. Estrogen therapy becomes useful in
most of the casesto restore back the situation.
(m) Vaglnal candldlosls : The conclition is
characterizedby the presenceof Candida albicans
in the femalegenital tract and bowel. In few cases,
Candidaglabrata may be colonizecl.However, no
severe symptoms are usually associatedwith this
conclition.
(n) Trlchomonas'vaglnltls: In this clisease,
usuallyvaginaand lower urinarytract of both, male
ancl female get attackecl.The symptoms inclucle
itching, burning, postcoital bleeding etc. The
vaginaldischargerangesin colour from milclyellow
to green. The diseasemay get transmitteclto male
from femaleduring sexualrelationship.
I7.T I OR,ALCONTR,ACEPTIVES
Populationhas been increasingwith an ever
increasingrate in an exponentialway. As far as
India is concerned,in the beginning of the ZOth
century, the country hacl a population of
23.8 crores.Now it has more than 9O croresinspite
of its division.Thispopulationexplosionis neecled
to be controlled in orcler to avoicl its adverse
effects on the country's economical, social ancl
environmentalaspects.The awarenessabout the
adverseeffiectsof population explosion began to
clevelop in the medical fielcl that was reflecteclin
the emergence of a new field "anti-fertility
research".The principle of hormonal contraception
Steroide
was known since 1919, when Haberlandt
implanted ovariesfrom pregnant rabbitsunder the
skin of normal fertile rabbit and found that these
animals beqame infertile. This shows that
hormones releaseclby the ovaries can prevent
pregnanqy.The use of the female sex hormonesto
prevent the developmentof the female egg was
suggesteclas early as 1940. For example,it was
known as back as the beginning of this century
that extracts of corpus luteum could be usecl to
inhibit ovulation. In 1944, Bickenbach and
Paulikovics showecl in a pilot experiment
(l patient) that a ctaily iniection of 2O mg of
progesteronecoulcl inhibit ovulation. Due to the
low solubility of progesterone, it became
impossible to prepare concentrateclsolutions
suitable for in.iection.Injections of crystalline
suspensionsof progesteroneare painful,and this
method of aclministrationwas not attractive for
contraceptivepreparations.In orclerto make it a
usefulapproach,potent anclorally active steroicls
hacfto be founcl.ln 1944, after Bickenbachand
Paulikovicsshowecl that progesteroneaclmini-
stration coulcl inhibit ovulation, Pincusancl his
associatesthen at the Puerto Rico family planning
centre,starteclextensivefield studiesin 1955. on
the use of steroiclalhormonesin oral contraceptive
pilfs.The ten yearsfrom 1960 to 1970haclbeen of
extreme importanceto this fielctof fertilitycontrol
resulting into clinical introduction of oral contra-
ceptivepills.
Ethisteronewas the first orally active progestin
However, its oral activity was still low that initiated
further SAR Stuclies.The first anti-fertility clrug to
be marketecl was ENOVID,a combination of
norethynoclrel(a progestin) ancl mestranol (an
estrogen) originally introclucedin 1957 for the
treatmentof menstrualdisorders.
OH
= CH
Norethynoclrel
Prhclplesol McdicinalChembfy (Vol.ll) ct6 Sroittr

OH
:---C = CH
OH
= CH
----C

H3CO
Mestranol
The exact clurationof survivalof the sperms in
the vagina is not known with certaingrbut it is
believedto be about l-2 hours.Immecliatelyafter
the coitus,they can remainactive for about 4O-45
hoursin the cervixanclthe uterinecavitv.
Apart from the coitus interruptus,theoretically
the furtility can be controlleclby :
(i) Controllingthe centralmechanisms.
(ii) Preventingthe union of sperm with ovum
by usingphysicalor chemicalbarriers,ancl
(iii) Using clrugsthat moclifuthe physiological
mechanismsinvolved in reprocluction.
Since hypothalamus plays a key role in
controlling the gonaclotropinsections,emotional
factors ancl drugs acting on hypothalamuscan
havean effecton ovulation.Forexample,irregular
menstrualbleeclingis known in nurseson night
duties and in air hostessestravellingover a long
distance.Similarlytranquilizerslike chlorpromazine
anclreserpineare reportectto moctiflrthe menstrual
perioclin women.
Following are the proposecl mechanisms
through which fertility can be controlleclwhen
steroidalhormonesir€ usecl:
(l) Inhibitingovulation
(2) Modifuin.g
the cervicalmucous
(3) Slowing down the rate of ovum transport
(4) Preventingthe ovum maturation
(5) Interfurringwith the implantationprocess.
(6) By inhibitingspernatogenesis in males.
Most of the oral contraceptivepreparations
contain both, an estrogen ancl a progestin at
varyrngclosage ratios. In estrogens, ethinyl
estradiol,mestranolancldiethyl stilbestrolare the
most commonly used agents. Mestranolacts as a
prodrug which upon in vivo hepatic metabolism
gets converted to ethinyl estradiol.
RO
Ethinylestracliol;R =H
Mestranol:R = CHr
C=C OH
I
czHs
Trans-diethylstilbestrol
Diethylstilbestrolmay be useclas a postcoital
contraceptivewith certain precaution.In progestin
series, usually clerivativesof l9 nortestosterone
are used as component of oral contraceptives.The
series began with ethisterone,the first orally
effective progestin. lt was developed by lnhoffu-n
et al from the male hormone testosteronethrough
the aclclitionof | 7 c-ethynyl group. lt resultsinto
a substantialdecreasein the androgenicproperty
with significant progestationalactivity. Other
members of the series inclucle,norethisterone,
norgestrel, lynestrenol, norethynoclrel,quin-
gestanolacetate,ethinoclioldiactate,etc.
OH
:--'c : CH
Ethisterone
OH
9Hr CH
Lynestrenol
Most of these orally active progestinsact as
the proclrug ancl get converted upon in vivo
metabolismto norethisterone.
Both the components (i.e. estrogen and
progestin)bring about their contraceptiveeffectin
the synergisticfashion.

Principlesof MedicinalChemistrygol. ll) 375
Though oral contraceptivepills containing
higher doses of progestin are more effective,
estrogen is required for good cycle control.
Reducingits quanti\r may result in a greater
inciclence of breakthrough bleecling. The larger
doses of progestin alone, may cause ovarian and
enclometrialatrophy and variationsin the levels of
FSH ancl LH may also occur. While if estrogens
are used alone, that may to enclometrial
hyperplasia.It also helps to proclucecomplete
sheclclingof enciometrium.Later it was founclout
that most of the side-effects of oral conrra,
ceptives are mainly clue to its estrogenic
component. For example, the estrogen is respon-
sible for nausea,headache,weight gain, hyper-
tension, thromboembolic ancl relatecl vascular
diseasesalongwith clisturbancesin carbohyclrate
ancl lipid metabolism. This leaclsto a graciual
lowering of the close of estrogens in the contra-
ceptive pills. Currentknowleclgesuggeststhe use
of those contraceptivepills in which the estrogen
contentsis lessor equal to 50 pg. A step aheaclto
this, minipills (progestin only) were clevelopeclin
order to eliminateestrogencompletely.Minipills
may be goocl choicein lactatingwomen or patients
who are sensitive to estrogenic adverse effects.
Types of oral contraceptlvcs :
The following are the most commonly
employeclmethoclsto effect contraception:
(D Combinationpreparations
(ii) Sequentialpreparations
(iii) Minipills (or Progestinalone)
(i v 1 Morning after or postcoital pills (or
estr{}genalone)
(v ) Vaginal contraceptive or spermicidal
agents
(vi) Interceptivesor abortifacients
(vii) Progesteroneblockers
(viii) Depot preparations
(a) Once-a-month preparations
(b) Intrauterineclevice
(c) Bioclegraclable sustain release
systems.
(cl) Non-bioclegraclable subclermal
implantsanclvaginalrings
(ix) Chemical contraceptives for men or
antianclrogens.
(i) Comblnatlon preparatlons:
The most common type of oral contraceptive
is the'combinationpreparationwhich containsa
progestinancl an estrogen.ln this, ovulation is
inhibiteclby the progesteroneplus an estrogen.
-
Steroids
The combinationpreparationsare taken for 2i
clays, beginning from the 5th day of menstrua-i
cycle. These steroids initiate the development oi
endometrium into the form seen in the proge-
stational phase of menstrual cycle. The fall oi
estrogen and progesterone levels at the end ci
treatment stimulatesthe shecldingof the enclo-
metrium leaclingto regular bleecting.Bleeding
usuallyfollows after a 2-4 clayslatent periocl.The
next courseis startecl7 claysafter the last dose or
5 days after the onset of menstrualcycle.
Thus "fhree weeks on medication and one
week off medication"is the general rule. In some
cases,a 28.claysregimerris given which include
6-7 inert tabletsor tabletsfor ferrousfumarate.
These preparationsgenerally contain 0.02 tc
O.l 5 mg of an oestrogen (commonly used estro-
gens are ethinylestracliolor mestranol)and varying
amountsof a progestin(e.g.norethinodrel, ethino-
cliol cliacetateor norgestrel).Efficaqyof the combi-
nationpills is clueto the inhibitionof ovulationb.
suppressionof the micl-qycleburst of LH.
Thereis now an increasingtenclencyto reduce
the amount of each steroicl in the preparatior:
without any loss of the contraceptive effective-
ness.Most of the preparationscontain 5O pg oi
estrogen but in a few preparationseven smalir.'
amountsare Present.
(ll) Sequentlalpreparatlons :
ln this methoclwhich is no longer used, the
tablets to be taken for the first 15 clays (starting
on clay 5 of the cycle) contain only estrogenwhile
those supplieclfor the next 5 days are of combr-
nation type (i.e. contain estrogen ancl progestin
Estrogenacts by inhibiting ovulation mainly b-.
blocking FSH releasewhile progestin promotes
maturation of the endometrium and facilitates
withdrawal bleeclingwhich generally begins 2-4
claysafter completing the regimen.The absencec.
progestin at micl-cyclein this preparationma,
accountfor higher rate of failure in comparisonrc
the combinationpills.
Becauseof increasinginciclenceof endonretria
tumours and a lower efficacyassociatedwith this
type, sequentialpreparationsare less reliableanc
less popular than combinationpreparations.
(lll) Mlnl-pllls or progestln only :
To reduce some of the risks associatedwirf
the use of higher closesof estrogens,this type is
developed which contains a small dose o'
progestinsonly anclis taken daily without the druE
free interval. Mini-pills are not as reliable a-.
Principles
of Mediclnal flol. il)
Chemistry ct7 Sterc*ls

combinationpreparationsand progestinsalone are (2) Bactericicfes

: e.g., phenylmercuric
acerare.
likely to permit "breakthrough"bleeding.They are benzethoniumchloricle,methylbenzethoniurn
only currently used in women who exhibit chloride.etc.
intolerancetowards estrogens.Sincethey are less (3) Acicls ; Boric acicl, tartaric acicl and
effective, pregnancy is possible during their
administration. phenols.
Meclroxy progesteroneacetate or chlorma- They must be appliecljust before the inter-
clinone acetate do not inhibit ovulation but coursecleepinto vagina.The contraceptivefoam is
interferewith the enclometrium,cervical mucous marl<eteclin the form of aerosol. Recently a
and perhaps the physiology of fallopiantubes. clisposable,polyurethanefoam sponge impreg-
Their use preventsmost of the side-effectsof oral nateclwith nonoxynol-9has been marketeclwhich
contracepuves. can be easily removeclfrom the vagina after the
(lv) Postcoltal or Mornlng after pllls : coitus, with the help of a rlbbon loop attached
"Morningafter"contraceptivepill are used to
to it.
prevent implantationof the ovum after some
hours of the fertilization.They are intendeclonly (vl) Interceptlves or abortlfaclents :
for emergencyuse. Forexample,for rapevictims. Thesesubstancesare capableof preventing
Starting no later than 72 hours after the coitus, further development of the fertilizeclovum even
ctiethylstilbestrol
25 mg must be taken twice a clay after the implantation has occured. Hence, they
for continuous 5 clays inspite of nauseaand are also called as abortifacients.
Examplesinclude,
vomiting which commonlyoccur.Sinceestrogens ergot alkaloicls,prostaglanclins(PGEZ,PGF2 s) ancl
clo not interferewith fertilization,thesepills will be
ineffective once implantation has occurecl.The their analogues.Salineinducedabortionshavealso
chronicaclministration may be
of cliethylstilbestrol been used in the past.
unpleasant and dangerousin some patients.These
pills incluceenclometrialchangesresultinginto
inhibition of implantationthrough hormonal ,'#cooH
imbalanceand the estrogensalso have luteolytic CH.,
(breakclown of corpus luteum) action.They also
alter the rate of ovurn transportation.Ethinyl I
estradiol5 mg daily to be takenfor continuousfive OH
days can also serve the function. Withdrawalof
PCE?
large doses of estrogen induces bleecling. Hq
Extenclecl period of therapyis necessary in certain .'*cooH
cases.Sinceestrogensare usedat relativelyhigher
concentration,it may result into productionof cHr
aclverse effectslike,eclema,menstrualirregularities,
thrombophelbitis, etc. I

(v) Vaglnal contraceptlves or spermlcldal OH

agents 3 PGF2a
Theseagentsfall Into three categories:
(1) Surfaceactive a3:enfsor sulfltydrylbinding
(vll) Contraceptlon by uslng progesterone
agents: e.g., Nonoxynol-9,otoxynol, etc. They
blockers :
act by solubilizingthe sperm membrane,thereby
causingrapiclimmobilization and celldeath.The uterine endometrlunnls kept in the
conclitionfavourablefor lmplantationancl main-
tenanceof pregnancyby varlousproteinswhose
(ocHzcHz)s synthesis is governed by progesterone incluced
cH s -(cHz)z - CHz - oH activation of DNA-clependentm-RNA. Proge-
sterone blockers may termlnate the pregnancy
Nonoxynol-9 through their interferencewith the binding of
progesterone to its receptorslteson the chromatin
material.The interferenceis causedthrough the
(cH3)3-c- o(cH2cH2o)sH competitiveantagonismof progesteroneby these
agents.These agents are usuallyadministerecl
CHs postcoitallyor monthly to induce progesterone
Octoxynol-9 withclrawalbleeclingand abortions._
Prlnclpler ol iledlclnal Chemlstry(Vol.ll) gt8 SteroC

ococHr
cHs N :---C = CH

OH
t__-C=C - cHs

o \z Quingestanolacetate
Even longer protection can ,be secured
glving largerintramuscular dosesof progestin
RU486 (Mlfepristone) Forexample,medroxyprogesterone acetatein
of l5O mg every three months, norethister
Mifepristoneacts as progesteroneantagonlst oenanthatein closeof 2OOmg every nine w
ancl causesbreakdownof the endometrlumand ancl norethinclrone enanthatein dose of 20O
dislodging of the fertillzedovum. Prostaglandin E1 every 12 weeks.'Ttre long'term use of th
preparatlons,however,ls not recommended
or Ez analoguemay sometimesbe used with RU to the associatecl risk of i:ermanentinfurtility.
486 to enhancelts efficiency. (b) lntra-uterlne devlce (lUD) r
.(vlll) Depot preparatlons : These are medicated devlces lntendec
(a) Once-a-month preparatlons : releasea small quantity of drug lnto the uterus
Thesecontalna long actlng estrogencomblned sustainedmannerover prolongedperioclof ril
wlth a short acting strong progestln.Theseare These contain progestln. The progestasert -
contalns a total of 38 mg of progester
taken for the first time on day 22nd of a normal
clispersed in the slllcone oll wlthln flex,'
menstrualperiod ancl every 28 days thereafter. T-shapeclpolymer that releasesabout 65
Fg
The short acting potent progestininducesnormal of progesteroneinto the uterlne area for
bleeding shortly after the aclminlstratlonof the I year to exhlbit effective contraceptive
tablet. The estrogen, however, by vlrtue of its without causlng the systemlc side-e
slow releasefrom fatt5lstorage sites, inhiblts the assoclateclwith other forms of horm
ovulationexpectedin the next cycle.An oll-filled contraception.Yet anotherIUD contains52
capsulecontalning2.0 mg of the long acting progesteroneand clelivers about 65
estrogen (e.9., 3-cyclopentylether of ethlnyl progesteronedaily for about two years.
estradlol, qulngestrol, etc.) and 2.5 mg of the
progestin(e.g., qulngestanolacetate)is glven after
eveqr4 weeks. Due to lts lower efficaql, the pill ls
less popularamongstthe users.

OH
:---C = CH flg' 17.9: lntre-utcrlnc dcvlce
The sllicone oil provldes thermodyn
ener$/ necessaryfor efficientdiffuslonof the
from the reservolrinto the uterlnecavi$1.Oncc
IUD is left in the uterus,it remainseffuctivei
long as three years. An additlonalcontrac
effiectis exerted by the releiaseof copper fror
IUD which interferes with the biocher
Quingestrol processesthat regulatelmplantatlon.
 Prhciplesof MediclnalChemlstryflol. ll) r/9 *rob

Though lUDs are devoid of usual adverse examples of drugs from this category include
effectsassociatedwith oral contraceptivepills due cyproteroneacetate, nitrofurazoneand myleran.
to their local and non-systemicaction, other side- Androgen-estrogencombination(17 c-methyl-
effects like, bleeding and pelvic inflammatory testosterone,
conditionsare usuallyassociatedwith their use. lO mg and ethinylestradiol,20 tg)
can be usedto glecrease the spermatogenesis. The
{c) Blodegradable sustaln release systems : sperm count returns to normal upon disconti-
It includesthe use of biodegradablepolymers nuation
and microparticlesto releasethe estrogen and of the therapy.
progestin. Releaseof active clrug occurs by cH"
erosion,diffi.rsionand cleavageof covalent bonds I o
C=O
betweenthe drug and the polymer. tl
Polymermatrixesincludecaprolactone,gluta- <---ff_{H3
mic acid,lacticacid and glycolicpolymers.
(d) Non-Blodegradable subdermal lmplants
and vaglnal rlngs :
The contraceptive effect for more than five
years was observecl from non-biodegradable
implantsin which 2OOmg of levonorgestrelwas cl
incorporatedin 2O.4cm of polydimethylsiloxane Cyproterone acetate
tubing. The diffi;sion of the clrug occursthrough Danazol,a gonaclotropin inhibitorin females,is
the silicon rubber tubing at the rate of also active in males if taken together with long
0.O3Omg/day. However, the implant has to be acting testosterone derivative. Gossypol, a
phenoliccompounclisolated,from cottonseedoil
OH has direct antispermatogenicactivity. lt has partly
irreversibleside-effects.Only (-) enantiomerof
:---C: CH gossypol is active as a male fertitity regulating
agent.

CHO OH
Levonorgestrel
removed by. microsurgeryafter its use. Due to the
cosmetic problem involvecl in the removal of cH-r
implant,vaginal rings have been developeclwhich cH(cH1)2
consistof a polyclimethylsiloxanecore with a thin
layer of levonorgestrel and estradiol (in 2 : I
proportion).This in turn is covered with a thin Gossypol
difrlsion layerof polydimethylsiloxaneto form a Upon chronic treatment, cholestasis,liver
ring structure. dysfunctioningand cardiovas'cularproblems may
(lx) Chemlcal contraceptlves for men or antlan- be initiated by these preparatlons.
drogens: (x) Mlscellaneous contraceptlve mcthods :
It is the most rarely used methocl. Anti- Besidesoral contraceptivepreparations,other
androgenscan be used to suppressspermato-
ways to - achieve fertltity control, coitus
genesis.However,the drug administrationmay
also lead to impotenqyanclloss of seconclary interruptus,rhythm method, appllcation of cap
sex (the
characteristicsin males. Hencethe antiandrogenis diaphragmand cervical caps) and loop, etc.
usually adrqinisteredalongwith a high dose of can be usecl. The sterilization methods are
androgen to achieve synergistic suppression availablefor both. males (Vasoctomy) ancl for
of gonadotropins and spermatogenesis.The females(Tubectomy).
Principlesof MedicinalChembtry(Vo!.ll) 3f)
Variousarssays and screeningtechniquesused
in anti-furtilitystudiesare mainlycategorisedas :
(A) Tests lnvolvlng centrally actlng mecha-
nlsms :
(i) lnhibition of gonadotropin secretionand
ovulation.
(iD Inhibition of releasing factors from the
hypothalamus.
(B) Tests lnvolvlng perlpherally actlng mecha-
nlsms :
(i) Regulationof uterine-cervicalsecretions,
(iD Inhibitionof implantation,and
(iii) Preventionof sperms capacitation.
I7.I2 PEAR,L INDEX
Results of anti-fertility studies about a
particulardrug in women are evaluatedin terms of
PearlIndex which is defined as the pregnanqyrate
per I OOwomen vurses years of exposure.This
term is thus an indication about the potenq/ or
efficaqyof the contraceptivepreparation.
Number of pregnanciesx l2OO
Pearlndex =
Total months of exposure
Table 17.4 : Contraceptlve fallure rates
Pearl
Method lndex
Nocontraception 80
Spermicides, rhythmmethod,coitus 25
interruptus
Condomsanddiaphragms 10
Intra-uterine
contraceptive
devices 2 (a) Oral contraceptive preparation,upon
Sequential
typecombinedoralconlraceptives 0. 5
Combinedtypeoralcontraceptives 0.1
Sterilization 0.02
I7.I3 MECHANISMOT ACTION
Femalesdo not ovulate during pregnanq/, a
time in which there is high levels of circulating
blood progesterone.This observationservedas a
basis for clevelopmentof oral contraceptivesin
general and combination preparation more
specificallywhere an estrogen is usuallycombined
with a progesterone in order to achieve full
efficacy. Due to the painful nature of cqrstalline
suspensionsof progesterone(becauseof its low
solubilitlr),attempts were made to develop orally
effective progesterone derivatives (progestins).
The prominenteffect of estrogenis to inhibit the
releaseof FSH(i.e.,inhibitionof growth of bllicles).
While continued action of progesteroneserves to
inhibit the releaseof LH (i.e. inhibition of the
release of matured ovum through ovulation
process).
Steroids
Followingare some proposeclmechanismsto
explain the anti-fertility action of the oral
contraceptivepreparations.
( I ) The primary mocle of action of the oral
contraceptive seems to involve blocking of
ovulationinhibitingthe secretionof hypothalamus
through feedback inhibition. In combination
therapy, estrogen component owes its
effectivenessmainly by inhibiting ovulationwhile
progestin seryes the major purpose of ensuring
promptwithdrawalbleeding.
(2) The correcthormonalrequirementwhich is
essentialfor the execution of proper functioning
of cervix, uterus and fallopiantubes to promote
fertilization, is clisturbed and cannot be
maintained.Fqr example, under the influenceof
progestin, atrophic endometrium often results.
lmplantationbecomesdifficult within such alterecl
endometriumenvironment.
(3) At the time of ovulation,the cervicalcell-
lining is favourablefor sperm migration towards
uterus. Thin and watery nature of cervical
secretionsfacilitatesperm penetration.However,
progestincausesthe cervidalmucous to become
veryrthick tenaciousanclthus provides a barrierfor
the passageof sperms through the cervix and
reducesspern survival.
(4) Progestinalso alters motiliry-rate of the
ovum by altering fallopiantube secretions.
EITICTS
r7.r4 ADVEnSE
administrationmay causenausea,vomitin.g(mainly
due to estrogen),heaclache(migrainelike, clueto
estrogen inducecl increase in cerebrovascular
pressure), corneal defects, photosensitivity,
retinal thrombosis, optic neuritis (all due to
progestin component) megaloblastic anemia,
breasttenclerness,ischemiccolitis, abnormalhair
growth, acne,and chloasma(skin hyperpigmenta-
tion). There occurs weight gain partly due to
anabolic testosterone like progesteroneactivity
and partly due to water and salt retention in the
bocly.Their administrationleadsto.higher plasma
levels of glucose ancl triglycerides.Upon chronic
administration, oral contraceptive agents may
induce hepatic lesion especiallypeliosishepatica
and hepatic adenomas.However the most serious
sicle-effectsof these agents include, their effect
on cardiovascularsystem ancl their tumorogenic
effect.
Principles
of Medicinal
Chemistry
flol. ll) 381 Ster<*ts

Table 17.5 : Progestogen-onlylnlectlons and aclministrationmay be beneficialunclerall these

lmplants for very long-term contraceptlon circumstances.
steroid Tradename Dosage regime (b) Tumorlgenlceffects :
Medroxyproge- Depo-provera150mgi,m,every Thiseffectis mainlyexertedon the organslike,
steroneacetateDepo-Clinovir3 months vagina, uterus, breast and liver. These benign
150 tumoursmay get earlyruptureddue to their high
NorethisteroneNoristerat 200m9 i.m.every vascularityresultinginto haemorrhage.Both,
oenanthate 9weeks or12weeks estrogens ancl progestin are responsiblefor
Megestrol 115mgasimplants tumorigeniceffectsupon long term aclministration.
acetate everv12-15 months Foc*rlnoclularhyperplasiaanclliver cell adenomas
Chlormadinone 32 .5 -5 5mg i n a are the usualformsof benignliver tumoursseen
acetate " ringintothe associatedwith use of theseagents.
"Silastic
posterior
vaginal fornix The tumours usuallyregressupon clisconti-
ProoesteroneProgestasert Uterineinsertion nuationof the therapy.
(c) Breakthroughbleecllng :
Oral contraceptiveagents also exert some Spottingor irregularmenstrualbleeclingarethe
clesirable sicle-effects.The incidences of common effectsof oral contraceptivepills. The
occurrenceof iron cleficientanemia,benignbreast estrogeniccomponentshoulclbe raisedif spotting
clisease,pelvic inflammatorydisease,functional occursbeforemicl-cyclewhile if it occursaftermid-
ovariancyst, premenstrualtensionand menstrual cycle,the progestinpart shoulclbe increased.
disordersare markedlvlowereddown. Hence,their
Table 17.6 : Somelmportant Inlectablecontraceptlves
Sr. No. Name Totat dose (mg)
Monthly Infectable hormonal preparatlons
Progesteronealone
ol. Norethisterone oenanthate z5
oz. Medroxyprogesterone acetate 50
03. 2Op-nycl roxy-I 9-norprogesterone phenylpropionate 50
04. Lynestrenolphenylpropionate 50
05. I 7 cr-hyclroxy-I 9-norprogesteronecaproate zo0
06. Dihydroxyprdgesterone acetophenide 200
07. I 7a-hyclroxyprogesterone caproate 500
Estrogen alone
08. Estracliolunclecylate 30
Estrogen-progestln comblnatlon
09. cll-Norgestrel+ estradiolhexahyclro-benzoate 2 5 +5
lo. Medroxyprogesterone acetate+ estradiolcypionate 25 + 5 ancl
50+ lO
11. Norethisteroneoenanthate+ estradiolundecylate 3 O +5 0
12. Medroxyprogesterone acetate+ estradiolvalerate IOO+ 20
13. Dihyclroxyprogesterone
acetophenide+ estradioloenanthate l 5 O+ l O
14. Dihyclroxyprogesteroneacetophenide + estradiol-3-benzoate, l5O+ lO
l7p-butyrate
15. 17a-hyclroxyprogesteronecaproate+ estradiolvalerate 5OO+ lO
Three-monthlyInlectablehormonalpreparatlons
16. ''clepot-Mecl
roxyprogesteroneacetate 't50
17. Norethisteroneoenanthate 200
18. Chlormaclinoneacetate 250
Slx-monthly lnlectable hormonal preparatlon
19. depot-Medroxvpro-qesterone acetate variousdoses
 Principles
ol Medicinal
Chemistry
flot. lt) 382
Steroids

Table | 7.7
Some Markcted Contraceptlvepreparatlons
Preparatlon Oestrogen (mg) Progcstlil (tg)
(A) t. Comblnatlon preparatlons (hlgh
dose oestrogcns)
Envoicl5 mg Mestranol 75 Norethynoclrel 5. O
Envoicl- B Mestranol 100 Norethynodrel 2. 5
Ovulen I mg Mestranol t oo Ethynodiolcliacetate 1. O
Lyndiol Mestranol 75 Lynoestre4_91
2. Comblnatlonpreparatlons (medlurn dose oestrogens)
NorinylI Mestranol 50 Norethisteroneacetate l .o
Anovlar21 Ethinylestracliol 50 Norethisteroneacetate 4. O
Norlestrin Ethinylestracliol 50 Norethisteroneacetate 2. 5
Ovulen 5O Ethinyl estraciiol 50 Norethisteroneacetate 1. 0
Ovran Ethinyl estradiol 50 D-norgestrel o.25
Minilyn Ethinylestracliol 50 Lynoestrenol 2. 5
Demulen5O Ethinylestradiol 50 DL - norgestrel 0. 5
3. Comblnatlon preparatlons (low dose oestrogens)
:
Microgynon30 Ethinyloestradiot 30 D - norgestrel o . 15
Eugynon30 Ethinyloestradiol 30 DL - norgestrel 0. 5
Loestrin20 Ethinyloestradiol
(B) Sequentlal preparatlons :
zo Norethisteroneacetate 1. O
Ovanon M e s tr a n o( lc l a y s l - 7 ) 80
Mestranol(clays8-27) 75 Lynoestrenol(clays8-22)
(C) Progestln only (Mlnl-pilts) : 2. 5
Mircronor
Norethisterone o .3 s
Femulen
Ethynoclioldiacetate o.50
Neogest
DL - norgestrel o .7 s
Microlut
D - norgestrel o.30
Turinal
Allylestrenol 0. 50
Exluton
Lynoestrenol o.50
(D) Postcoltal Diethylstilbestrol z5 twice clailyfor 5 clays
(E) Depot Hormonal preparatlons
:
Depo-Provera Medroxy progesteroneacetate 400 - IOOOmg initiallywith a maintenance
doseas low as 4OOmg per month
Once - a- month
Quinestron Quingestanol
(norehinclroneacetate- 3 _cvclo_
pengl enol ether)
Horrirone-releaslnglmplants :
I Progestasert ProgesteronereleasingIUD 38 mg

aoo
 TE.I INTR,ODUCTION
INTRODUCTION

NOMENCLATURE
ANDCHEMISTRY
The prostaglanclins(PGs) are unsaturated
OF
PROSTAGLANDINS fatty aciclderivativescontainingZOcarbonatoms.
All the prostaglandinsare formecl in the animal
ANDilETABOLISTIOF
BIOSYNTHESIS
PROSTAGLANDINS bocly by ring closure ancl oxygenation of essential
polyunsaturatedfatty acids such as arachidonic
PHARMACOLOG!CALACTIONSOF
PROSTAGLANDINS
acicl.

METABOLISM
OF PROSTAGLANDINS ln the reprocluctivesystem PGEI ancl PGE2
increasethe contractionof the pregnant uterus,
PROSTAGLANDIN
ANTAGONISTS
but inhibit the motility ancl tone of the non-
CLII{ICALLY
USEDPROSTAGLANDIN
ANALOGS pregnant ur-erusancl intravaginallyuseclto induce
ADVERSE
EFFECTS
therapeuticabortion. PGF2increasesthe motility of
OF PROSTAGLANDIN
ANALOGS both spermand uterincetubes.

OF PROSTAGLANDINS
SAR. STUDIES In the GlT, prostaglandinsintrease motility
and climinishgastric acidity. They increaserenal
blood flow, inducing a sodium and water cliuresis
and also redistributeblooclfrom medullato cortex,
thus antagonisingrenin production.

(383)
Principles
of Medicinal flol. ll)
Chemistry 384 Prostaglandin

In 1933, Maurice Goldblatt and Von Euler PGE1,PGE2, PGE3and PGFrAlThe table 18.1sho*-=
independentlyfound that a humoral principle some of the tissuesand fluids in which prosu-
presentin the human seminalfluicl leaclsto both glandinsare present.
smooth muscle contraction and vaso-constri- Table t8.l : ProstaglandlnspresentIn human
ction. Euler (1935) identifiedthe lipiclssoluble tlssues
nature of that component and gave the name,
prostaglandinto these substanceswith the belief Source Prostaglandins
that the biologically active substancefound in the 1. Bronchi PGE2, PGFzd
human semen was a secretion of the prostate Cardiacmuscle PGE2
gland. He clefineclprostaglandinas a "lipid soluble Cervicalsympathetic nerve PGE2, PGF2cx
smooth muscle stimulatingand blood pressure
lowering factor with acidic properties in human Endometrium (lung) PGE2, PGF2cx
seminalfluiclanclsome accessorygenitalglandsof Maternalvenous blood PGE2, PGF2c
man and sheep." durinolabour
The work on the identification of prosta- Menstrual fluid PGE2, PGF20
glandinswas commenceclby Bergstrom(1949).He Placentalblood vessels PGE1,PGE2, PGF1o,
recognizecl the presence of more than one PGF2cr
unsaturatedhydroxy fatty acict in partially purifiect
prostaglanclinextracts. The isolation in pure Semn PGA1, PGA2,
PGB1,
crystallineform from sheepvesicular glandsof the PGB2, PGE1,
PGE2,
first two prostaglandins,now called prostaglandin PGE3, PGF1G,
PGF2q
Et (PGEI)and prostaglandinFt., (PGF16r) was 9. Stomach mucosa PGE2
reported by Bergstromand Sjovall in 1957. Later, 10. Vagus nerve PGE2, PGF2CT
additional compounds having related structures
were isolateclfrom different organs.The natural IE.z NOMENCTATUR,E AND CHEMISTRY OF
prostaglandinsare hydroxylateclCzo- polyun- PN,OSTAGLANDINS
saturatedfat$ acids having extensive and variecl
activitiesin mammaliansystem,suchas
(a) stimulating or relaxing uterine smooth
muscles,
-\AA.'.JcooH
t0
(b ) constrictionof bronchi,
(c) lowering or raisingblooclpressure,
(d) inhibitinggastricsecretions,
(e) mecliatinginflammation, Prostanoicacicl
( D promotingsocliumion excretion,and Structurallyprostaglanclinsare derivativesr
inclucinglabour. prostanoic acid and have a cyclopentanering wir
G) two sicle-chainsattached to adjacent carbc-
Thus they qualify to be callecl as local
hormones. atoms. Systematicnomenclatureof prostaglandin:
Occurrence : is basecl upon the hypotheticalparent 'prostanoi-
Although prostaglanclins were first cliscoverecl acicl' numbereclas shown. With the increasing
in seminalplasmaanci in vesicularglands, their numberancllpes of prostaglandinscominSout,
clistributionis not restricteclto the male accessory becamevirtually essentialto clefinethe norms o
genital glands and their secretions.Prostaglandins nomenclatureancl classification of prostagland ins
are known to be distributeclwiclely in mammals. The present classification is based upon the
They can be extracteclfrom most animal tissues. nature of
The total prostaglandin procluction in the aclult (a) cyclopentanering
trumanis I to 2 mg per clay.Human seminalfluid
(b) Wvoacljacentsicle-chains, and
contains the highest concentration and the
greatest number of prostaglanclins(about 3l (c) configuration of newly introduce:
prostaglandins).Similarlysheep prostate contains functionalgroup.
Principles
of Medicinal
Chemistry
flol. ll) 385 Prostagffir

(iii) (ir')

Hd Ho
A-t ype B-type C-type E-type F-type
(Unstsble)

(a) Nature of the cyclopentane rlng :

Depending upon the nature of functional -\'=5coon
groups present, the cyclopentane ring may be
categorisedinto cHr
! fl)
(i) A-type cyclopentanering contains1O, I 1 OH
- unsaturated9-ketonefunction
(ii) B-fype cyclopentanering contains8, 12 - .., .- cooH
unsaturatecl9 -ketone function
- -
(iii) C-type cyclopentanering containsll, 12 CH.,
-unsaturated9 - ketone function HO (II)
(iv) E-type cyclopentane ring contains
p-hydroxy ketone system In the above structures, (l) contains cyclo-
pentane ring of type A ancl two clouble bonds in
(v) F-type cyclopentanerinS;contains 1, 3 - the side-chains.Hence the name will be PGA2.
diol system While, the structure (ll) containsthe cyclopentane
PCA ancl PGBwere so calleclbecauseof their ring of type E ancl only one double bond in the
stability in acids ancl bases respectively.The sicle-chain.Hence it can be named as PGEI.
namesof other prostaglanclins were baseclon the In all the natural prostaglanclins, the upper
separationprocedures,i.e. PGE partitioneclinto sicle-chain.isattached to the cyclopentanering
ether ancl PGFinto phosphate (Fosfatin Sweclish) through an q,-bond (i.e., projecting behincl the
buffer.Other grpes like.PGC,PGD, PGGanclPGH plane of the ring) ancl is shown by a clotteclline.
havealsobeendescribecl. Sinrilarlythe naturally occurring prostaglanclins
(b) Nature of acllacentslcle-chains: possessan o-hyclroxyl group at Cls atom. Any
change in this configurationmust be specifieclby
Two side-chainsare attacheclto the cyclo-
pentanering at carbonatoms 8 and I Z. The upper aclclingepi- as a prefix to the name alongwith the
number of carbon atom at which this change has
rg carboxyl (:COOH)group at its
occurecl.
. mecl as carboxylhexylor c-sicle
chainwhile the lower side-chain(attacheclto C12)
having hydroxyl at C15 is callecl as hyclroxyocgrl CooH
-----^ ----z
(co)sicle-chain.Compounclsin these groups, are
further characterizeclby a subscript l, Z or 3 CH,
clepenclingon the numberof cloublebonclsin the OH (ll1
sicle-chains.
The sicle-chainsmay containas many
as 3 to 4 doubleboncls.Forexample, epiPGE,
 of MedicinalChemistry(Vol.ll)
Principles 386 Prostaglandins

Hq cooH -z COOH
-- -, .., .^\--y--..-

-
c Hr cHr
I
HO OH OH

PGFt(x o6FrD

(c) Nature of the conflguratlon : I8.3 BIOSYNTHESIS AND METABOTISMOf

This parameteris neecleclto clefinethe confi- PNOSTAGTANDINS
.gurationof newly introducedfunctionalgroup in Prostaglandinsare synthesizedenzymatically
the molecule,The literatureprior to 1968 was from certain open chain C2g unsaturated fat$l
extendeclby Anderson(1969)to designatefurther
acidswhich include
possible isomers ancl the optical antipocles.For
example.PGEcan be convertedto PGFby reducing (a) 8,11,14eicosatrienoic
acid
the Ce-ketoneto a hyclroxylgroup. Thus the PGF (dihomo-7-linolenic
acid)
group can be further clivicleclinto PGFqand PGFg
types, clepenclingon whether the hyclroxylat Ceis
behinclthe plane (c) or above the plane (0) of the cooH
-> PGE,
nng. CH,

The generic name, eicosanoiclsis given to a

classcontaining prostaglanclins, leukotrienesancl
relateclcompounclsbecausethe basic skeletonis (b) s.8,r 1 l4-eicosatetraenoic
acid or arachiclonic
of ZO-carbonfatg acictcontaining3, 4 or 5 double acicl
bonds. In man, arachidonicacicl (precursorof
prostaglqnclins)is either clerivecl from clietary
linoleicacid or is ingestedas a dietaqrconstituent. cooH
Thromboxanes(TX) contain a six member oxane PcE'
ring insteacl of the cyclopentane ring of CH:
prostaglandins.While prostacyclin (PGl2)has a
clouble-ringstruciurein adclitionto a qyclopentane
nng. (c) 5,8,1l ,14,17-eicosapentaenoic
acid

Hydroperoxyeicosatetraenoic acids (HPETEs)

are obtained from arachidonicaciclby the attack of cooH
lipoo4ygena-se enzymes.The HPETEs are unstable PGEr
intermecliatesancl are further metabolised by a CH,
variety of enzymes.All HPETEsmay be converted
to their corresponding..hydroxy fatty acid (HETE)
either by a peroxidase or non-enzymatically. These acids are precursors of the in vivo
Similarlyleukoqrtesconvert 1S-HPETE to trihydro- prostaglandinsynthesis.The overall sequenceof
xylatedmetabolitescalledlipoxins. reactionsinclude
 Chemistry(Vol.ll)
Principbsof Medicinal gl PrGtagffii3

Arachicrohic
o.,o-9' H.ETE-* HETE.

PGG-'
6 - OXOPGI" PGI.

TXB.,<- T'XA,I
@
PGD,'
19_oH <.<- 19- hydLo^y PGEI .--+ pQpr,, l5-ketoPGF,'
PCA, PGE,
-
w-
, . , "t-2 pca
-

l3: l4-dihydro
I 9- O H l5-ketoPGFro
Dr-:t

tls. l8.t : Blosvntheslsof varlous rosteslandlns

where, (a) Gastrolntestlnal system :
HHT : lZ - L - hyclroxyl - 5, 8, ll - hepta- Prostaglandinsare found to exert following
decatrienoicacicl actions on Gff system :
(i) decreasethe gastricacicl.secretion
MA: Malondialclehycle
(ii) increasethe non-acidsecretionin rats
HETE:1Z - L - hyclrory- 5,8, lO, 14 - eicosate-
(iii) inducecontractionof smooth muscles
traenoicacicl
(b) Urlnary system !
HPETE : 12 - L - hyclroperoxicle
analogue SpecificallyPGE2and PGF26, increasebladder
EnzymesInvolved In thc blosynthesls of proste- activigrand help to maintainblood flow.
glandlns : (c) Bronchlal and tracheal smooth musclcr :
(1 ) lipo-oxygenase Some.prostaglanclins (e.g. PGA, PGE1,PGE2)
(z)cycloxygenase(PG-endoperoxidesynthe- relax the bronchialsmooth muscleswhile PGF
tase) inducesbronchoconstriction.
(3 ) serumalbumin glutathione-s-transferase (d) Reproductlrie system :
(4) PG-endoperoxidereductase Prostaglanclins increasethe rate of synthesiS
and releaseof testosterone.Hence PG - cleficienqy
(s)PG-endoperoxide-E-isomerase in male may leacl to infertiligr. They stimulate
(6) PG-endo-thromboxaneA isomerase myometrialsmooth musclesthat leads to uterine
(thromboxaneA2 synthetase) contraction(e.g. PGF2q ). Henceclinicallyit may be
(71 PG-endoperoxideI isomerase. used to induce abortion.
IE.4 PHARMACOTOGICAIACTIONSOt (e) C-erdlovescularsystem :
Prostaglandlhendoperoxideand TXA, cause
" PN,OSTAGLANDINS platelet aggergation and vasoconstriction.While
Prostaglandinshave been extensivelystudied PGl2(prostaqyclin) decreasesplatelet aggeregation
becauseof their profound effectson physiological anclleadsto vasodilation.SimilarlyPGE2and PGA2
processes.All such important biologicaleffectsof produce peripheral vasodilationand they may be
prostaglandins include used in the treatment of hypertension.
Principles Chemistry(Vol.ll)
of Medicinal 388 Prostaglandins

COOH COOH

I 2, |4-cicosatlicnoic
acitl fJ.12, |4-cicosatctrlnoic
ilcru

(0 Nervous system : therefore, appear to be clifferent. The prosta-

glanclin antagonistsSC-19220 ancl polyphloretin
Prostaglandinsaffect mood, behaviour,brain
phosphaie antagonize the excitatory effects of
excitabilityand EEG-pattern.The CNS-effiects
Vary
PGEancl PGFcompounclsbut not the inhibitory
from CNS-clepressionto excitation.However,they
(circularmuscle)effectsof PGEcompounds.
do not influenceA.N,S.functioning.
I8.5 METABOTISMOT PROSTAGTANDINS Certain compounds inhibit prostaglandin
syntheslsby competitive antagonism.This abiilty
Gastric tissue easily metabolise prosta- is clueto their structuralresemblance with prosta-
glandins,as Shownin the rat. Only aboutO.1 o/oof gfanclinprecursors. They inclucle,(l) 8, lZ, 14 -
prostaglanclinsin the lumen reaches the serosal eicosatrienoic acicl ancl (Z\ 5,8, 12, 14-
surfaceunalteredbut it is not known which meta- eicosatetranoicacicl.
bolites are formecl. Besidesthis, other possible
Besiclesthese,golcl,silver,zinc and cupric ions
sitesof PG-metabolisminclucleliver, kidney, lungs,
inhibit the prostaglandinsynthesis.Non-steroidal
adrenalglanclsand uterus.For example,in lungs
the 1S-hydroxylgroup of prostaglandins E1, Ez,Az anti-inflammatoryclrugsinhibit the qyclo4ygenase
ancl F261are metabolisectby means of an enzyme enzvmes.
system thought to involve 1S-hyctroxyprosta- Other important prostaglanclin-antagonists
glanclindehyclrogenase. The lS-keto compound is inclucle
then reduceclto the 13, 14-dihydroderivative,a (a)
reaction catalyzecl by prostaglandin 413 -
reducetase.Subsequentsteps involve p and cl
oxiclationof the sicle-chainsof the prostaglandins, ."'O'., r, .,, COOH
giving rise to a polar clicarboxylicacicl,which is
I
excreteclin the urine. I
H
18.6 PROSTAGTANDINANTAGONISTS
The receptorsites at which prostaglandinsact
in isolated segments of gastrointestinalmuscle 7-oxa prostanoicacid
have been investigatecl mainly by the use of (b)
selective pharmacologicalantagonists.It was
founcl that PGE, and PGE2inhibit the circular
muscleof the human, guinea pig and rat gut by
acting at sites on the muscle which are different R = C H .r l C H ( C H 1 ) ,
from c,- and p-adrenoceptors.The excitatory cH,c(,Hs
receptors appear to cliffer from receptors for
CONHNHCOR
a cet ylcholine , 5-h yd roxy t r y pt am ine and
histamine.Theexcitatoryr (longitudinalmuscle)ancl
inhibitory (circular muscle) PGE receprors, Bibenzoxazepine
hydrazidederivatives
 Chemistry(Vol.ll)
of Medicinal
Principles
(c)
o 1OOmg 4 times daily or more . Misoprostol,2@ ug
tl
cocH'cH) o- P-
I 3OOmg 3 times daily, in healingduodenalulcers
OH
Polyphloretinphosphate
(cl) Other drugs Iike morphine,quiniclineancl
procainewere also reporteclto have antagonistic
actions.
I8.7 CLINICATTYUSED PR.OSTAGTANDIN
ANATOGS
Thesehave been baseclon moclificationof the
structure of natural prostaglanclins(rnainly PGEl
anclPGE2),to increaseresistanceto metabolism,or
achieve a lower incidence of side-effects at
\\er<lrerr\rs*\sses. Ssrse".'rrs\<\\1 q\\\:\\ - N\\
re\ative.\y \ong ha\t-\ives. Ttre. mairr prostag\arrd\n
rsNsgs<re,\rs\e\\e\s.sl.
\a\ Nn\rarss\\
--
It is an analog of 1S-methylpGEz.lt is rapidly
absorbeclancl eliminateclwith a short hatf_life.
Dosesof approximately2 pglkg produce more
than 600loinhibition of basal ancl stimulateclacicl
output in humans. Anti-secretory closes of
arbaprostil(150 pg 4_timesa clay)heal duoctenal
ulcers but lower cytoprotective closes(l O pg to
25 pg about 4 times a ciay) are ineffective.
Arbaprostilmay inhibit gastrinreleaseanclhas been
shown to protect {gainst aspirin incluceclgastric
injuryrin dosesof O.6pglkg/ clay.
(b) Trlmoprostll :
It is 1l-methyl analog of pGE2which is welt
absorbecl.Dosesin the range 7.5-1Opg/kg reciuce
the basal acid secretion while closes upto 4O
pglkginhibit meal stimulatedaciclfor upto 3 hours.
Doses in the anti-secretoryrange (Z mg/day and
upwarcl) reduce aspirin injury. Trimoprostil
stimulates gastric bicarbonatesecretion. When
given, 75O pg 4 times daily, it is less effectiveat
healing duoclenal ulcers and gastric ulcers than
cimetidine, 2OOmg 3 times claily and 4OOmg at
night.
3&) Prostagiandlns
(c) Mlsoprostol :
Both ulcer healing ancl pain relief effectscr
misoprostol are dose clepenclentin the closesof
4 times daiiy, was of similar efficacyto cimetidine.
anclgastriculcersover 4 weeks.
Misoprostol is a methyl ester of 1S-methyl
PGE1. lt is rapictlyabsorbeclafter oral aclmini-
stration. lt is rapiclly de-esterifiedto free acid,
binds to albumin ancl is concentratedin gastro-
intestinal,hepatic and renal tissues.lt is rapidly
oxiclizecland eliminateclwith a half-life of about
1.5 hours. It has been shown to inhibit basal,
claytime and overnight acicl secretion and that
stimulateclby histamine,betazole,pentagastrin,
tetragastrinanclcaffeine.lt helps to reducealcohol
injury in man and produces a substantialdose-
clepenclentrise in cluoclenalbicarbonatesecretiori
(d) Rloprostil :
This is a me\\ PGEI derivative,ora\ we\\
tsssr\e\ .s\r\ I \sr\\i\\r\s_.\sses s\ \\\ \s
6\N1lgre{rrce\\asl\rsi\s\rsstNNe\rq_r\:sqre\rsrr
and pepsin output. lt also prevents gastric
bleeclingand prornotes healing rate. With this
closingregimen,diarrhoeaanclabclominalpain were
saiclto be infrequent.
(e) MDl"-646:
This is a PGE, - derivative which has local
protective effectson gastric mucosa.Single closes
of MDL in the rangeof 8OO-12O0 pg reduceclbasal
aciclig but had much lesseffect on stimulateclacicl
output.
(D Enprostll :
About 35-140 pg per clay of enprostilheals
cluoclenalulcersanclgastric ulcers.However, dai!_v
closesof 7O pg are less effective than ranitidine
3OOmg in heating cluodenalulcers. Maintenance
treatment with enprostil, 35 pg at night is less
effectivein cluodenalulcer patients than ranitidine
l50 mg.
(g) Prostacyclln :
It causecla reductionin cluoclenalulcersizein a
closeof 5 trglLgln infusedfor 5 hoursper clayover
6 clays. lt also increasesgastric bicarbonate
secretion but does not affect pentagastrin
stimulatedacid secretion.
Principlccof MediclnalChemictry(Vol.ll)
IE.E ADVERSEI,IFT,CTS O] PR,OSTAGTANDIN
ANATOGS
Acid inhibition by available prostaglanclin
analogsis moclerate.Comparativestudiesare few
but there are no analogues where it is clearly
establishedthat clinically useful doses are more
effiectivethan cimetidine. All availableanalogues
causecldiarrhoeato va4ling ciegree.Thereare also
ct\nces that the motility of the pregnant human
uterusbe increasedto induce abortion.
Dlnopro.ptonc :
It is marketed in the form of vaginal
suppositories containing20 mg of PGE2. lt is used
to induce abortion ancl to treat benign
hyclatidiformmole. Carboprosttromethamineis a
solutioncontainingO.25 mg of carboprost(15-
methyl PGF2q)per ml. It may be usecl intra-
muscularlyto induce abortion or to treat post-
partum haemorrhageowing to uterineatony.
391 Prostagilrxtrs
TE.9 SAT.-STUDIES OI PR.OSTAGI.ANDINS
( | ) Expansion or contraction of the cyclo-
pentane ring or its replacementby heteroaromaric
rings resultsin decreasein the activity in the E2and
F2series.
(Z) Replacementof hyclroxylgroup in the ring
gives more stable analogs.For example, thia-PGl2
(l) possesses platelet aggregation-inhibiting
activity with vasoclilatoryeffect. Similarly the
aromatic pyriclazoclerivative (ll) is an excellent
vasoclilator.
(3) Modification of the carboxylicacicl sicle-
chain has also been reportecl.For example, the
phenoxyclerivative(lll) is about 1O times more
active than PGE as an inhibitor of platelet
aggregationwhile the sulfonamic'le derivative(lV) is
| 5-30 times more active than PGE' a5 an antr-
fertility agent ancl possessesless side-effucts.

o cooH
tl
c- ocH-l

cHi
I
I
I Hd I
oH
OH
(l ) (tr)

o
tl
c- NHSO2CHI

o - c6H5
HO
(ilr)
(l V )
Principles
of Mediclnal (Vol.ll)
Chemistry gt Prostaglanoins

co o H '

oI
I
-a*-.a..,.1-/COOCH.I
H3C-r
CHr
I
HO I
OH

(v) (VI)

(4) The 7-oxo and 7-thia analogswere founcl
to show an antagonistic activity on isolatecl
smooth-muscles.
(5) Incorporation of a methyl group in the
lower side-chainleads to an increasein uterotonic
activity. For example,carboprostand cornpouncl
(V)are useclto induceabortionswhile nileprost(Vl)
is an. expenmen(a( anr(u(ce|-igenr. The former
probably inhibit' the dehydrase enzyme that
inactivatesprostaglandinsby removing the 15-
hyclrorytgroup.
ooa
 r9.r TNTRODUCTTON
INTRODUCTION
In the earlierdays,purely randomizedsearch
METHODS
proceclures were involveclin the cliscoveryof new
OF LEADDISCOVERY
drugs. ln such methods, the experlenceand
OF THE LEAD
OPTIMIZAT]ON intuitionof medicinalchemistswere the important
factorsto reclucethe stochasticnature of search
APPLICATION
OF BIOISOSTERISM
IN techniques.ln view of the ever increasingnumber
OBUG-DESIGN
of chenical compounds and In partlcular the
heavierdemandsto be ntet by rtew chemlcals
PRODRUG
D ESIGNING
randomizedsearchis no longer effective;lt is too
TYPESOFPRODRUG time-consumlng;guaranteestoo little successand
is too expensive.
CARRIER-LINKED
PRODRUGS The chanceof discoverlnga new agent has
climinishedto 1 in IO,OOOand wlll decreaseenen
DRAWBACKS
OF PRODRUG
A PPROACH
further,whereasclevelopmentcosts have risen to
SOFTDRUGCONCEPT
more than 4O million dollarsper new drug. This
necessitatedthe developmentof a new logicaland
19,10 COMBINATORSAL
CHEM]STRY scientificapproachin cliscoverylof a new drug
whichis knownas'clrugdesign'.

(3e3)
 Principlesof MedicinalChemistryflol. ll)
, lt involves the stucly of effects of biologically
active compounds on the basis of molecular
interactionsin terms of molecularstructuresor its
al,.properties involvecl. It studies
>y which the drugs proclucetheir
effects, how' they react with the protoplasm to
elicit a particular pharmacological effect or
response, how they are moclifieclor cletoxifiecl,
metabolisedor eliminateclby the organism.
Dispositionof clrugs in individual regions of
biosystemsis one of the main factorscletermining
the place, mode ancl intensigrof their action. The
biological activigr may be "positive" as in clrug
clesignor "negative"as in toxicology. Thus, drug
clesigninvolves either total innovation of lead or
an optimization of alreaclyavailable lead. These
concepts are the builclingstones upon which the
eclificeof clrugclesignis built up.
The current trend in the clrug clesign is to
clevelopnew clinicallyeffectiveagentsthrough the
' structural moclification of a leacl nucleus. The lead
is a protogrpe compouncl that has the clesired
biological or pharmacologicalactivigr but may have
many undesirablecharacteristics, like high toxicity,
other biologicalactivigl, insolubilitlror metabolism
problems. Such organic leads once iclentified,are
easy to exploit. This process is rather straight
forward. The real test resides with the
identification of such lead compounds and the
optimum bioactivepositionson the basicskeleton
of such leads.
The examplesof drug discoverywithout a lead
are quite few in number. The most prominent
examplesincludepenicilliumand librium.In 1928
AlexanderFlemingnoticed a green molclgrowing in
a cuftureof Staphylococcusaureus,anclwhere the
two had converged, the bacteriawere lysed. This
led to the accidentaldiscoveryr of penicillin,which
was proclucedby the mold. Dr. Ronald Hare,
colleagueof Dr. Fleming,found that very special
conditionswere requireclto proclucethe pheno-
menon initially observed by Fleming. Another
extraordinaryrcircumstancewas that the particular
strain of the mold on Fleming culture was a
relativelygood penicillinproducer,althoughmost
strains of that mold (Penicillium)produce no
394 DrugDesign
penicillinat all. Themold presumablycameftom the
laboratoryjust below Fleming'slaboratorywhere
research on molds was going on. Thus, the
discoverylof penicillincoulclbe possiblebecausea
combination of all unlikely events took place
simultaneously.
The full extent of the value of penicillin was
not revealecl until late l94Os because of
emergence of the sulphonamide antibacterialsin
1935 and the outbreakof World War Il. Thereafter
the original mold (penicillium notaium) was
replaceclby Penicilliumchrysogenumbecauseof
relativelylow yielcl of penicillin from the former.
The correctstructureof penicillinwas reporteclin
1943 by Sir Robert Robinson (Oxforci) ancl Karl
Folkers(Merck). Once the structurewas known,
penicillinbecameleadnucleus for futureanalogs.
Yet another example of clrug, discovered
without a lead, is librium,the first benzocliazepine
tranquilizer.A seriesof quinazoline-3-oxides (1)
was synthesizeclby Dr. Leo Stembachat lbche in
a program to develop a new classof tranquilizer
clrugs.Sincenone of these compounclswas founcl
to be active,the schemewas terminateclin 1955.
However, a vial from the above scheme which
remained untesteclwas found in 1957 cluring a
generallaboratorycleanup.
R-',
(1)
The compound(Z) presentin it, was submitted
for pharmacologicaltesting to complete official
formalities.Surprisingly,it gave very promising
resultscluringpreliminarylscreeningfor tranquilizing
activigl. lt was founcl to be benzodiazepine-4-
oxicle, presumably producecl in an unexpected
reaction of the corresponding chloromethyl
quinazoline-3-oxide with methylamine.
lf that vial had not been 'found in the
laboratorycleanup,the benzodiazepines may not
have been discovereclfor many years to come.
Thus, librium once identifiedas a lead. was then
exploited to develop future analogslike diazepam.
The latter is about lO times more potent than the
lead.
Prlnclpleof MedlclnalGhemlstryOol. ll)
cH,cl
cH.lNH'
CI
H NHCHl
N N
(2) Librium
The alkylating agents stood as the first
systematic approach to cancer chemotherapy,
especiallyin leukaemlawhere leukogrtesmultiply
in an uncontrolledfashlon.They were developed
to lower clown high toxlcity of mustardgas whose
anti-leucocytic action was evidenceclwhen a shlp
loadeclwith mustardgirs w.ls bombed In an ltalian
harbour.The milltary personnelwho came ln
contact with this gas showed an unusuallylow
white blood cell count.
19.2 METHODSOT IEAD DISCOVERY
There are several approacheswhich can be
employed for lead ldentification. In order to
iclentifua lead nucleusln a glven series,the whole
seriesshould be analysedfor a particularblological
activigl. Once the lead is identiffed, lt can be
structurally modified to improve the potency.
There is a diffierencebetween the terms, actlvity
and potency. Activltlr is the particularpharm4co-
logical activigr while potincy is the strength of
that effect. Followingare some of the important
methodswhich can be used for lead ldentlfication.
(a) Randomscreenlng:
In this method, all compounds (includlng
syntheticchemlcalsand natural productsof plant,
marineand microblalorlgln) from a glven seriesare
tested. Besidesthe age old examplesof morphlne,
cocoine, digitalis, nlcotlne, muscarlne,tubo-
curarine,quinine, etc. recently anticanceragent
tarcoland antimalarlalagent artemisininhave been
discoverecl from plant source. Insplte of
buclgetaryand manpower overuse,thls metbocl
may be used to discoverdrugs or leadsthat have
unex pec tec l a c t iv lt ie s . Ant ib lo t lcs llke ,
streptomycin,tetraqycllnes,fungal metabollteslike
lovastatinand cyclosporinwere found out by this
methocl.Similarlypotent anticanceragent,euracin
A was obtainedftom a marineqyanobacterium.
s Drug DdF
H
N NHCHl
cFlrcl
CI ;\
o-
CI
F*-o"
(b) Non-random screenlngr
It is a modifiecl form of random screening
which was developeclbecauseof budgetaryand
manpowerrestrictions.In thls method, only such
compoundshaving similar structuralskeletons
with that of leacl,are testecl.
(c) Drug rnetabollsm studles :
Metabollsmof clrug occursas an attempt by
metabolizingenzymesto cut short the period of
stay of the drug in the body. Structuralmodlfl-
cations(1.e.metabolicbiotransformatlon) are done
in clrug moleculeby the enzymesto Increaseits
polarigr.lt ls brought about regardlessof whether
the resultlng drug metabollte possessesmore
activity or toxiclty.The dlscoveryof sulfanilamide
is reported through the metabollc studies of
prontosil.
The antlpyretic actlon of acetanllide was
discoveredby chancewhen a nurse by mistake
clispensedacetanilideto a patlent. Due to lts
toxicltles, acetanllide could not stand in the
market.Metabolicstudiesshowed that the toxl-
cities are due to its in vlvo metabOllte,p-amlno-
phenol.Theseobservationsled to developmentof
phenacetinand paracetamol.
{d) Cllnlcal obsewatlons r
Manytimesthe clrugpossesses more than one
pharmacologicalactivlties. The maln activity is
callecl as therapeutic effect whlle rest of the
actions are known as slde-effectsof the drug.
Such drug may be used as lead compound for
structuralmodificationsto lmprove the potenqyof
secondary effects.
Principles
of Medlclnal Oo1.ll)
Chemlstry 396 DrugDeslgn

Sulphonamicleoral hypoglycemics arose synthesizecl.Pyrimethaminewas designecl by

ciirectiyfrom the clinlcalobservation,in 1942,that cleletingthe bridgingbetweentwo rings.
a sulphathiazolederlvative,which was being used NH,
N:
specificallyfor treatingtyphoicl,low'eredthe bloocl
sugar clrastically.The pronounced hypoglycemia o
exertedby 5 - isopropyl- 2 suiphanilarnido - 1, 3, N
Hs
4-thiacliazoleinclicateclthat an arylsulponyl Diaminopyrimidine Pyrirrethanrine
thioureamoiety (ArSO2- Nl-l-C(= N) - S) presentin With the knowledgeof antirnalarialactivity of
thiadiazolesis responsiblefor their blooclglucose s ulf apy r im i d i n e sa t h a n c l . B r i t i s h m e d i c i n a l
lowering effect. This observation lecl to the chemists F. L. Rose ancl F.H.S.Curclspottecla
developmentof carbutamicleby Frankeancl Fuchs tautomericprotonshift in aminopyrimidines which
through openingof thiazolering to give a thiourea was supposeclto be an essentialprerequisitefor
moieg in which = S was then replaceclby = O. potent antimalarialactivity as per Schonhofer's
hypothesisproposed for amino-quinolines.Less
toxici! may be expecteclfrom pyrimiclineseries
when comparecl with quinolines/acridines, as the
H,N SO.N HCONH - nC.tHn
formerare componentsof nucleotides.
The antihypertensive activityof clonidinewas
Tolbutamide revealedduring clinicaltrialscarrieclout to verifuits
In orclerto nullifothe toxicity anclantibacterial predicteclvasoconstrictoractivity. Silclenafi I citrate
activity of the 4-amino group, it was replaceclby (Viagra)is yet another exarnpleswhose penis
other substituentsresulting into tolbutamide, erectilepropertyway revealeclcluringclinicaltrials
chlorpropamicle ancltolazamide. to screenits antianginalactivity.
o CH"
t-
H..,C -
SO"NHCONH *t
QsHz N

Tolazamide
Using 4-methylhistamineas a leacl,Ganellin
ancl his colleaguesclevelopeclH2- receptoranta-
gonistswith a sicle-chainterminatin._e in a thiourea
group. Becauseof severe sicle-effectsseen in
these thiourea derivatives,thiourea group was
bioisostericallyreplaced by guanicline.Cyano-
guaniclinewhen introclucedinto the side-chain,
resultedinto cimetidine.
A seriesof aminoalkylderivativesof imino-
dibenzyl was synthesizedas analgesics,sedative
and anti-histaminicsby Hafliger ancl Schincllerin
1951. Imip r a m in e ,o n e o f t h e co mp o u n d s,
appeareclto be potential anti-clepressant during higher selectivityand less adverseeffectsare
clinicalstuclies by Kuhn in 1957.Many tricyclic
anti-depressantsthereforewere synthesizecl.
NH,
H"N NH
CH
Chlorguanicle
Similarly, clue to the antifolateactivity shown
by chtorguan icle,various cl
iami napyrimiclines were
CgHz
_ CH,
tl
U
\J siroeiani
(e) Ratlonalapproachesto lead dlscovery:
The l<nowledgeabout the receptorsand their
mocleof interactionwith clrug moleculesplays an
importantrole in clrugclesign.Thisknowleclgemay
be used to clevelop conformationallybioactive
sl<eletons having exact three-dimensional
complementarityto a receptor.Greaterpotency,
expectedby reclucingthe flexibilityof the drug
structure.Forexample,replacement of a terminat
N, N-ctiethylamino group by piperidinoexploitsthe
decreasing valencyangleat the tertiarylnitrogenof
the latter so that access of the basic group to
anionicsitesmight be improved.This modification
ieads to the developmentof major tranquilizers,
local anaesthetics,antihistaminicsand spasmo-
lyt)cs. lncorporatinga rigid ring'leads.to altered
ph arm aco\) n eti c antt plr armacotrynam\ c \ ea\ures
due to altered pKa of the amineanctlipophilicityof
the molecule.
Principlesof MedicinalChemistry{Vol.ll) sl7 OrugOcsgr

This approach is of greater importance in Sincethe aminobutyrophenones are 6-amirp-

identificationof lead nucleus.lt involvesthe use ketones, homologs were synthesized. Molindone
of signs and symptorns of the disease.Most a Mannich base of pyrrole ketone, is used as an
diseases,atleastin part, arise from an imbalanceof antipsychotics.
particularendogenousbioactivesubstancesin the In a chancetest, numbing of the tongue was
bocly. These imbalances may be corrected by exerted by 2-dimethylamino-2-acetotoluicline, an
agonism or antagonism of a receptor or by intermediatein the synthesisof gramine. This lecl
inhibitionof a particularen4yme.Oncethe realsite to the synthesis of various anilides to get local
of suchimbalanceis identifiecl,the naturalenzyme anaesthetics.The presence of two stbrically
substrateor endogenoussubstancemay be usecl hincleringortho methyl groups protect the anilide
as a leacl nucleus. For example, endogenous linkage from hydrolysisancl increasethe duration
hormones,progesteroneancl 17 B-estracliolwere of action of lidocaine.This principlewas extended
used for developing oral contraceptives.The Further to clevelop mepivacaine ancl ciimeth-
development of an anti-inflammatorydrug, isoquine.
indomethacinfrom the lead nucleus, serotonin Hypoglycemlc Agents :
resultedat Merck with a belief that serotoninis a
(a) Insulln analogues :
possiblemediatorof inflammation.
Paul A. j. Attempts were made to synthesize various
Janseenclevelopedmeperidine insulin analogues by specific amino acicl sub-
derivativesby replacingmethyl group on pipericline
stitutionsof the p - chainof insulinmoleculeusing
nitrogenby allqylaqll keto groups. While searching
for a better substituent to replace carbethoxy recombinantDNA techniques.These analogues
group, tertiaryalcoholgroup was finallyselected. have diffierentpharmacokineticpropertiesthan the
clinicallyusecl insulin. The monomeric insulin
analoguesappearedto be less immunogenicand
allergicthan insulin.
cooc.'H5 (b) Somatostatlnanalogues :
Somatostatin,a tetraclecapepticle is a inhibitor
oF growth hormone release.It may also improve
glycemic control by slowing down nutrient
N
I absorption from the gut. Several somatostatin
(cH:).r-co analogues have been synthesized. However the
high cost of production of these pepticles may
Substitutionof the aryl nucleus by halogens limit theirclinicalutili!.
and pseudohalogens (F3C) ctemonstrateclthat (c) tat$ acld oxldatlon Inhlbltorc :
fluorine para to the keto group was optimal for In cliabetic person, always an increased
neurolepticpotency. Out of severalhundredsof utilisationof fatty acids occurs. The fatty acicl
analogs,halopericlolwas selecteclin 1958 finally oxiclation
inhibitorsexert hypoglycemicactivity
for clinical trial. Haloperidol was subjected to
by promoting increaseclcarbohyclrateutilisation
various molecular moclifications to enhance
neuroleptic activigl at the expense of analgetic ancl inclucinga reduction in fatgl acid oxidation.
properties. For example, tetrahydropyriclyl ancl Theseagents selectivelyblock carnitine palmitoyl
piperazinylrings'were useclto replace pipericline transferase (CFl-),a l<eyenryme in the oxidationof
nng. long - chainfatty acyl groups.

o c:Hs
- CH" OCOONTt

CH,
Nt
H

Molinclone Chlorphenylpengrloxiranecarboxylate
Principlesof MedicinalChemistryflol. ll) sts DrugDesign

rldationby the enryme, hexokinaseand (ii) polyol

pathway by the enzyme, aldose reductasewhich
2-Tetradecylglycidate reducesglucose to fructosevia sorbitol. Glucoseis
preferentiallymetabolisedby glycolytic pathway in
normal person. In diabetic patient, the high
(cHr)rtt - cooH glucose concentration leacls to saturation of
glycolytic pathway. Excessglucose is then meta-
NH,, CI
bolised by polyol pathway resulting into
2-(3-Methyl
cinnamylhydrazone) productionof sorbitoland fructose.Sincethe rate
propionate of formationof sorbitol is higher than its rate of
conversion to fructose, sorbitol selectively
accumulatesand causescomplicationsof chronic
cliabeteslike, cataract, neuropathy and retino-
pathy. Tolrestatis an example of clinically used
agent usefulin the prophylaxisof ctiabeticneuro-
pathy, retinopathyand cataract.
Aminocarnitine
(d) Anorectlc agents : Weight loss is an
effective means to achieve improvecl glycaemic N. COOH
.,
control in the treatment of obese non-insulin
clepenclentdiabete millitus. A varie\r of anorectic
agents which may be used for short-term therapy,
include
HlCO Tollestat
cl
CF.,
Antlmalarlals :
The planarconformationof the acriclinering is
optimal for antimicrobial activity. However
.oH separationof incliviclual
phenylring from the whole
tricyclic skeleton does not affect activi!. This
observationlecl the synthesisof Z - (p-chloro-
phenyl)aminopyrimidinesby Rose,thus retaining
N the overall flat area.Sinceclialkylaminoalkylamino
Ciclazindol
M azindul siclechainwas alreadypresentin some of the anti -
(e) Inhtbitors of carbohyclrate absorptlon : malarials,it was attachedto the skeleton.In order
The intestinal carbohyclratecligestion can be to simplifothe structure,the pyrimiclinering was
clerayeclby inhibiting the enzymes which cleave openeclto get biguanicles.However becauseof the
the terminal glucose.Acarboseis a clinicallyusecl increasecl basicity(clueto cliethylaminogroup ancl
example. two basic guanidines),the terminal guanidino
(0 Alclose reductase Inhlbltors : Glucoseis group was replaceclby simple alkyl groups. This
mainly metabolisecl in bocly by two pathways resultedinto developmentof chlorguanicle where
(i) .qlycolyticpathwav involvin an initial hospho- the alkylgroup is an isopropylmoiety.

CH , O H
cH,'oH C H ,OH

HO
OH

Acarbose
Prlnclples
ol Mediclnal Pol. lf
Chemlstry g Dn gD!.+i

cHr
NH
ll
\*n - c - N
N(CH,),,NRl tl
Biguanide ( c Hr ) r N( C) Hs ) ,

Antlcoagulants : Sincevitamin K may alsogeneratea cyclicketal-

(l ) H eparlno lds : Heparinoids are the like structure,the oral anticoagulants may act by
sulphuric acld esters of varlous polysaccharides. antagonislng vitamin K competitivelyat the actlve
Theywere found to be more actlve than heparinin sltes.
animals. Besides methocls clescribes above, other
(2) ln 1922, a dlsease characterlzeclby
\rrterrra\ b\eed\ngslas repox\ed \n ca\\\e, v.t\\c\ vlas sre\\ods \\ke screen\ng of tragmen\ \\brar\es,
founclto be due to the ingestion of sweet clover computer-aldedclrug deslgn, combinational
hay. Investigationsof the later identified 3, 3 - synthesisand NMR-aiclecl drug cleslgnare recently
methylenebis(4-hydroxycoumarin)as a causative
agent. At the same tlme, warfarln, another introducecl weapons in identifflnglead skeletons.
coumarln derivative was routinely used as a I9.3 OPTIMIZATIONOT THE LEAD
haemorrhagicrat poison.Using both these leads, Once the lead nucleusls ldentified,it is easyto
various synthetlc compoundswere prepareclby exploit. This process is rather straight forward.
molecularmodifications. Variousapproachesare employed in order to
(3) Indanedlone,yet another lead was
improve the:deslredpharmacologlcalpropertiesof
clevelopedby rlng contractionof coumarin.This
the leadnucleus. lmportant amongst them, are
resulted in the introductionof phenindioneand
cliphenaclione. They exert anticoagulantaction by (a) ldentlflcatlon of the actlve part (the
inhibitingprothrombinblosynthesis as well as the pharmacophore):
synthesisof factors Vll, lX and X, through the Any clrugmoleculeconslstsof both, essentlal
formation of actlve cvcllc ketals. and non-essential parts.Essentlalpart is important
in governing pharmacodynamlc (drug-rec,eptor
CH., interactions)propergr while non-essentialparf
influencespharmacokinetic features.The relevant
groupson a moleculethat lnteractwith a receptor
are known as bioactivefunctlonalgroups.Theyare
R responsible for the activity. The schematic
representation of nature of such bioactive
cHr functionalgroups along wlth their interatomic
Postulatedcyclizationof vitamin K distancesis known as pharmacophore.

OH OH

Potential clic ketalstructuresof oral anticoaqulants

Prlneirlesof UcdlclnalChemlstry(Vol.ll) /m DrugDesign

Once such pharmacophoreis identified' H

structuralmodiffcatlonscan be done to improve H H
pharmacoklneticpropertles of the drug. For I I
I
example,the presenceof a phenylring, asymmetric
carbon, ethylene brldge and tertiary nitrogen are
found to be minlmum structuralrequirementfor a /

narcoticanalgeslcto becomeactive.Similarlythe H/C -N 3.604 H

presenceof two anionicsitesanclone catlonicsite
R _ N_R Type - Il : histamine
I
H.lCO

tlg. l9.t : Pharmecophorefor

nucotlc drug
5.6A" \-+.so t o.2A

Type-l: ant ihist amine

Ilg. 19.2 : PharmrcoPhorefor

chollncrglc drug
must be presentin cholinergicagent. Morphine'
the prototype narcotigagent has a pentacyclic
structure.The complexity of structure leaclsto
appearanceof several adverse-effects.Hence the
pharmacophoreof morphine has been recognizecl
tfirough moleculardissectionancl was usecl to
develop still simpler and even acyclicanalogs.For
example, methacloneis as potent as analgesicas
morphine. O active sites, having abili$ to undergo H-boncling'
tl
c:Hs
3.60A
TyPe- II : antihistamine
flg. t9.3 : The two nearly equally preferred but
slgnlflcantly dlfferent conformatlons for
hlstalnlne.
Similarly in estrogenic compounds two bio-
shoulcl be separatedby a minimum distanceof
8.5 Ao .
ln 17-B-estracliol, the clistanceis 1O.9Ao while
in cliethylstilbestrolit is 12.1 Ao .

CuHs cHr

Methaclone
HI cHr cHr
I
I
I I
/\ C
\/ I
oH cH.r
. L-l\ R
ts/ \-
TI

T y p e - l : h l s ta m i n e Buprenorphine
Principlesof MedicinalGhemistryffol. ll)
On the contrary,in certaincases,an IncreaseI n
structuralcomplexlty(increasedrigidity) is required
for selectiviglof action and to increasepotenqy.
Forexample,buprenorphine is aboutl0-12 times
potent than morphine and has a very low level of
clependence liability.
(b) tunctlonal group optlmlzatlon :
The activig of a clrug can be correlated to its
structure in terms of the contribution of its
functionalgroups to the lipophilicity,electronic
anclsteric featuresof the clrug skeleton.Hence,by
selectingproper functionalgroup, one can govern
the drug distribution pattern and can avoicl the
occurrenceof side-effects.Forexample,the amino
group of carbutamide (antibacterialagent) was
o example, sulphonamiclesare founcl to be
tl
s o 2 - NH- c - NH - ClHe
Carbutamicle: R= NHz
Tolbutamide:R= cHr
replacedby a methyl group to give tolbutamicle
(antidiabeticagent). Similarlyremovalof sulfon-
amiclesicle-chainof chlorothiazicle(an antihyper-
tensive clrug with diuretic activity) helpecl to
clesign diazoxicle (an antihypertensive clrug
without cliureticactivity).
cl
H H
H)NO"S
Chlorothiazicle
al
Diazoxicle
Sincea neurolepticactivity runs parallelwith
the c-adrenoceptor blocking actrvrry,plPeroxan,
(J
(: )-- N
lllc
Piperoxan Pentamoxane
/0,| Drr€ O.-gn
an alpha adrenoceptorblocking agent was chG€n
as a lead to get pentamoxanewhich showedhigh
neurolepticactivityin animalstudies.
The replacementof - Cl by CF3in ring position2
and the modificationof the basic side-chain to
includea piperazinemoiegl is thought to enhance
neuroleptic potency by increasinglipophilicity so
that CNS-entryof the drug is facilitated.
(c) Structure'actlvlty-relatlonshlp studles :
The physiologicalaction of a molecule is a
function of its chemical constitution.This obser-
vation is the basis of SAR-stuclies.SAR stuclies
usually involve the interpretationof activig in
terms of the structuralfeaturesof a clrugmolecule.
Generalisedconclusionsthen can be macleafter
examininga sufficientnumberof drug analogs.For
associatedwith diuretic anclantidiabeticactivities
in addition to their antibacterialactivity. The
generaliseclstructures neecleclfor incliviclual
activi$rare representeclbelow.
NH'
so.,NHR
Antibactedalsulphonamicle
;------J
Antidiabeticsulphonamides
(X =O , S orN)
HTNOTS S .N H
oz"\o
Diureticsulphonamides
Because of hepatotoxic sicle-effects of
hyclrazines
ancl hyclrazides,structurallycliversifi
ecl
compoundswere synthesized resulting into the
introductionof pargyline ancl tranylcypromine.
Principlesof MedicinalChemistry(Vol.ll) & DrugDesign

Tranylcypronnine was developedas a structural in a very graclualmanner.A homologousseriesis a

analogof amphetamineand is used as an anti- group of compounds that dlffer by a constant
depressantagent. Due to pronouncedeffect on unit, generallya CH2group. Forexample,the alkyl
bloocl pressure,the former was used as an substituentsof ethers,amines,estersand amides
antihypertensive agent. Furtherstructuralmocli- are easilyvariecl.Suchvariatlonshelp to iuclgethe
ficationof parglline skeletonresulted into cyclo- clepthanclwiclthof hyclrophoblc cavity presentin
grline. the target receptor.Usuallylncreasingthe lengthof
CH1 a saturatecl carbonside-chainfrom one (CHr)to 5
II (pentylto nonyl)producesan increase
to 9 atoms
HC = CH -CH, - N - cH)c6H5 In pharmacological effiects.FurtherIncreaseresults
in a clecrease ln the activity.Thls ls probably either
Pargyline
due to Increascin lipophilicltybeyoncloptimum
value (hence decreaseclabsorptlonand distri-
bution)or decreasein concentratlonof free drug
H C = C H -CH r - N - ( C H 2) r - O (i.e., micelleformation).For example,maximum
hypnoticactivity is seen from I -hexanolto 1-
Clorgyline octanol. Thereafteractivity decreasesfor higher
homologs. Similarly in a serles of 4-a-lkyl
CH.r substituted resorcinolderlvatlves,4-n-hexyl--
I resircinol(clinicallyused toplcal anaestheticin
cH2-N -- cH: - cuHs throat lozenges)was found to possessmaximum
antibacterial activity.While in a serlesof mandelate
Cyclogyline
(cl) Homologatlon : esters,n-nonylester has maxlmumantispasmodic
activity. ln the same series, branching leads to
Thevariationin the substituentcan be useclto
clecrease in the activig, probably due to inter-
increaseor decreasethe polarit5r,alter the pKa,ancl
ference with receptor blnding. For example,
change the electronlcpropertiesof a rnolecule. primaquine(an
Explorationof homologousseriesis one of the antimalarial agent)Is much more
potent than its seconclary or tertlarylhomologs.
most often useclmethod to inducethesechanees

NI CI
I
cflr- cH,'- cH: -

(i) (ii)

CI N CI
I
CHr- CHr - CHz - cHr
cHz-
(i i i ) (iv) Prochlorperazi
ne

Cvclizationof the sicle- chaln

Principlesof MedicinalChemistry(Vol.ll) 4{B On{ h*i

(e) Cicllzatlon of the slde-chaln : Over They are known as non-classicalbioisosteres-

simplificationof the structuremay sometimesbe Nonclasslcalbioisostersdo not have the sarr-
responsiblefor increasedside effectsand recluced number of atoms ancl clo not fit the steric and
acitivitjlor selectivity. Two straight forward electronicrules of classicalisosters,but thqy do
strategiesfor enhancingbinclingaffinity involve producea similarigrin biologlcalactivity.fluorine
re clu c i ng c o n f o r m a t io n a l f le xib ilit y a n d has the same size as hyclrogenbut is more
incorporatingsubstituentsthat bring aclclitional electronegative.l-'lence,it is used as an isosterene
blnding interaction.Changein the potency or of hyclrogento vary the electronicpropertiesof
change in the activity spectra can be brought the clrug without changing steric parameters.
about by transformationof alkyl side-chaininto MoreoverC-F bonclsare not easilybrokencluring
cyclicanalogs.Forexample,chlorpromazine (i) has rnetabolism.Hence the antitr
more neurolepticactivit5rthan its cyclicanalog(ii). fluorouracilis a powerful block
Similarlythe compound(iii) has anti-depressant enzyme than its naturalsubstrate,uracil. $lrrole
(imipraminelike) activitythan neurolepticactivity. ring may be sometimesused as non-classical
While in compound(iv) the antiemeticactivigl is isosterefor an amide to increasethe activityand
greatlyenhancecl. Similarlypartialrigidity may be selectivityof the drug" More recentlyBurgersub-
incorporated by introclucinga double bond, clivicledbioisostersas
alkyne,amide or aromaticring in the flexibleside (l) Classlcalblolsosters
chain. (a) Unlvalent atoms and groups r
Lockinga rotatablebond into a ring is not the Suchgroups Include
only way to rigidifu the structure.Sornetimes (i) Cl,Br,I (ii) CH3NHz,-OH and -SH
briclging of two carbon atoms (seconclary (b) Blvalent atoms and groups I
cyclization)also leaclsto an increasein potenqyor (l) R-O-R;R-NH-&R-CH2-&R-S-R;R-Se-R
change in activity spec-trum.Examplesinclude
thebaine(oripavine)derivatives,atropine,briclged (iD -COCHzR; -CONHR.; -CO2R;-COSR
piperazinederivativesof phenothiazines, etc. (c) Trlvdent atoms and groups
(f) Blolsosterlsm: The purposeof molecular (t) 4 H=; - N= ( i i )- P : ; -As =
moclificationis usually to improve potency, (d) Tetravdent atoms :
selectivigr,clurationof actionand reducetoxlcity. I I
Bioisostersare substituentsor groups that have (i) = c= ;= N = ; = P= ( i D_C-; - s -
similarphysicalor chemicalpropertiesand hence @ I
similarbiologicalactivitypattern.lsostericgroups, (e) R.lngequlvalents :
according to Erlenmeyer'sdefinition are iso- 0 -CH= CH- ; -S-(e.g.,benzene,thiophene)
electronicin their outermost electron shell. (ii) :CH = ; -N = (e.g.,benzene, pyridine)
Bioisostericreplacementmay help to decrease (iiD-O-; -S-; {H2 ; -NH-
toxicigror to changeactivity spectra.lt may also (e.g., tetrahydrofuran,tetrahydrothiophene,
alter the metabolic pattern of the drug. The pyrrolicline).
parametersbeingchangeclare molecularsize,steric Qrclopentane,
The size,3hape, electronlc distribution,lipict
shape (boncl angles, hybridization),electron solubillg,watersolubilitSr, pKa,chemlcalreactivity,
clistribution, lipid solubiligr,water solubility,the and hydrogen bonding are the parametersthat
pKa, the chemicalreactivityto cell components, influencethe potency,selectivi$land durationof
anclthe capacit5lto undergoH-bonding(receptor action of the drug. Bioisosterism becomes
interaction).Evenif the bioisostericreplacementis effective becauseit affects all the above para-
relativelyminor (Cl for CH3or vice versa).Cl may meters to less or more extent. In the design of
block metabolichyclroxylation, whereasCH3may bioisosters,the biochemicalmode of action may
be bio-oxiclizecland the compound may have play an lmportant role e.g., aspirin acts by
shorterhalf-life.Forexample,tolbutamide(R= CH3) acetylatingcyclo-oxygenaseenzyme. lsostersof
has shorterhalf-lifethan chlorpropamide(R = Cl). aspirin are inactive becausethey cannot release
Erlenmeyerclefineclisosters as atoms, ions or the ace$dgroup at all (X = CHz)or at an aclequate
functionalgroupsin which the peripherallayersof rate(X = S,NH).
electronscan be consicleredto be identical.These
are known as classicalbioisosters,where same
valency ancl biological activity are important. cooH
However, it is the retention of same biological x - cocH3
acitivity which determineswhether a group is
bioisostereand not the valency. Hence non-
isostericgroups can also be used as bioisosteres.
!i

Princlples ChemlstryUol. ll)

of Mediclnal M DrugDesign

(lI) Non-classlcalblolsosterss
ExarnplesInclude
(a) llalogens r Cl, F,Br,CF,CN
'cN
(b) Ethes: l
_s-; -o-, / N\
\

(c) Carbonyl glouP 3

o o o
(rl) C-arboxyllcacld group r ll tl
_S_OH
ll
; _P _ O H
,C_OH; tl I
o NH,,

o
il
- S:O
H
-cN I
NHz
l-lydrc;<amic
acjcl Aqylqyanamicle Sulphonami,cle
o o
ll tl
(e) Hydroxygroups-OH; -NH-C - R ; - NHSO2R;- CH2OH;- NH - C - Nl*lz
(0 Catechol:

H Ol N

(g) Thlourea: S N _CN

tl tl

(h) Spacer Sroup r

- (CHz)r
- ;

+
(l) Ionlzlng analogs: Ar - O H+ ; Ar NHSO2CH3 ATNHCN
Principlesof MedlcinalChemistry(Vol.ll) {5 DrugDesign

r9.4 APPUCATTON
Or BIOISOSTERTSm
IN Diethylstilbestrolhas about the same potenq/
DR,UG.DESIGN as that of naturallyoccurring estradiol.The central
(a) An important compound from catechol- double bond of diethylstilbestrolis highly
amine series is phenylephrinein which phenolic important for the correct orientation of the
hydroxyl group takes part in H-bonding with phenolic and ethyl groups (trans)at the receptor
bioactivesite on the receptor.The hydroryl group site.
can be replacedby other group having abilig to (c) Bioisosteric analogs in neuroleptic
unclergoH-bonding. Hence alkylsulphonamido categqry include
clerivativeof phenylephrinewas found to retain
activity.
OH - (cH2).1
- x
ICH- cH r - NHCH3 o
tl
where X =/C\ or CHCN
H

Phenylephrine
(cl) Bioisostericanalogs in anti-inflammatory
OH category inclucle
l
I
cH-cH,- NHCHr
o
ll
RO.'SHN C H ' - C -x
Alkylsulphonamidoderivative CH.,
(i ) X =OH
(b) A classicexampleof ring versusnon-qyclic (Intlorrethacirr
)
structureis cliethylstilbestrol
ancl I 7p-estracliol. (i i ) X = N H OH
=o N- N
tl
N --- N
x= H

trans-Diethylstilbestrol
cooH
CH.,
OH

( i) CH.'O;Z=C l
(ii) Y= F:
/.=

l7 B-estracliol o
Prlnclpbsol Medlclnal
Chemlstry
ryol.ll) 4(F Drugtl,erlgn

(e) Biolsosterlsmln Anti-histamlnlcagents Metoclopramldesharesfuaturesof both

R-X- (CHJn-Y ; X = NH,O, CHz antichollnerglc(-O- is blolsosterlcally
replacedby
NH) and antldopamlnerglc(antlemetlc)agents.lt ls
(i) Y = N ( C H 3 ) 2( n = 2 )
in factusedas antlulceragent.

(i i ) y= ( n = l)

H cl
(iii) NH
|= ( n = l,2)
HlCO
coNHcH2cH2N(C2H5)'

Metoclopramlde
(h) Pirenzepine,an antlmuscarlnlcagent,
possessesstructuralslmllarltSlwlth trlqyclicanti-
depressant agents. However, lt lacks anti-
depressantactivlty due to lts poor penetratlon
N ability In the CNS. Hence other trlcyclic anti-
depressant agents(e.g.,cloxeplnand trlmlpramlne)
Diphenhydramine Bioisoster are undergolngclinicallnvestlgatlons fur antlulcer
(lsobenzofurans) activity.
(f) The non-thlazide category of dluretic (i) Replacement of the lmldazolerlng (prone
agents has been developed by replaclng rlng SO2 to metabollsm)of the antlfungalagent ticonazole,
by carbonyl group. e.g., Qulnazolinonederi- with a 1, 2, 4-triazolering leads to fluconazole
vanves. havinglmprovedstabillty.
Table l9.l
Parent compound ' Blolsosters ActtYlty of percnt compound

Adenoslnedeamlnaseactivity
2
HO
Principlesof MedicinalChemistry(Vol.ll) 4n Dn€ erTn

OH OH
:- - CH .t

Anclrogenic
(+)

OH OH
{-CH.r

Anclrogenic
(+)
I
I
H

o o
tl
tl o-c-cH.,CH.r
o-c-cH2cH.r

Anclrogenic

I
I
H

CH
@
Hs-O
e
-l
IC Hor'/e Diuretic
6"C
ICH -NH - C (+)
tl
o

HO cH"cH"NH2
Increasesinhibition
HO
Dopamlne
(+)-+ activity of bioisoster similar to parent (-) -+ activity of bioisosternot similar to parent
compound. compound.
Principles Chemistry(Vol.ll)
of Medicinal 4(B DrugDesign

.l consiclereclas a side-effect today, may be

Table 9.1 contains a variety of bioisosters
(including classic and non-classic bioisosters) appreciatedas a therapeuticeffect tomorrow. This
which are either clinicallyuseclor used as investi-
will be possibleonly if two componentsof action
gational compouncls.If a particular substituent are based on clifferent mechanisms of action at
does not change the activity of the original essentiallyclifferentsites of action.
compound, it cloesnot necessarilyfollow that the
istamines with a strong
groups substitutedare bioisosteric"lt may simply
lorprcmazine) as a sicle-
be that substitutionat this site plays little role in
the interactionof the molecule with its site of effect were latter deveioped as neurolepticsancl
action. Accorclingly,groups can only be acceptecl tranquilizing agents. The tranquilizing properties
to be truely bioisostericwhen they can be replaced(strong seclation,state of inclifferentanct dis-
in a numberof clrugseries. interestwithout effectingsleep) of chlorpromazine
lnspite of the great success of the classicalwere obseryeclcluring its clinical evaluationas an
methoclsof clrug clesign,their unpreclictabilityancl
anti-h istamines.
the tremendous amount of wasted effort Sulphonamicles, used as antibacterial agents
expencled,have necessitatedthe clevelopmentof exhibitecl acidosis as a side-effect clue to its
more rational methods with a much higher inhibition o f renal carbonic anhyclrase.This
preclictivecapability, in an effort to project clrug
observation lect to the clevelopment of the
design as a science rather than an art. The
approach involving selection of leacl nucleus cliuretic, acetazolamicleand subsequently the
remainsunchanged,the organicchemistryuseclin chlorthiazicle group of cliuretics.Since guanicline
the design of its analogswas still there; however was found to lower bloocl sugar level, poly-
ways to select substituentsfor structuralmocli- methylene cliguanicleswere synthesizecl.To
fication were changeclancl moclels based on improve hypoglycemic action ancl to decrease
multiple regression analysis ancl pattern toxicity of these synthalins,biguanicles(e'g.'
recognitionmethods, using computer techniques phenformin)were prepared.
areemployedas aicls. I9.5 PRODRUGDESIGNING
The knowleclgeof clrug metabolismin vivo can
be utilized to improve a wide variety of drug Proclrugis a chemicallymodifieclform ofa clrug
characteristics.Using this knowleclge,an active which has a superiorcleliveryproperties.The term
drug is not modified irreversibly,but in sucha wayproclrugwas coined by Albert.
that it will be regeneratedby metabolicprocesses. Another similar term clrug latentiation'
Such temporarily modified structure usually proposed by Harper (1959) is defineclas the
inactivein natureis calleclas proclrug. chemical modification of a biologically active
compoundto form a new compounclwhich, uporr
The searchfor a new drug became a risky affair
clueto the monetarycost, the time involvecl(from in vivo enzymaticattack,will liberatethe present
7 to lO years) and high rate of failures.These compound. It refers to a pharmacologically
factorshave compelled the medicinalchemiststo inactivecompound that is convertedto an active
drug by a metabolic biotransformation at
fincl out new ways of putting the existing clrugsto
better use. Two major objectivesthat lie behincl appropriatetime and place in the bocly without
the optimizationof the lead nucleus- substantial direct elimination or untoward
(a) to maximizethe drug's desiredactivigranclmetabolism.Thisactivationmay occurat any time
during absorption,distributionor metabolism.For
(b) to minimizethe intensi\r anclfrequencyof instance, castor oil is a laxative because it is
side-effectsassociateclwith the clrug. Drugs hyclrolyzedintenstinallyto the active, ricinoleic
usuallyhave multiple pharmacologicaleffectsand acid. Another classicalexample is conversionof
the drug clesignertries to improve selectivityof prontosilto sulfanilamicle.
action.Theaim of a medicinalchernistshouldbe to Prodrug thus m4y be consicleredas clrug
optimize ancl not only to maximize the activity, to
containingspecializednon-toxic Protectivegroup
provide better affinityto the target sites.One of
utilized in a transientmannerto alter or elirninate
the ways is to improve the intensityof beneficial
undesirablepropertiesin the parentdrug.
side-effiectassociatedwith the drug. An effect
Principles Chemistry(Vol.ll)
of Medicinal 4ott
Proclrugdesigning is required to overcome
many formulation Pharmacokinetic or pharmaco-
clynamic clrawbacks.The prominent clrawbacks
include
(i) unpleasant taste or odour (gastric
irritation),
(iD a w,iclerange of adverseeffects,
(iiD shorter duration of action.
(iv) instability.
(v) site non-specificity,
(vi) poor absorptionor distribution,
(vii) poor water solubility.
(viii) some compounds are more active but
unable to reach the site of action (e.g.,
GABA).
19.6 TYPESOf PRODRUG
(a) Non'lntentlonal prodrug :
Sometimes, after aclministrationof the clrug
the metabolicstucliesinclicatethe proclrugnature
of clrug. lt becomesacciclentailyeviclent that the
activig of a clrug is becauseof its metaboliteancl
not becauseof the parent clrug. Exampleinclucles
the anti-inflammatoryagent, sulinclac.
(b) Carrler-llnked proclrug :
It is a compoundthat containsan active drug
linkecl to a carrier group that can be removecl
enzymatically,such as an ester which is hydro-
lysed to an active carboxylicaciclcontainingclru.g.
The carrier group must be non-toxic ancl bio-
logicallyinactivewhen detatcheclfrom the clrug.lt
shoulclbe removed easily to allow the active clrug
to be releaseclefficiently in vivo. The most
common reaction for activation of carrier-linkecl
proclrugis hyclrolysis.
A simple hyclrolysis reaction cleaves the
transport moiety at the aclequate rate (e.g.,
progabide,bacampicillin).
Targettlng of Drugs : The sicle-effectsassoci-
ated with a drug are the outcome of non-specific
distribution of the clrug administered.Targettecl
drug delivery not only decreasesthe side-effects
but also helps to lower clown the therapeutic dose
cl =Q
Dn,tg DEqr'
of the drug by enhancing the selectivity of ar'"acr
T h i s c a n be achievecl by selecri, -€
pharmacologicallyinert, ready to degracleand ntrl-
immunogeniccarriersto conveythe drug molecuks
selectivelytowards their target cells . The link
betweenthe drug anclits carriershoulclremaininen
ancl stable in the blood stream ancl extracellular
spacesbut should be sensitiveto the enrymes
present in or around the target sites.
Nonaparticles,microspheres,lisosomes,glyco-
lipids, antibodiesand peptide hormonesare being.
evaluatedas carriersfor a variety of meclicinally
active agents. At present targettecl drug delive4r
systems have been utilized for the chemotherapy
of cancer ancl protozoal diseases.lt may also be
extended in the chemotherapy of intracellular
infectionssuch as those causeclby protozoaand
vl ruses.
(c) Bloprecursor :
The bioprecursordoes not contain a tempo-
rarylinkage between the active clrug ancl a carrier
moie$, but clesignedfrom a molecular mcdi-
ficationof the active principleitself.
It is a compound that is converted to active
clrug through metabolic blotransformation.For
example, if the clrug colrtains a carboxylic acicl
group, the bioprecursormay be a primaryamine
which is metabolizedby oxidation to the alclehyde
which is further metabolizeclto the carborylic acid
clrug. (e.g. fenbufen, phenylbutazoneoxyphen-
butazone),acetaniIicle (Paracetamol), imipiramine
(clemethylimipram ine).
Similarly pyrrolines are the bioprecursorsof
GABA and its analogs. N-alkylaminobenzo-
phenoneswere clesignedto get in vivo benzo-
diazepinesby N-clealkylation of tertiaryamine and
ring closure. The linkage between the drug
substanceand the transport moiety is usually a
covalent bond.
Sulinclac,a non-steroiclalanti-inflammatory
bioprecursor,gets converted to the sulphicle
metabolite(activeclrug)via sulphone.
f,= H; Alprazolam
f,= Cl; Triazolam
Prlnciplesof MedicinalChemisfy (Vol.ll) 411 hTD-r

Prednisoloneand methylpreclnisoloneare
poorly water-solublecortico steroicldrugs. Preclni-
solone phosphate (PO3Na2)is a water-soluble
proclrug for preclnisolonethat is activated in vivo
by phosphatases.Methylpreclnisolonesodium
11\CO
succinate is a water-soluble proclrug of methyl-
preclnisolone.Since amiclasecatalyzeclhydrolysis
occurs rapiclly in human serum, water-soluble Naproxen- 2- glyceride
amicle prodrug forms of benzocaine can be (lessgastricirritation and higher plasmalevel)
preparedwith various amino acicls. tlg,. 19.5 : Llpophlllc carrler prodrugs
(b) Prodrugs for lmproved absorptlon and When ampicillin, is aclministeredorally only
dlstrlbutlon : about 4ooloof close is absorbecl.Hence ampicillin,
when presentecl in the form of its esters, has
Drugs applieclto the skin are poorly absorbecl. increasedoral absorption,e.g., bacampicillin,
Corticosteroids for the topical treatment of pivampicillin.
inflammatory,allergic and pruritic skin conclition-s
can be made more suitablefor topical absorption o
tl
by esterificationor acetoniclation.Once absorbecl CH-C_NH
through the skin, an esterasecan releasethe clrug. I
Examples include fluocinolone acetonicle ancl
NH.'
-o ff ft"
Co'-cH,-o-c-c-cHl
fluocinonicle.,Dipivaloylepinephrine (ctipivefrin),
a
Pi vr n r p i ci l l i n c c llr
prodrug for epinephrine, has better cornea
penetration rate than epinephrine and is usecl in
the treatment of glaucoma. Similarlyestracliol-3- o
benzoate-17-qyclooctenyl ether was designed for il
CLI-C_N}I
a sustainedreleaseformulationof oestracliol. I
N H-o
, O
ll
co,-cH-o-c-oc.Hi
OH l}rcanrpicillinc CH,
ICH (c) Prodrugs for site speclflclty :
- CH''- NHCH.l
The clesigningof centrallyacting clrugsneecl
ability to cross the bloocl-brain-barrier. The
approachis'baseclon attachinga lipophilic carrier
to the hycirophilicdrug in a loosely bound form.
(i) Epinephrine:R=H The complex releaseshyclrophilicclrug in the CNS.
(ii) D i p i v eftn:R = ( C H 3) 3C CO For exam-ple,p-lactam antibioticsmay be used in
the treatmentof bacterialmeningitis.Sincethe B-
lactam antibioticsare hyctrophilic,they enter the
brain very slowly, but they are actively trans-
porteci back into the bloocl. Boclorancl co-workers
have synthesizecl clihyclropyricline-penicillin
proclrugsthat deliver B-lactamantibiotic in high
concentrationsinto the brain.
The phosphoamiclasesare abundant in
neoolasticcells than in normal cells ancl hence,
cyclophosphamicle is developectby phosphory-
lating the nitrogen mustard.The clrug might be
hyclrolyseclin tumour cells by the enzyme phos-
Estracliol- 3 - benzoate - 17 - qycloocteirylether phoamiclases.
 Principlesof MedicinalChemistryOol. il) 412 DrugDcsign

y - glutarnyl
transpepri(hse

Nt{
,-

DOPA-decarboxylase
Dopalnine

Yet anotherexample of site-specificdelivery_

o
llo N acid (DOPA)decarboxylase
I leaclsto the clevelopmentof y-glutamyl_DOpAas
cHl
Another example is progabicle which is a
neurotransmitter,GABA.
a bowel sterilantthat is
/ [Jiven..An orally active
rcl (R = CH3CO) which
;, oxyphenisatin,in the
r5ls.
prodrug design is the conversionof clopamineto
L-clopaancl preparationof aliphaticand steroiclal
estersof GABA.
The high concentrationof trvo enzymes,
y-glutamyl transpepticlase ancl L_aromaticirnino
presentin the kiclneys
a selectiverenalvasodilator.
(cl) Prodrugs for stabllity :
Extensivefirst-passmetabolism in liver is the
most important cause that restrictsoral effective-
ness-of many clrugs. Metabolic stucliesof clrugs
provicle such clues as t
resistantto first-passme
oral effectiveness. For example, the maior
N H C H (C H .r),

ORr

anolol
R1=R2=Jl
H R= H; O x y phc nis at in metabolites of propranolol were founcl to be
Another approach for site specific propranolol - o-glucuronicle(R1= H, ORz= glucuro_
, .. clrug nicle),p-hyclroxypropranolol (R1= OH, & =-H) ancl
to ctesigna,proctrugthat requires
1:1,."._Zy_': an en?ymefounclpiedominanily its o-glucuronicle(R1= OH; ORz = glucuronide).
at
rne desirecl site of action. Diethylstilbestrot Hence oral aclministration of -propranolol
l^.1"11_Loy
cliphosphate(R : pO;l was designecl hemisuccinate(R, : H, Rz = COCH,'Cf-1,COOfil
for site- elevates plasma levels of propranolo-l about
specific cleiivery of cliethylstilbestrolto prostatic
carcinomatissues,since tumour cells were
founcl
to have higher concentrationof phosphal"les
amiclases than the normalcells. "nd

C:H s
1
C =c
I
C
Principles
of Medicinal flol. ll)
Chemistry
8 times. Similarlynaltrexone(R : H), unclergoes
extensive first-pass metabolism. When its ester
analogs,namely anthranilate(R = CO -o- NOzPh)
and the acetylsalicylate(R = CO -o- ACOPh)u sed,
the bioavailabilityof naltrexone was found to be
increasedto 45 ancl Z8'times respectively.
(e) Prodrugs for slow and prolonged release :
It can best be achieveclby making a long chain
aliphatic ester because these esters hydrolyze
slowly. This principlehas been well elaborateclin
the drug clesigningof sex hormone clerivatives
e.g.; progestinsor androgens.Examplesinclude
haloperidoldecanoate[R = CO(CHz)eCHsl which
when injected intramuscularly as a solution in
sesameoil, its activity lasts for about one mcnth
o
tl
C\,A,/
CI
in comparisonto haloperidol(R = H) as such
(2-6 hrs). Similarly another antipsychoticagent,
fluphenazineenanthatetR = CO(CH2)5CH3l and
decanoatetR = CO(CHz)e-CHrl have durationof
action of about a month in comparison to plain
fluphenazine(6-8 hrs).
cF,
(CH'').r- N. )'l - CHrCH, OR
When a glycine conjugate(R = NH CH2COOH)
of anti-arthritisclrug,tolmetin sodium(R = O -Na+)
is used, both potenry and duration of action are
prolonged becauseof the slow hydrolysisof the
prodrugamicle linkage. Among local anaesthetics,
o o
I ll
Hrc C cH,-c-R
R=O H
Tolmetin
( 338
413 Dqft
procaine is an ester, and is thg1sfg1s az<.ihr
hydrolyzed by esterases.By conversion of Jr
ester into an amicle (lidocaine),the duratlrr cr
action is increasedby severalfolds.
(fl Prodrugr to lower toxlclty proffle :
Examplesinclude the use of prodrug dipiva-
oylepinephrine(R = Me3CCO)insteaclof epine-
phrine (R = H) in the treatment of glaucoma.
Similarly,the side-effectsassociatecl with the use
of aspirinare gastricirritationanclbleeding.Esteri-
fication of aspirin (R = alkyl) greatly suppresses
gastriculcerogenicactivig.
cooR
o-c-cH3
o
Aspldn (R = H)
(g) Prodrugs to lmptove patlent acceptance :
Clindamycin(R = H) has a bitter taste,so it is
not well acceptedby children.lt was founclthat
by increasingthe chain-lengthof Z-acyl estersof
clindamycin, the taste improved from bitter
(acetateester) to a non-bitter taste (palmitate
ester). Bitter taste results from a compound
dissolving in the saliva ancl interacting with a
-N H
c- N
tl HO
o
scH.l
OR
ClindamYsin;R = H
bitter taste receptor in the tongue. Esterification
with long-chainfatty acids makes the clrug less
water-soluble,resulting into non-bitter taste. Yet
another example from this category is chloram-
phenicolpalmitate.
Thus in summary,proclrugconcept may be
utilizedto improve the undesirablepropertiesof
the drug.Suchunclesirable propertiesmay inclucle,
-

Prlnclples
of Medicinal
Chemistry
flol. ll) 414 DrugDesign

o
o \ ll
z CH'
_
o c_,.,2c\cH., OH

Hydrolysis
In cornea

C=O C =O
I I
CHt
l-
NHCHl NHCH]
Diisovaleroyl Adrenolone
adrenolone
Adrenaline
Flc. 19.6 : Ophthalmlc dellve of drugs (adrenallne dlesterc)
(a) Physico-chemicalproperties : e.g. poor (b) lmprgve site specific clrug clelivery;e.g.
solubilig, instability,unpleasnt taste or oclour. epinephrine.
(c) Prolongation of drug action e . g .
(b) Pharmacokinetic properties : e.g. poor testosterone.
bioavailabiliglclue to incompleteabsorptionor (cl) Decreasesicle-effectsancl toxicig : e.g.
shorter duration of action due to high rate of NSAID.
nretabolism. (e) lmprove t.rste ancl odour : e.g. chloram-
(c) Toxicities or side-effects: e.g. gastric phenicolpalmitate.
irritation.Sometimesdrug may be more active but (R Deiivery to brain : e.g. dopamine to
unableto reach its site of action. ln other cases, L-clopa.
clueto largevolume of clistribution,clrugmay get L-ctopato its methyl ester
clistributedto other sites alongwith its site r:f GABA to its aliphaticanclsteroidesters.
action. This leaclsto appearanceof sicle-effects, 19.8 DRAWBACKSOT PR,ODRUG APPR.OACH
becauseof clrug concentrationof unintenclecl Although the prodrug concept may be utilizecl
sites. In all such cases prodrug concept can be to improve the unclesirable propertiesof the drug,
applied.Howevertoxicig testingof prodrugis also it may becomea potentialsourceof toxicitiesif,
necessary. (a) the proclrug generates toxic metabolites
Oxiclationin liver which are not generated by the parer:t
Terbutaline Bambuterol
clrug;
(Proclrug)
(b) increasedconsumption of glutathione
Appllcatlonsof proclrugconcept : cluringthe conversionof proclrugto active
(a) Increasing absorption of drugs e. g. metabolite may leave vital cell consti-
ampicillinesters. tuents unprotected;

o o L H3 oH
R
tl
C
tl
C cH'-NH-
Ic I
CH CH' N H -C CH,
CH,
I
L- Hl
I
I
cH..

OCQR

Ketone-diestcr
ot t-butulinr: t- Bu tu l i n 0
Frhciplesof MedicinalChemistry(Vol.ll) 415
{c) rne rnert car er morew coutc not remaln
inert and leadsto formationof toxic metabolites.
cl) the prodrug orlancl carriermoieg generate
such metaboliteswhich alter the pharmacokinetic
featuresof the parent drug by either inctucing
metabolicenrymes or by competing the active
drug for bindingwith plasma-proteins.
r9,9 SOFTDRUG'CONCIPI
Prodrugsare cleslgneclin such a way that the
active drug is generated by the major metabolic
pathway. Proclrugsmight effectively eliminate
some toxicities by protecting the drug from
unwanted degradations, particularly those
occurringin Gff prior to and c{uringabsorptionor
possiblycluringthe first passagethrough the liver.
The application of the concept of 'soft drugs'
l s necessaryto overcome and to improve
(a) pharmacokineticinsufficiencies(b) transpor-
tability, ancl (c) site specificity.The soft drugs are
definecl as therapeutically beneficial agents
characterizedby a predictableand controllablein
vivo metabolismto non-toxic moieties,after they
achievetheir therapeuticrole. The site-specific
delivery via chemical moclificationsinvolves the
design of a soft drug from an inactivemetabolite.
The clesigneddrug is then transformedby facile
ancl predicted routes of metabolism ultimately
resultingin the delivery of the active clrug at the
expected sites o[ action. The concept was
successfullyapplied to local cleliveryof steroids,
clrugsacting on specificareasin the eye, brain ancl
testes. If it is possibleto cleliverpotent drugs
exactly at the site of action, very less close'will be
requirecl, which will . not cause unexpected
toxicities. For example, increaseclseparation of
activigl from toxicity (i"e" improved selectivity)
may be achieved by using 3-spirothiazolicline
derivative of hydrocortisone. Unlike hydro-
cortisone,it lacks specifichydrocortisonebincling
and affinig properties, even if it is absorbed
systemicallyduring topical administration.This is
because,the 4, S-unsaturatecl 3-ketone group is
absentin this derivative which is slowly generated
in clermalcells by stepwise hyclrolysisof thiazo-
liclinering to deliver the active 3-keto compound.
Usingsimilarapproach,an antiacnetopical proge-
steronepreparationwas developedcontainingthe
cystein 3,ZO-bisthiazolidine derivativeof proge-
sterone.
Dr-g D6€r
cH^,-..
I
C= O
---OH
ROOC
The concept of 'soft drug' may also be appliect
to clevelopselectiveand saferocular drug delivery
systems for the treatment of glaucoma, ocular
inflammations and infections. It was found by
Bodor et al. in 1978 that diester clerivativesof
aclrenolonehave a high level of ocular sympa.tho-
mimeticactivitydue to the conversionof formerto
adrenalinevia a combined recluction-hydrolysis
process in the eyes. Using same approach,
tertbutalinewas generateclselectivelyin the iris-
ciliary tissues by the action of reductasesancl
esrerases on ketone-diester precursors of
tertbutaline.
OCOR OH
ocoR
C=O CH_OH
I I
cHzNHCH3 cH,Nllcll.r
Diesterof Aclrenalone Adrenaline
Similarlypropranololis generateclat the iris-
ciliary body by the action of esterasesand
reductaseson the topically applied keto-oxime
derivativeof propranolol.
Q-cH z- C_ CHz- NI I CH( ClJ . r ) z
ll
NOH
The 'soft clrug' concept was utilized to
develop loteprednoletabonate,a topical anti-
inflammatoryl and anti-allergic
agent.
It is locallypotent but systemicailysafe.
Principbsof MedicinalChemistry(Vot.
il) tfl6
DrugOcdgn
Table19.2: Dual actlng hybrld noteculcs

o
duplicataon
o n-
asplrln aspirin diaspirin HO
ldentlcaltwin drug

o associatlon
HO

H
N
H
salicylicacid paracelamol acetaminosalol
nonldentlcaltwin drug

oHo
dicumarol
gossypol

rl

s02NH2

OH

IJ-blocker
+ diphenylalkylamine
Ca - antagonist + sullamidediuretic
B-blocker

ocH3

N OH
I
N prizidilol
p-blocker+ hydrazine OH
vasodilator
+ capsaicinpositiveinotropic
IJ-blocker
ry; NHZ
o
co2H
R'COHN

COrCHph,
Dual-acting
quinolone-linkedcephalosporin
as antibacterial
 of MedicinalChemistry(Vol.ll)
Principles 418
and this encouraged many groups to clevise
libraries around other strurcturalmotifs which
potentially offer other activity profiles.
Synthetic libraries that have been targetecl
more specificallyat a particularfamily of receptoror
enzyme, by incorporating a key recognition
elementfor bincting,are alsoavailable.One suchan
example i s the hyclroxamate libraries , of
metalloproteinaseinhibitors.
For novel targets, there is the requirement to
clevice libraries of fundamentally clistinct
structureswhich offer the best chance of fincting
novel screening hits. The synthetic hurclles to
such librariesare not inconsiclerable ancl it is not
surprising,therefore, that much more emphasis
has been given over the past two years on
applying software clesign techniques to enhance
the content of such libraries,while constraining
the size. One of the elementsof the ctesignthat
reflectslibrarycompositionis moleculardiversi$.
ln a new approach,the concept of librariesfor
information was proposecl, where in the
informatorymolecules,useclto proviclefingerprint
of the structuralrequirementof the target, have
been clesigneclon promiscuity rather than
cliversi$r.The overall clescriptionof a promiscuous
molecule is its proven ability to interactwith a wicle
range of targets.Subsequentlibrariesare clesignecl
and synthesized to allow the separation ancl
iclentificationof the specific binclingcharacteristics
that are relevantto a particulartarget unclerstucly
and this is achieveclby an iterativebut convergent
approachusing experimentalclesignand testing.
Library Diversity : One approach to procluce
diverse library products has been to ensure that
the set of precursorsuseclto constructthe library
are as diverse as possible. lf all the suitable
precursorsfor a given diverse site are groupeclon
the basis of some clesirablefeatures, such as
distributionof potential pharmacophoricpoints,
then selectingno more than one from each group
should ensurethat the set is cliverse.To produce a
diverse library, it is therefore desirableto assume
that everyprecursoris takenfrom differentgroup.
DrugDesign
,4.recentstuclyhas suggesteclthat maximizing
cliversity among the prect-rrsorset !'naV not
necessarily give the most diversepossibleset of
libraryproducts.Att alternative!s ic consiclerthe
products themselves.
diversi$ arn{}ngthe }ir,=.rary*
This may be measurctl by enumeratingthe library
proclucts ancl either clustering them and
attemptingto picl<as few cornpoundsas possible
trom each clusteror using a cell-baseclpartitioning
methocl attempting to picl<as Few compounds as
possiblefrom each cell.
l9.r I DECONVOTUTION
numberof solutionshave been suggestedto
the problem of cleconvolution.These inclucle
tagging beaclswith varioustypes of chemicallyancl
spectroscopicallyreaclablelabels or proclucing
librarieson siliconchips whose iclentitiescan later
be cletermineclby racliofiequencyscannings.Once
this informationis l<nown,selectivesynthesisancl
testing of all the compounds in the librarywith
that molecularweight will be requirecl.Sinceit is
desirableto l<eepthis worl< to a minimum, it is
sensibleto design a combinatoriallibraryto have
the smallestpossiblenumber of compoundsof
any one molecularweight, given the constraintsof
the requireclsize of the libraryand the availabilityr
of the precursoi. For a given number of library
procluctsall having the same molecularweight,
deconvolution will be simplified further if
substituentsused at the cliversitv sites have
clifferent moiecular weights. lt is therefore
desirableto minimize the substituentmolecular
weight redundanciesfor each given product
molecularweight. ln a 'mix ancl split' strategyfor
combinatorialsynthesis,the pools of compounds
that result from the acldition of the final diversity
sites are often not mixed. Since these pools are
screenedindivicluallvthe cleconvolutionproblem
appliesto eachsubpoolseparately.A librarydesign
strategymust thereforebe able to suggestpools
within each of which there is the minimum
products and substituent molecular weight
redundancy.
 Principlesof MedicinalChemistryflol. ll) 419 ILl€fr-r

lnitial'deconvolution'
t
Mostactive'hitpool'is
as 1Opoolsof 10com

Iinal 'deconvolution'
s
pool'is
Mosractive'hit
'l
as '10poolsJf comP

'Lead'identified

Fig. 19.7 : Example of deconvoluti on process;repeatedresynthesisof subsets of

ation of the active compound(s)in a mlxture
hit pools results ln the identific

Problem Slze : Ihe number of precursorsthat I9.IZ ADVANCESIN COMPOUNDTIBRARY

are suitablefor use in combinatorialmixture libraryr
is often larger than the number that can be
reasonably be used. Hencetypicalmixturelibrary
designproblemshavehugesearchspaces,the size
of which are best illustrateclby an example.
In a library, two sites of cliversity were
available,there were 36O commerciallyavailable
precursorscompatiblewith the chemistryfor Rt
and 259 for Rt. There are therefore, 92, Z4O
possiblelibrary procluctscompouncls.The clesign
of this library requires production of 1O,OOO
compoundsby combining l0O R1swith 10OR s.
The number of ways of selectingk objectsfrom n
ts:
nC k = n!/( n-k)!k!
And so the numberof librariesis
z5nC l m = 2.5 x 10164
3 5 o C roo.
PR.ODUCTION
Libraqlclesignis comple<problem,requiringthe
optimization of a number of often competing
factors, over a vast search space. Genetic
algorithms have been successfullyapplied to a
wicle range of such problems in both chemicalancl
non-chemicalclomains.A genetic algorithm is a
computationaltechniquethat mimics the process
of Darwinianevolution. A potential solution to a
problem is encoded in a representationtermed as
chromosome. This is typically a string of bits,
integers,real numbersor symbolseachof which is
termed as gene. A genetic algorithm operateson a
population of these chromosomes that are
generateclby assigning values to the genes in
chromosomes, often at random. A fitness
function measures how well adapted each
chromosomeis to its environment.

i
Principlesof MedicinalChembtry (Vol. ll) @ DrugDesign

There are two pre-requisitesto being able to phase,but capableof facilecleavageto free up the
apply a genetic algorithm to a problern.The first isfinal product.The ideal linkerwould be one capabie
to choose a representationthat allows every of product releasewith formation of a carbon-
possiblesolutionto the problemto be encodedin hydrogenbond in placeof resinattachment,thus
a chromosome.The second is that it must be leaving behind no memory of the site of
possibleto write a fitnessfunctionto decoclethe attachment on the solicl phase support.
chromosomeanclproducea scorethat reflectsthe Classes of potential drugs synthesized
qualityof that solution. recently by using solicl phase techniquesinclude
most promising new approach to drug 1,4-dihyclropyridinesand polyisoxazolines.
discovery concerns the synthesis in one-pot more general separation technique, which
reaction,without isolation or purificationancl the introclucesthe concept of'third phase, the so
reactionmixture is screenedusing a competitive called fluorous phase relies on the. preferential
bincling assay basecl on pulsed ultrafiltration, partitioning of heavily fluorinateclsubstratesinto
electrospray mass spectroscopy (PUF/ESMS) fluorinated solvents such as FC-72. which can
which tentatively iclentify those clerivatives then form a third phase separablefrom both, the
havingthe highestaffinityfor the target receptors. aqueousphaseand common organicsolvents.
As a model system to test this approach. a In librarysynthesis,either reactantor procluct
syntheticschemedesigned to preparea seriesof can constitutethe pre-fluorinateclsubstratewhich
analogs of the aclenosinedeaminaseinhibitor, then is separated from organic or inorganic
erythro-9-(2 - hyciroxy-3-nonyl) actenine(EHNA), contaminantsby liquid-liquid extractionvia the
as diastereomeric mixtures,was carrieclout. Pulsed fluorinated solvent. Thus spectroscopy and
ultrafiltrationscreening of the crude reaction chromatographycan be used to both, monitcjr
mixtures against controls without protein, analyticalpurigl and as a preparativetool to isolate
cletectedprotonateclmoleculescorresponclingto purified procluct.
EI-lNA-typederivativesancl three of its linear,alkyl
In conclusion,the synergy of structure-based
homologues. lt, clicl not show protonated
designwith combinationalsynthesisis an obvious
molecules for an isobytyl or benzylic EHNA
marriagein enhancingall technologies.As can be
derivative,suggestingthe latterwas inactive.
seen, there are many design strategiesfor lead
An important feature of combinatorial generationlibraries.All share certain aspectsin
chemistryis the synthesisof compoundson solid common,notablythe desireto reclucethe physical
support allowing "split ancl pool" methodologyto size of the library while maintainingor enhancing
be employeclfor library construction.The method the informationcontent.
involves the use of an appropriate linker to tether
the initial starting substrateto solicl support. The ooo
linl<erneecls to be stable cluring the synthesis
( e1)
Principlesof MedicinalChemistry(Vol.ll) @ Synthesis

O-C: O
HN(CH:)Z

3-Pyridinol Dimethvlcarbamovl dimethyl

3-Pyridyl
chloride carbamate

(2)ADRENERGICDRUGS:
(a)Norepinephrine:

CCt,4l NH:
clcH2cooH
POCl.l
ctcH2co
Catechol Chloroacetic
acid

Pd/ RaneyNi

Norepinephrine

(b) Methyl dopa :

ocHs conc.FlCl,0"C ocH.r

aq.NaNO, cHz-c-coocH3
-5"ro-lo"c Acetone.
8 hours
HzN ocH,r ocH.l

9cH, OCH
ocHr ocHl ocH.
i) HCOOH 857o Liq.NH,,
100"C,2hours cl cl
ii) NaOH
C - COONa cH,-
IC - COONa cHt -
II
I I
I I
a-"'t
H- CHI CH:
oH

48%'HEr
NH"
Heat
CH,-
t-
C- COOH
I
I
CH., Methyldopa
 of Medieinal
Principles (Vol.ll)
Chemistry @ Syntt€sis

(c)Isoproterenol:

ccl4/ (cH.r).'cHNH2

c
ll
Catechol Chloroacetic
acid o

Pd/ RaneyNi

Ist-rproterenol

OAc OAc
cH2oH cHroAc
(cH.rco)20,
csH5N (cH.r)]cNc,
cH..cooH
c6H6.
a (CrH-5)?O.
Roorntemp.
l0 days
CHO
4-Hydroxy-3-hydroxymethyl
benzaldehyde CH,QH
LiAIH
24hrs.,Reflux

(e) Propranolol:
cHl

+ CICFI?- CH - CH2 + H"N - CH

cHr
OH
(i) NaOH,C2H'OH
at 100'Cfor l0 hours
in sealed
tube

cHl

-cH2-NH- CH
OH CH:
Propranolol
Principlesof MedicinalChemistry(Vol.ll) &4 SYnthesis

(f) Isoxsuprinehvdrochloride
o o
tl - NaCl il
ONa + CICH, c cHl ocH? c-cH1

Reduction
amlnatlon

O NH'
I
t-
-ocH2 - cH-crt
cH-crl
cHt
/rLf
\-r rl
An amine
An amrne

ItH

(ii)
tl | , HCr
nL l
OH

cH-

hYdrochloride
Isoxsuprine

(g) Naphazolinehydrochloride :
(

HCHO ; HCl
rloromethylation
I

Naphthalene chloride
i-Naphthyl-methyl

Lfl2Ll't
" -*

I -Naphthyl-acetonitrile

175"- 200"c

Naphazoline
hydrochloride
Principles Chemlstry(Vol.ll)
of Medicinal M Synthesis

(h) Metaraminolbitartarate:
o
tl Yeast
c-H c-c N- cH,c6
additives

m-Hydroxybenz
HO
acetylcarbinol
aldehyde m-(hydroxyphenyl

OH NH.

c-c N -c H ,
HH

(i) Ephedrin :

Br
I
+ CH , CH COBr

c - Bromopropinyl
bromide

H
Ephedrin

(3) ANTIHYPERTENSIVEAGENTS:
(a)Guanethidine :
monosulphate

ctcHzcN
nitrile
Chloroaceto

Guanethidine
monosulphate
Principlesof MedicinalChembtry(Vol.ll) Synlhesb
'f,26

cH.,Br

p-Toluene
acid
sulphonic

(c) Hydralazinehydrochloride :
OH
cooH NH POCIr N
- HrO
+ HrN- NHz IN IN
cHo
Lactim-form
o-Aldehyde-benzoic
acid Hydrazine

NH .NH, C1

N (i) H?NNH, N
IN HCI <-4
(ii)- Hcr
IN
HV(lralaztne
nvorocnlonoe Chloroderivative

(d) Hydroflumethiazide:

F.,C Noz Frc NO2O2N CF.,

Na"S + S / H,o
cH.cooH
+
ss

F.,C NHz Frc Not Frc Noz

Fe/ NHocl NH4OH

so2NH2 so2NH) sorcl

H
(i) CISOTH
at l50C Frc NHt F.rc
HCHO
(ii)NH4oH
H"NO"'S sorNH? HTNOTS

o/
Hydroflumethiazide
Principlesol MedicinalChemi*try(Vol.ll) a7

(e)Phenoxybenzanrine
:

OH

An alcohol

(i) Benzylchloride OCH,,CHCHl H"NCH,'CH,OH

(ii)socl, HNCH,CH20H
cHrcH2cl
Phenoxybenzamine (A secondary
amine)

(4)ANTICONVULSANTAGENTS
(a) Diphenylhydantoinsodium:

+ (NH.),CO3

Benzophenone Diphenylhydantoin
sodium

(b) Trimethadione:

H,c
HCN HlSO4/ CTH5OH
-+
Hvdrolvsis
/ Esteriflcation

Benzophenone Acctonecvanohvdrin Ethyldimethyl

glycolate

C'H. - ONa.
O = C (NHr)r

HrQ
o NaOH
H.,C (cHr)2s01
N- CHl

Trimethadione 5, 5-dimethyl-
oxazolidine-2,
4-dione
Prlnciplccol ttledlcinalChem.turyOol. lt) a8 Synthcds

(c) Ethosuximide:
o o o
tl tl tl
HsC- C-C 2H5 NC - CH2- C- O C2 Hr :H 2 - C - OC 2 H 5

cH3 cN
Methylethylk etone Ethylcanoacetate Ethyl-2-cyano-3-methyl-
2-pentenoate

(i) Protoncatalyzed o
HOOC-C-CH(CN)-COOH
saponification tl_oc2H5 HCN/C,H.OH
(ii) Decarboxylation cHz- c
I
cHr CN CN
2-Methyl-2-ethyl Ethyl-2,3 - dicyano-
succinonitrile 3-methyl-pent enoat e
H
I
o N
ll Cyclization
- NH,
:H( CN) - C_ NH2
CH,
CH,

Ethosuximide

(5) SEDATIVE.HYPNOTICS
(a) Phenobarbitone:
NaNH, (i ) N a/E t.,O
(ii) c2H5l

CN
(i) Urea I
CoH-t-
(ii) NaOCrH,
cooc2H5

KNH2/ Liq.
(cHr)" CHCH2CH2l
Ro o mtemp./l hour

(cH3)2
cHcHrcl
L iq .NH.,/O= C( OC2 H' ) 2
Princlphsol Medicinal (Vol.ll)
Chemistry ffi

CINCO
cfllcHo tl l l
CHTCH"C: C - MgBr CHI C- C- CH- C
(i i ) PC ls
bromide
I -butynylmagnesium

CHi
Ethyl-(l -methyl-2pentYnYl-
cyanoacetate

CH = CHz CH,- CH
n-Methylurea CH"CH= CH,'- _Br
<==_i.!--

I = CC'H5 H.C'(
I
., cH,l

Methohexital Ethyl- (l methyl' 2 pentynyl)

allyl cyanoacetate)

(d) Thiamylalsodium:

o o
ll tl HCI/Et-OH ;
CICH2- C-O H + NaC N + NC- CH"- C- OH
Monochloro H5 c,o 1
aceticacid
Diethyl e STer ol malonicacid

I
Br - CH ?- cH = CH1

z
trz
CH' CH= CH' z CH'CH= CH'
/ 2 - Bromopentane a
./

c c

I
Diethvlesterof allyl malonicacid

o
tl

(ii) NaOH
lt
O CHI

ThiamYlalsodium
Principles
of Medicinal
Chemistry(Vol.ll) €0 Synthesis

(6)NARCOTICANALGESICAGENTS:
(a) Dextropropoxyphene
hydrochloride:

+ HN (CH,), + HCHO CH"- CH, - CH"N(CHj)2

Propiophenone Mannichbase

o
ll
'opionylation
( C H r ) ,N C l
Cl

Dextropropoxyphene
hydlochloride

(b) Pethidinehydrochloride:

(cH.,cH,)oH),,

t
Benzylchloride Benrylchloride

Bt

Ethyl-4- phenylisonipecotate 4 -Cyano-4- phenylN_benzyl

piperidine

cH,
tJ
I
N

(ii) HcF
'cooc2Hs' Hcl
(iii) Hcl

Pethidine
hydrochloride
Principlesof MedicinalChemistryflol. ll) 431

(c) Fentanylcitrate :
o o
lt tl
CH, -CH z - C - C l + H-N - HCI cH3cH'
C -N N_H
Propionylchloride

N - (4 - piperidyl)
- anilline N - (4 - piperidyl)- propionate

(i) Phenethyl chloride

cHrcH2
co - cH)- cH,
(ii) Citricacid

cH"cooH
HO-C - COOH
Fentanylcrtrate cH2cooH

(7)NON-STEROIDAL
(b) Ibuprofen:

cH2cH(cH3)2

C *COCI
(OC2H5)3 Pd/ (H) (oc2H5)2
co
Alcll NaOCrH.

cH(cooc"HJ,

(i) H NaOCrH.
/ CH.,I
(ii)-co2,A
HOO C - H C - C H 3 HrC-C-(CO O qHs ) 2
Ibuprofen

(b) Oxyphenbutazone:

ocH2c6H5 NaOCrH.

o? N

p - Benzyloxyhydrazobenzene Diethyl- n - butylmalonate

fr+r

Prlnciplesof MldicinalChembtry(Vol.ll) & Synlhcalr

(c) Indgtnethacin:

HsCO H3CO cH,coocH"

EIOH/ HCI 80'c
NH cHr
frrr*"r"'e
o
..1
lsoDutvlDenzene

H3CO H3CO cH"coocH-.

N HCI N cHr p-Chlorobenzoylchloride

C
Io I
Co

Indomethacin

(d) Meclofenamatesodium :
COOH cHr COOH CI CH:
Cu- Bronze NH NaOH Meclofenamate
HzN +
- Hl sodium
cl
o-lodobenzoic
acid 2, 6-Dichloro
m-toiuidine Meclotbnamic
acid

c
I
Ivlethylpyrrole
Acetonitrile

N cHrcN
Fridel- Craft'sreaction
- HCI
Tolmetinacetonitrile
C
IN
CHTCOONa
( ii) Na OH

Tolrnetin
sodium
Frhclpler of MedicinalChemaltry(Vo[ n) tsB

(f) Flurbiprofen:
o (i) Wilgerodt
ll
c (ii) reacuon cH2co
I
-
Esterification
cH3
An aceticester

(cooc2H5)2
(i) H*/ H"O I Alkvlation
c-cH. #-
(ii)-co,
(cooc,H5)2
cH-cooH
IcHr
Flurbiprofen

ITAMINICS:
]nrramlne:

p-Chlorobenzy $ridine 2 - (p - Chloro)benzyl

chloride hydrochloride pynolne (andpheniramine)

(b)Tripelennamine:

+
/ [Hl
Catalyst
CH= N CH2NH
cHo NH ,

ctcH
\a".,.
N. N-Dimethylamino
I flDelennamlne ethylchloride
Prlnchl€! ol MedicinalChernislry(Vol.ll) 4

ZnlllaOH

l,
Benzophenone Benzhydrol
-l ll
eflux

lmrne

(d) Pyrilamine maleate:

clcH2cH2- N (cH3)2

2-Dimethvl
aminoethvlchloride

(i) p-Methoxybenzyl
chloride
(ii) NaNHz

.cooe

Pvrilamine
malbate Pvrilamine
base

(e)Antazolinehydrochloride:
N c N

coHs-cHz-NHC6H5 N -C H 2
I IH
H

Antazoline
c N-
HCI
N -CH 2 N
IH

Antazoline
hydrochloride
1
Principlesof MedicinalChemistryflol. ll) r*35

i9) ANTIDEPRESSANTAGENTS:
(a,tAmitriptyline:

(cH,),N-(CH.,)1Cl cH.cocl/cHCl.
---:-a-4>

- (cH.t),
(CH').rN cHcH,cH"
I
AmitriptylineN(cH

Impiramine:

Iminodihenzyl I-chloro-3-
(N-methyl- N - carbethoxY)
Propane

HCHO/ HCOOII

N
I
cH2cH2cH' C - NHCHl

(c)Doxepin:

cHr cHr CH,Br (i) CuH.ONa

socl2 Br, (ii) MeOH/ KOH
(iii)Hcl
cooH cocl COBr

cH2oc6Hs
(cH3)2N(CH2)3CI socl, / N2

cooH
tl

(i) Mc,A 2- Be nz y lo x Y
(ii) NH4cl Dibenz(b,e) oxepin- I I -one
benz oicac id
(iii)Hcl
o

CH-CH
Doxepin
 (Vol.ll) ts6 Synthois
Ghemistry
Prlnclplelof Medicinal

( IO)TRANQUILLIZERS:
( andDiazePam
a) Chlordiazepoxide

NH.,OH.HCI NFI" (i) ctcH"cocl cHrcl

csH5Ni c'H5oH (ii)cH,cooH
c= N-oH
**o
cuHs CI
I coHs
2-Amino-5-chloro cuHs
benzophenone 257omethanolic
cHrNH,

CH. NHCHl
I I
c
I Ni HCr
(H)
\ cl [-t'\o cl
CuHs cuHs CnHs CoHt

Diazeparn Chlordiazepoxide

(b)Nitrazepam:

trH: NHCOCH.,llr NHCOCH"NH?

C IC OCH'B r dioxan/ NH.
loc6H5 o ,N coc(,H5 coc6H5
_

165'- I 87"C
For5 rnin.
c6H5
Nitrazepam

(c) Chlorpromazine:

hur
h CH" = 61'1611
/ 507oNaOH
A / 5 hours
cl
H

. --'tr,- -c- -a\-

Raney
Ni(H)
DMF
cl
IcH2cH2cN
Chlorpromazine
Principles
of Medicinal
Chemisrry
(Vot.il) g7

(d) Haloperidot:

CI

CH.rMgBr ( i) NH4 C| /HCHO

HBr/CH.COOH
(ii)CH,O",
(iii) aq.atkati
"a,
cocH.l H ., C=C-CH.,

Aq. NaOH
o- C - (CHz
l,
l,
I
OH
O=C-CI J2CH ' C H. , _N Kt / c6H6
t00" llO"c
Haloperidol

(e)Tlbamate:

CH,
I CH,
Hsc'ooc
Toluene,
phosgene
H,SO4(dil)
cooc?H5 dimethyl-anitin-
cH2oH
Diethylmethylpropylmalonare
2 - Methyl - 2 - propyt_ l, 3 _propanediol

CH,
I
I CH,
CH.r(CH,)-TNHCOCH n - Butyiamine
I I_
_- cH2cH2cH3
cH"oH
cH2oH
2-M e r h y i- 2 - p r c
propylbury 2-Methyt-2 - p n
propylchlor

Ethyl urethane cH.1

[(CH3)2CHO]3 Al I
cH3(cH2)3NHCoocH"
_ c -cH2cHzcH3
I
clH2ocoNH2
Tlbamate
Prhchlcl of ilcdlclnal ChGmbtry(Vol'll) tB Syntr€.b

($ Meprobamate:

UnderN,

Urea/ alu.isopropoxide
- c
cH3cH2cH2

Meprobamate

(g)Ttifluoperazine:

NaNHr/CoHu
Br(CHr)rCl
l8 hours
/A
CFr N cFr
I
cH2cH2cH2cl

(i) H -cH
NaI/ CTHTCOCH,
-CF,
(ii) A
2cHrcH2 - cH., (iii) H2O/HCI

Trifluoperazine

(TT)ANAESTHETICAGENTS
'(a) Ketamine:
Cl MgBr o o
il 1l
CN c c
(i) Retlux72 hrs. Br, / CClr
+
(ii) H2o

o-Chlorobenzo-Cyclopentyl
magnesium
nitrile bromide

N - CH.,

A / 2.5hrs. llc cH3NH2

OH
Ketamine
Prhcbh. of l|€diclnalChombtsy(Vol.ll] m Syrdti

(c) Dibucainehydrochloride:
cooH

(cH3co)2o NaOH
.T
H cocH3
Isatin N-Acetvlisation ic acid
2-Hydroxycinchonin

coNHcH2cH2N(C2Ht2 cooH
(c2H5)2NCH2CHzNH2

cl cl
2-Chlorocinchoninovl
chloride

+
coNHcHzcH2NH(C2Hs)2

CI
ocH2cH2cH3

Dibucainehydrochloride

(c) h,ocaine :

coocFl2cH2N(c2H)2
Xylene
ozN cooH+ HOCH2CH2N(C2HJ2
- Hzo

P-Nitrobenzoic
acid
Noz

HCI Pd(H)

czHs
ozN

Procaine
 of MedicinalChemistryryoLll)
Principles 41

(13)CNS- STII\IULANT AGENTS:

(a) Nikethamide: r\
ll
cooH c--o--so-, D i c th y l
bcrtzenc
a HO.1S
- H.,O srrlphonamide
co
II
Nicotinicacid sulphonic
Benzcnc rcid N (C 'H .,-
Nikethamide

(b) Bemegride:
c
H.1 Cz[ls
FIrc Hs
- Ii,o Cy l t nr t 1 1 q g 1 1 -
C + CH.' -_+ NC coNH,
nridc
il
o NC
CONH. O= C CN
I
I
NH-'

Hrc C tH t H.,C H,C

NC NC CooH str,,ng
bur. NC
Decarboxylation

N NH N N
I I I
H FI H
Bemegride

(T4)SEX HORMONES:
(a) Diethylstilbestrol(Doddsetal r939):
ol.t o
KCN I tl
2CH10 cHo cH,ro CH - C ocHr

Anisaldehyde Arriosion
o
CH,COONa/ C2llil il SnCl.'
cHro CH'- c ocH.l

Deoxyanisoin
H

cH3o ctt-c OC CH-C ocH.1

tl I
o H
C-,I
Bt,

EthanolicKOH
C==C oH *-frfi;i;- cH3o c- c
I I
crHs czHs
Diethvlstilbestrol
Principles
of MedicinalChemistry(Vol.lt)
42

(b) Dienestrol:

o C"H. OH
tl Na/Hg l--l
2HO c - cH2cHj c-c
(Reduction) OH
rl
oH c
para- Hydroxypropio-phenone

o cHCH o (i) c6Hscocl

tl tl il
c-o C-c o-c (ii) CH.COCI/ Ac.O
tl
cHcH3
Die stroldibenzoate

c,'HiOH
HCI-l.r

C- C
il
tl
H. CCH

Dienestrol

(c) Progesterone
(Marker etal, 1940):

.AcrO

200"c

HO

Diosgenin

ft'
C= O f"'
C= O
f",
C =O
(i) H, - Pd
Openauer (ii) Hydrolysis
oxidation

Progesterone Pregnenolone
 !
J
I o
T'
(d) 1 7 B- e s t r a d io l: o
ln
o
=
o
CL
o
:
0t
()
CrO,- AcOH 1i) Zn- AcOH 5
o
(ii) Br, ---.+
(ii) HydrolysisU a
o a

Br Br Ac
c
Br Br
Cholesterol uenvoroeDl
androstel'one
o
Cholesteryl
acetate
dibromide

ococ6H5 ococsH5 OH

Br,/ HBr Oppenaur

oxidation (i) Benzoyl chloride
(ii) Mild hydrolysis
CH-.OH - NaOIi

o
I
A
ococ6Hs ococ6Hi ococ6H5
Refluxwithpyridine Heatat 500'C
in tetralone
solvent

OH

Hydrolysis
with KOH

estradiol
 .o
t
o
!
o
o
o
(e) l9-norsteroids':
OH OH =
o
OH e
o
t
D
o
t
o
Birchreduction HOCH2CH2oH 3
.--- at
Li lNHl p-Toluene acid
sulPhonic
H3CO H3CO
o
Ketal
Estradiolether enolether
Unstable

CrO. / Pyridine K C=CH

.------z-
F
o
l7 - Ketoneketal l 7 - a - Ethynyl- l7 p - hydroxyderivative

+
H

= CH = CH

't- +

Norethisterone (isomerof norethisterone)

Norethvnodrel U'
(impuritY)
Mestranol t
:'

I
 !
J
o
(1s)coRTrcosTEROrDS: E
o
U'
(a) hednisolone : o
AcO cH,' =
o
\ a= o I c
C= O c--o o
3
o
Marker's
Selective o
degradation c0-, (i) NaOH hydrogenation
t
o
3
AcrO;200'C tii) rbutyl U'
alcohol H,/Pd
o
cl{1
I
C=O
CH.,
I
C=O Rhizopus
nigricerns C=O (i) Benzene
f",
C= O
( i i ) Cyclohexanone
( i i i) Al (isopropoxide

| | -Hydroxyprogcslcrone Progesterone
Diethyloxalate,
Na-methizide
cH,cocooc-,Hi
cH,oH
H C _ OH |'-

cH.,COCOOC,Hs cH,cooH C= O
CH'OH
CH
I I
CH C= O
(i) CrOr
( i) llydrolysis (ii) C.,11-t DDQ
( ii) LiA tH{ ( i i i ) A c ,O
C'onisol

Prednisolone
DDQ: DicylnoDichloro
euinonc

U'
I
 !
t
o
!
o
6
c t {r
(b) Betamethasone: CH,
I
c=o Cl=6
1",
C=O
o
3
o
CL
o
J
o
o
5
Rlrizoous nisricans CrO.' o
+
Dioseenin ' _:dt 3
a
o
o
Progesterone I I -Hydroxyprogesterone

CH. CH, CH. CH.

I I I I
C=O C=O C= O C= O C= O
cHr N=N
cHr Hzoz A c.tv
Catalyst -r -N ?

s
CH. CH,OAC
I tHroAc
C=O C=O C= O
N-Bromoacetamide
cHl CHI CH:
& HCIO4in dioxane
&
water(Ac"O/HOBr)

CH,,OH CHTOAc
l- CH,OAC t-
C=O C= O

cHr CH: cHr

Anhvdrous HF in
F E
tetrahvdrofuran
o @
 E
a
o
!
o
o
(c) Triamcinolone: CHrOAc o
cHroAc
Ic =
o
1. C=O o.
o
cHroAc CHTOAc :
D

C=O C=O
o
t
o
3
SOCI"/Pvridine
at - 5oC --OAc o
Darzen's
dehydration Grignardreagent (i) AcrO
O o
(ii) B-Bromoacetamide
andHCIO.in
dioxane
and
watermixture
Ac"O/HOBr
Ethyleneglycol
&
p-toluensulfonic
acid CHTOAc CHTOAc
t- t-
C=O C=O C= O

-OAc KOAc/CH.COOH -OAc $

<-.-- -OAc

C= O C=O
-OAc HO
-OAc -oH

(i) Cornybacterium
simplex(-Ac) Acetone
I
(ii)DDQ F Triamcinolone
acetonide

Triamcinolone

o
ID
6
l. Tracethe evolutionof oral contraceptives.Indicatethe currentfields of activity in this category,
stressingupon their prospects.
Z. Give the chemistry,mode of action and mode of administrationof oral contraceptives.Outline the
synthesisof diethylstilbestrol.
3. Give the variousways through which fertility can be controlled.Give an enlightenedaccountof the
various formulationsof oral contraceptives,with examplesof clinical agents.
4. Discussthe constitution of estrone. Give its relationshipwith estradiol and e'striol.
5. (a) Write note on 'Oral Contraceptives'.
(b) Give the structureand IUPACnamesof
(i) Testosterone (ii) Estradiol
(iiD Lynoestrenol (iv) Mestranol
(v) Norethindrone (vii Norgestrel
6. (a) What are corticosteroids ? Write their mechanism of action. Give the synthesis of
prednisolone.
(b) 'The minor changesin the steroidalstructurecan causean extensivechange in biological
activig." lllustrate above stateinent with referenceto steroidal anti'inflammatory agents
current! in use.
7. Write short notes on :
(i) Aclrenalcortex hormone
(ii) Topicalanti-inflammatoryagents
(iii) Non-steroidalestrogens
(iv) Mineralocorticoids.
8. Give the route of synthesisfor :
(a) Triamcinolone (b) Betamethasone
9. Give the structuresand IUPACnamesto :
(D Triamcinolone (iv) Dexamethasone
(ii) Fluclrocortisone (v) Preclnisone
(iii) Paramethasone (vi) Fluocinolone
10. (a) Draw the structuresand give IUPACnamesof :
(i) Cholesterol (iv) VitaminK
(ii) Cholecalciferol (v) Niacin
(iiD Paramethasone
(b) How is the structureof Riboflavincletermined?
1 l. Draw the structLrres of any five water solublevitamins.Give the synthesisand biochemicalrole of
VitaminB or VitaminC.
12. Write short notes on :
(a) Haemopoieticvitamins (cl) VitarninH
(b) Steroidalvitamin (e) Ascorbicacid
(c) Antipellagrafactor
13. Define the term 'Vitamin'. Draw the structuresof fat soluble vitamins. Give the synthesisand
biochemical role of VitaminA or VitaminD.
14. Givethe biochemicalrole of :
(a) Vitamin86 (b) Folicacid
(c) Hydroxycobalamin (cl) Pantothenicacid
I 5. (a) Discussin detail the chemistryr of acetylcholine.
(b) Relate the structural features of bethanechol,carbachol and methacholine with acetyi
choline.

4tt8
 Princlpb of tledlclnal Chenristry(Vot.ll) tltlg SampbOueetlons
1 6 . What are reversibleand irreversibleanticholinestrases ? Give mechanismof action of irreversible
anticholinestrases.
1 7 . Givea detailedaccountof SARof parasympathomimetic drygr.
1 8 . Givean enlightenedaccountof the cholinergicreceptors.
1 9 . Write short notes on :
(a) Cholinergicagonists
(b) Reactivatorsof cholinestrases
(c) Antispasmodicagents
zo. Give the classificationof antispasmodicagents.Reviewthe sAR of eachclass.
zt . (a) Give a brief accountof 'Belleau'sconceptof en4ymeperturbation'.
(b) Discussthe significanceof Ing's ,Ruleof five', in SARof parasympathomimetic
drugs.
zz. Classi$the sympathomimeticdrugs.Give the chemicalfeaturesof eachclass.Discussthe SARin
general.
23. Write notes on :
(a) Adrenergicreceptors
(b) ct-adrene;gicreceptorblockers
(c) p-adrenergicreceptorblockers
(d) p-adrenerglcagonists
,(e) Clinicalsignificanceof p-btockers
24. "9-adrenergicblockerswill serve to continue as a source of new promising
anti-hypertensive
agerrts 'cornment on the above statementwith suitableexamples.
2 5 . Give a detaiicclaccountof biosynthesisand metabolismof neurotransmitterin
a sympatheticnerve.
L 6 , (a) Discussthe drug-receptorinteractionsin sympatheticnervoussystem.
(b) Outlinethe synthesisof epinephrinefrom catechol.
z7 ' (a) (+) Acetyl- p-methylcholinehasabout 2oo times highermuscarinicactivigr
than its epimer.
Explain.
(b) (l-) Epinephrineis more activethan (d-) epinephrine.Explain.
28. Discussthe chemistryof CNSstimulants.
29. Give the chemicalclassificationof analeptics.Draw the structuresof at least
two drugs from each
class.
30. Write notes on :
(a) MAO i rhibitorsancltriqyclicanticlepressants.
(b) Mode of action of anticlepressantclrugs
(c) Hallucinogens
(cl) SARof antidepressant drugs.
3r. Discussthe SARin dialkylaminoalkyl estersof aromaticacids for local anaestheticactivity. Give the
synthesisand specificusesof:
0 Lignocainehydrochloride
(iD Cyc!omethycaine
(iii) Procairi'ehydrochloride
32. Classifuthe anticonvulsantclrugson the basisof chemicalstructure.
Show the common structural
featuressharedby them. Give the mode of action of hydantoins.outline
(each the synthesisof any two
clrugs one from clifferentchemicalclass).
otl \z
)

3 3 . ThestructureR, c ls commonto many local anaestheticagents.Comment

,

on the possible variations with respect to R1, R2,R3,X ancl Y ancl their
effects on local anaesthetic
activity. Give the synthesisof (i) Cyclomethacaine
(ii) Lignocaine.
34. Givean accountof non barbituratesused as seclativeanclhypnotics.
 of MedicinalChembtry(Vol.ll)
Principlec tSO SampleQuetiom

35. What is an isostericreplacementof atomsor groups ? Explainwith referenceto phenothiazine.

36. Definethe term 'Neuroleptics".
'Structuralchanges in molecule produces not only quantitative changes but also qualitative
changesin biologicalactivity."
Explain this statement giving examples of phenothiazinederivatives.Outline the synthesisof
promethazine.
37. What do you mean by tranquilizer? Discussthe chemistryin details.Give the synthesisof any two
drugs in this category.
38. Wrife noteson :
(a) fVlechanism of action of neuroleptics
(b) Mechanism of action of local anaesthetics
(c) Mechanismof action of benzodiazeplhe.
39. (a) Define Sedativeand hypnotic agents.\What do you mean by HanschOuantitative SAR?
(b) Classifosedativeand hypnotic drugs. Write SARof barbituratesand give synthesisof any
two barbiturates.
(c) Write the synthesisand SARof phenothiazine.
40. Drawthe structures,give IUPACnameand medicinalusesof :
(a) Cyclobarbitone (cl) Diazepam
(b) Trimethadione (e) Diphenhydramine
(c) lodipamide
4l . (a) Give a brief accountof applicationsof 'FergusonPrinciple'.
(b) Outline the metabolicpathwaysof :
(i) Procaine (iii) Phenobarbitone
(ii) Meperidine (iv) Chlorpromazine
42" (a) Give the structureactivitlr relationshipof hydantoinsand oxazolicline-2, 4 - diones as
anticonvulsants.
(b) 'Certainmono amino oxiclaseinhibitorsact as anticlepressants'. Explain in cletails,with
suitableexamples.
(c) Write a note on 'Tricyclicanticrepressants".
43. What is hypertension? Give the classificationof antihypertensiveagentsaccordingto their mocle
of action.Give in brief a methoclof synthesisof guanethidineand clonicline.
44. Write noteson :
(a) Chemistryof carcliacglycosides
(b) SARof cardiacglycosicles
(c) Mechanismof actionof cardiacglycosicles.
45. Give the structuralfeaturesof cardiotonics.Explainthe mechanismof action of cligitatis.
46. Write noteson :
(i) Antianginalclrugs
(ii) Receptortheories
(iii) Antiarrhythmicdrugs
(iv) Etiologyof hypertension.
47 . (a) How clo adrenergicblockingagentsact as antihypertensive ?
(b) 'ln hypertensiontherapy,cliureticagent gives better results'.Explainwith suitableexamples.
48. Draw structureof morphine anclshow important functionalgroups in it due to which it exhibits
biologicalactivity. Give the structureanclsynthesisof any two syntheticagentswhich are potent
analgesics as morphine.Write briefnote on analgesicreceptorsanclclrugaction.
49. What are narcoticanalgesics? Discussthe sitesof moclificationon Morphinanprototype.
50. Explainthe term 'clrugclependence' anclgive SARof Morphine.
5l . Write a note on 'morphineanclits analogs.
Principlesof MedicinalChemistry(Vol.ll) tl51 SampleOuestims

52. (a) Describemorphinemodificationsinitiatedby Grewe.

(b) Outline the synthesisof methadoneand pethicline.
53. What doyou mean by non-narcoticanalgesics ? Give theirclassificationanclmechanismof Action.
Give the structuralfuaturesof saliqylates.
54. Classifothe non-narcoticanalgesics.Give the synthesisof one drug from each class.
55. Give the chemicalclassificationof non-steroiclal anti-inflammatory agents.Give the structuresof at
leasttwo drugs from eachclass.
s6. (A) Give structure of :
[a) Oxyphenbutazone (b) Indomethacine
(c) Aspirin (cl) A.qtipyrine
(e) Mefenamicacicl (0 Tolmetin
(g) lbuprofen (h) Naproxen.
(B) Give the mechanismoFaction of non-steroidalanti-inflammatory agents.
(C) Outline the synthesisof lbuprofen.
57. Classi$the antihistaminicagentsaccorclingto their chemicalfeatures.Give their generalSAR
58. Give the structureof :
(a) Cimetidine (0 Triprolidine HCI
(b) Cyproheptacline (9 Antazoline
(c) Promethazine (h) Diphenhyclramine
(d) Pheninaclamine (i) Tripelenamine
(e) Parathiazine (il Phenbenzamine
59. Write noteson :
(a) Mocle of action of anti-histaminics.
(b) H1-receptorblockers
(c) Hz-receptorblockers
60. Classifoon purely chemicalbasis,the variousanti-histaminic agentswith suitableexamples.Give
structure,chemicalname and synthesisof
(a) Diphenhydramine
(b) Antazoline
State the therapeuticusefulnessof anti-histaminics.
61 . Give an illustrateclaccount of your unclerstancling of drug metabolism studies. How such
informationcan be helpful in drug clesign? Give examples.
62. Give an enlighteneclaccount of the forces involved in clrug-receptorinteractions.
63. "Biologicalresponseis not the function of purigl of the clrug but is functiqn of its physiochemical
parameters".lllustrateabove statementwith suitableexamples.
64. Discussin detail the factorsaffectingaccessibility of a drug to its activesites.
65. Write noteson :
(a) Receptorsite theories
(b) Proteinbinclingof drugs
(c) Steric factors affecting pharmacologicalactivity
(cl) lsosterismanclpharmacologicalactivigr
(e) Bioisosterism
(0 Drugmetabolism
66. What clo you mean by the term 'Bioisosterism'7 Discussin cletail the recent bioisosteric
applications.
67 . 'Thepharmacological activityof a clrugin manyways,is the consequence of its metabolism."
Justifu
the above statementwith suitableexamples.
 of MedlcinalChemistry(Vol.
Principles SampleQuestionc

68. Write short noteson :

(a) Drug interactions (d) Hanschquantitative SAR
(b) Fergusson principle (e) Stereochemical aspectsof drug rnetabolism
(c) Drug conjugationpathway (0 Drugeliminationprocess
69. 'lonisationof a drug modifiesbiologicalactivigr'. Explainthe statemen'givingsuitableexamples.
70. Outline the metabolicpathwaysof
o
O
zcHr
I (CHl)CH2CH2CH1 HuN
tl
c- ocH2cHzN(czHJz
il

(a) (b)
7 1 . What are anticlepressant
clrugs? How clo they differ from analeptics? Draw structuresand method
of synthesisof any two drugs acting as anti-depressants.Give in brief the SAR of tricyclic
antidepressants.
Rl
7 2 . The structure is common to most of anti-histamines.
Commenton the
R2
possiblevariationswith respect to Art, Ar2, X, R1, R2and their effect on antihistaminicactivigr.
Outline the synthesisof chlorpheniraminemaleate.
7 3 . Give chemicalclassificationof hypnoticsand sedativeswith structureoFatleastone drug from each
class.Outline the general schemeof synthesisfor barbiturates,--Discuss the SAR of barbiturate
class.
74. What are the ideal requirementstor good anti-hypertensive agent ? Outlinethe synthesisand give
the mode of actionfor methylclopaanclguanethidinesulphate.
75. Discussthe molecularmodificationsin p-phenylethyloamine for aclrenergic(pressor)activity.
76. Write short notes on (any three) :
(D Therapeuticapplicationsof anticholinergicdrugs.
(ii) Narcotic antagonists
(iii) Anabolicagents
(iv) U. V. irradiationproductsof sterols
77. "Goneare the clayswhen the importanceof Physico'chemical parametersin drug clesignwas lookecl
uponwith scepticism".
Justifuabovestatementwith suitableexamples.
7 8 . (a) Discussthe significanceof Belleau'sconcept of enzyme perturbationwith referenceto
parasympathomimetic clrugs.
(b) Definethe term receptor.Give an itlustratedaccountof occupationtheory.
(c) Write a note on : "Recentbio-isostericapplicationsin drug clesign."
79. 'The clinical failure of classicanti-histamineslike Tripelennamineto block the excessgastric acid
secretionbecamea sourceof frustationto MeclicinalC hemists."
List out the names(alongwithstructures)of clrugswhich then overcomedthis frustation.
80. "A lot has been talked about Benzocliazepines as antiepilepticsand anxiolytics,yet there existsa
very fine shade of clifferencebetween the personalitiesof above two categoriesof benzo-
cliazepines".Illustratethis clifference
with suitableexamples.
81. Discussin cletailthe SARof barbiturates,used as sedative-hypnotics.
 Principlesof MedicinalChemistry
flot. ll)
'f53 Sample
Ouestions
82. 'The sustaineclefforts of a medicinal chemist.to clevelopnew
clrugsof steroiclcategory, itself speak
volumes about the multidimensionalactivitiesof 1',z,
- cyc[pentenophenanthrene nucteus..
lllustratethe above statement in the tight of crinicailyusecrdrujs.
83. searchlightthe variouscarriclorsof activitiesexhibited by barbiturates
with the examplesof front
runnerdrugs from each category.
84. (a) 'The benzodiazepinesstartecltheir carrierprimarilyas
seclative-antianxieglclrugs but also
establishedthemselvesas effectiveantiepilepticclrugsin pastyears".
Comment.
(b) Cive structureand tUpACnamesof the active
ingreclientsof the followingcontraceptive pills :
(l) Ovulen @ (3) Anovlar2l@
(z) Lyncliol@ (41 Demulen@
85.
ft'
C= O
cH.'oH
t-
C =O
l-------OH

-+ -+
o
(a) (b)
Being a Medicinalchemist, you have been askeclto_clevelop potent
a steroiclal
anti-inflammatory
agent.SARstudiescerti! that drug havingstructure(b) wii
L. potent ar
than the clrughavingstructure(a).-sfetctr-outthe rouie -or" for drug (
startingmaterial. "i'rfntn.ri,
86' (a) "Medicinal is a cornpulsivegambler. Always the next compounclis
.chemist
Illustrateabove statement in the liglt of intellectriir efforts a real winner,,.
of Black et al to fincl out H2-
blockerclrugs. I
(b) Discussthe various types of forcesinvolved
in clrug-receptorinteractions.
47. 0 Namethe vitaminwhose co-enzymeforms perform the function
of carriersfor one carbon
units.
(iD Sketchout the role of vitamin A in vision through proper
ctiagram.
(iiD what is the differencebetweenpemiciousanemia
and Megarobrastic
anemia ?
(iv) Name the vitamins which are involved in
biologicaloxiclative-recluctive
processes.
(v) Sketchori th. route of synthesisfor nicotinic
acicl.
88' dru-gsdesignedpurely on the excellentsAR calculations
I*v die in the courseof preclinicaltrials if
their physico-chemicalstatus is not interrogateciproperty".
Explainthe statementswith the help of
suitableexamples.
89.

coNH,'

log llC lActlvtty) Electronlc factor Parthlon coefflclent

(l) - 2.6
(zl - 2. 6
Beinga QSARpractloner,how will you diagnosethe observationsgiven
in abonretable ? Which one
of interpretationsis correct? fusti!.
t-

ffoL ll)
ol MedicinalChemistry
Principles 4V SampleQuestions

90. (D Give the classificationof adrenergicclrugs.

(ii) Give the generalformulaof direct-actingadrenergicagonists.
(iii) Give the structureof prototype of p-aclrenergicblocking agents of anti-hypertensive
category.
(iv) Give the nameof 'secondmessenger'involved in adrenergicsystem.
(v) What is lng's rule of five ?
(vi) Give the namealong with structureof one irreversibleanticholinestrase agent.
9 1 . Draw the structureof cholinestraseenryrriealong with its active functionalgroups.
92. (i) Draw the conformationsof acegrlcholinenecessD/ to exhibit (a) muscarinicand (b) nicotinic
activitlr respectively.
(ii) lllustratewith figure, three areasof ace$rlcholinemolecule which offer sites for molecular
modifications.
(iii) lllustratewith figure,mechanismof action of cardiacglycosicles.
93. (i) Define the terms : (a) lnotropic effect, (b) Chronotropiceffect.
(ii) Give two examples alongwith structuresof para amino phenol category of non-narcotic
analgetics.
(iii) Sketch out the basic skeletonor structuralfeaturesrequired.to develop an iclea-lnarcotic
analgetic.
(iv) Give the name along with structure of protogpe of thircl generation of norcotic analgetics.

cH,{

OH
IC c(cH.r).1
\

CH,
ocH,1

Buprenorphine
Buprenorphineis a very lipophilic drug and as such woulcl be expecteclto easilycrossthe bloocl
brain-barrierfor entry into centralnervoussystem.In fact, such clrugsnormally shoulclhave very
rapid onset of action.But buprenorphinehas slow onsetand long clurationof action.Justi$.
95. (a) 'The icleathat steroidalskeletonis of specialsignificancefor oestrogenicactivi$l of a clrug
moleculeis ratherold".lusti! the statementwith suitableexamples.
(b) Give the structureanctIUPACnamesof the followingdrugs :
(l ) Testosterone (Z) Estracliol
(3) Lynoestrenol (4) Prednisolone
(c) "ln the searcho[ a better clrug,molecularmoclifications will continueto servethe meclicinal
chemist.'lllustrateabovestatementin the light of steroidalanti-inflammatoryr agents which
are recentlyin use.
96. Followingthe guide-linesof SAR iclentiff whether the given clrug is,
(a) Potentandrogenicin natureor not,
OH OH

(il) (ilt)
Principles
of Medicinal (Vol.ll)
Chemistry 455 SampleQuestions

(b) Potentanti-inflammatoryagent or not

cHroH
C=O C= O
HO
'-----'cHr

(l) (il)

CH.
I
C=O C= O

(ilt) (I V )
(c) Potent oestrogenicagent or not

OH OH
C =CH

(l) (tr) (ilr)

97. (a) Write short noteson :
(1) Oral contraceptives
(Z) Topical steroiclalanti-inflammatoryagents.
(b) Sketchout the route of synthesisfor preclnisolone.
98. (a) "Whereobservationis concerried,successfavoursonly the prepareclmind."
Justifu above statement with referenceto nuclear modifications of morphine to evolve
methacloneseries.
OR
(a) Traceout the clevelopmentof currently availablesteroidalanti-inflammatoryr agents with the
help of well documenteclSARstudies.
(b) Give the IUPACname along with structurefor,
(D Oestracliol (iv) Cortisone
(ii) Progesterone (v) Norethisterone
(iii) Testosterone
99. (i) Registerthe clifferencesbetween heart activigr of aclrenalineand cardiotonicclrugs.
(ii) Vasodilatorsclo not carry potential as good antianginalclrugs.Comment.
(iii) Spell out the 'thirclapproachtreatment' for the hypoxia in carcliacmuscles.
Principles
of Medicinal
Chemistryffol. ll) 456 SampleQuestions
COOH
(iv)
x-co-cH., (a) X = O -+ Acetylsaliqylicacid
(b) X= NH -+ Bioisosterof (a)
(b) X= S + Bioisosterof (a)

Forecastthe activities of (b) ancl(c), if any. Whichone of above three,will be a better analgeticanti-
inflammatoryragent ?
(v) Salicylicacid has quite appreciableantibacterialactivity but the para isomer is inactive.
whv ?
(vi)
Draw the structuresof leaclsfor progestins.
(vii)
Figureout the part of morphine nucleusat which antagonisticactivi\r appearsto resicle.
Explainthe terms : 'toleranceanclclrugdependance'in the light of neuronalchanges.
(viii)
(ix)
Draw the structuresfor the following :
(a) Any androgenicsteroidalagent
(b) 18 P, 17 a - ctiethyl- 17P- hydroxy-gon-4-en-2one.
(x) The only compoundwith purelyanabolicbut no androgenicactivityis .............
100. Writeshort notes on (any three):
(a) Narcoticantagonists (c) Non-steroidaloestrogens
(b) Etiologyof hypertension (cl) Mechanismof action of cardiotonics
1 0 t. (a ) 'The acetylcholinemoleculeoffersthree area for the required molecularmodifications".Define
these areas ancl show how structurai changes affect the activi\r in each of these areas ?
(b) Discussin brief the "SAR'of phenylethylamineclerivativeshaving agonist property. List out
the therapeutic uses.
I 02. Answerthe followingquestionsin brief (Any Ten):
Benzocliazepines clo not producehangovereffect.Why ?
The more bulky the substituentson nitrogen,s-receptor activig clecreasesand p-receptor
activi$ increasesin adrenergicseries.Explain.
(c) Hypocalcemia increasesthe sensitivity of post-synaptic membrane towarcls seizure
generation.Explain.
(d) N-all<ylation does not affectthe antiepilepticactivity.Why ?
(e) Replacementof oxygen by sulfur at C-2 in barbiturates,shortensthe onset and clurationof
action" Whv ?
(0 Draw the structuralfeaturescommon to most of the antiepilepticclasses.
G) Draw structuresof atleasttwo hallucinogenswhich also find use as anaestheticagents.
(h) Show the isosteric relationship in hyclantoin,oxazolidine-Z,4-dione, succinimicleI'and
acetylureasanticonvulsantagents.
(i) Cive the examplesof inhibitory neurotransmitters.
0 Give two examplesalong with structureof minclexpanclingclrugs.
(k) Give the generalformulaof clirectactingaclrenergicanalogs.
l03. Write noteson :
(a) Hallucinogens
(b) Sympathomimetics with CNS-stimulant activig.
tc) Ultra-short acting barbiturates
(cti B-blockers
(e) Anal epti cs.
lO4 . Gi v e an accountof any two of the following :
(a) Complex of events between clrug aclministration and its action.
(b) Pro-drugsin clrugmetabolism.
(c) Oxidation-recluctionpotential and clrug actiori
(cl) Bioisosterismand clrug action.
lO5. Outlinethe synthesisof 5, S-ctialkylbarbrturicaciclanclSARof barbiturates.
 Prlnciples
ol MedicinalChemistryOol. ll) 457 SampleOuestions

l06. What is the meaningof antipyreticanalgesics? Classifothe variousclassesof antipyreticanalgesics

with suitableexamples.How they reclucepain anclfeversimultaneously?
1 0 7 . Classiffthe various psychotherapeuticagents.Explaintheir clinicalutility in psychosis.
1 0 8 . What are vitamins ? Why are they groupeclseparately? Give account of thiamine and its
defrcienqysyndrome.
109. Give an account of adrentrcorticoicls.
1 l o . Discussantidiabeticagentsanclgive chemistryanclSARof the importantsulphonylureas.
1il. outline the chemistryanclsAR of ethylenediamine derivativesanclam,inoallryl etheranalogsusedas
antiallergicagents.
I 12. 'The'storylof psychotropicclrugsmay go on for centuries.The more we ask, the little we seem to
know". lllustrateyour answer with reference to SAR and mechanismof action of tricyclic
neuroleptics.
I 13. Discussin briefabout (Any Three):
(D Fate of anti-hisiaminics
(ii) Benzocliazepines as anxiolytics
(iii) Antisecretoryclrugs
(iv) Vitamin812
114. 'Theterm drug clesignis usedto impressthe peopleratherthan to expressit". Discussin detait,how
clrug metabolismstuclieshelp in discoveryof new ctrug?
I 1 5 . Write short notes on (Any Three):
0 VitaminA
(iD Applicationsof RecombinantDNA Technology
(iiD VitaminBt
(iv) SARof antiallergicagents.
I 16. Give an accountoiany two of the followings
(a) Roleof cytochromeP-45Oin oxiciativebiotransformation.
(b) Bioisosterism.
(c) Partitioncoefllcientand biologicalactivig of drug molecules.
I 17. Discussthe SAR of morphine. Outline the synthesisof a morphine clerivativewhich is devoid of
aclclictivepropertiesbut having analgesicproperty.
l 18. (a) Classifu the non-steroiclal
anti-inflammatory agentswith
ith one example from each class.
(b) Describethe general mode of action of non-steroiclalanti-inflammatoryagents.
(c) Cive the synthetic steps involvecl for the following :
(i) lbuprofen, (ii) Inclomethacine
I 19. (a) Discussthe propertiesof cranclp-adrenergicreceptors.
(b) classifocranclp-aclrenergic blockingagentswith one examplefrom eachcategory.
(c) Write steps involveclin the synthesisof
(i) Propranoiol, (ii) Tolazoline
t2 0. Give an accountof any two of the following :
(a) Forcesinvolveclin clrug-receptorinteraction.
(b) Oxidation-recluction potentialanclbiologicalaction.
(c) Suggestthe metabolicpathwaysof propranololand diazepam.
121. Describethe biosynthesis,storageanclreleaseof histamine.Which clrugwilt be able to inhibit the
releaseof histamine? How will you synthesizethat clrug?
t z z .Describethe synthesisanclbiochemicalrole (modeof action)of vitamin 86.
.l lz3. Define anabolic steroicls.What is their mode of action 7 How will you synthesizemethanclro-
stenolone(Dianabol)?
ooo
Abanoquil,
113 Almokalant,29T
Abortifacients,
377 Alprazolam,
191,194
Acetanilide,
262 Alprenolol,
115
Acetazolamide,
150 Alurazolam,
181
Acetophenazine,
174 Alverine,94
Acetyl-p-methylchotine,
80 Ambenonium
chloride,
86
Acetylcholine
metabolism,
82 Amcinolone,350
Acetylcholine
, 70, 75 Amiflamine,
183
Acetyienic
GABA,152 Aminooxyacetic
acid,152
Acetylurea,
148 Aminopentamide,
91
Acipimox,
301 Aminopyrine,263
Acrivastine,
244 Amiodarone,296
Aclin,277 Amiphenazole,
225
Activation
- Aggregation
Theory,47 Amiquinsin,313
Activetransport,
3 Amobarbital,
129
Adrenochrome.232 Ampoxapine,
195
Adrenocorticoids,
343 Amphetamine,226
Adrenolutin,230 Amrinone,
285,291
Alcuronium,332 Amylnitrite,
301
Aldosterone,
353 Amylenehydrate,137
Alfaxalone,
125 Anacardiol,225
Alfentanyl,
209 Analeptics,
223
Alfuzosin,
113 Androgens,
365
Allopurinol,2Tl Androstenedione,
369

( 45s
Princlples
of MedlclnrlChcmlqlryl!to!ll) 1€0 ln*r

Androsterone,
369 Autonomic
nervous
system,
67
Anginapectoris,
280 Azapropazone,
264
Angiotensin,3l9 Azaspirane,
172
Anileridine,208 Azatadine,244
A nipamil, 318 205,216
Azidomorphines,
Anisatin,
155
Antazoline,
244
Baclofen,
334
Anti-hypedensive
agents,302
Beclomethasone,
350
Antiandrogens,
370
Bemegricle,225
Antiang
n aldrugs,
297
Bemidone,208
Antiarrhythmic
agents,
292,295
Benorylate,
262
Anticholinesterases.
83.85
Antiestrogens, Benzapril,
320
359
Antipyrine,
263 Benzestrol,
357
Antisecretory
drugs,248 213, 216
Benzomorphanz,
Alfuzosin,113 221
Benzonatale,
Almokalant,
297 Benzphentamine,226
Anabaseine,
95 Benzpyrinium,
85
Antispasmodics,
89 Benzyfimidazole,274
Apomorph
n e ,1 7 8 , 2 0 0 B e p r i d i l ,3 18
Aprindine,
296 Betamethasone,
348
Arbaprosti
, 390 Bethanechol,
83
Arecoline,
82,31 116
Bisoprolol,
Arrhythmias,
280,293
Bitolerol,
110
Aspirin,259
Bretylium,296
Astemizole,
245
198
Bromazepam,
A tenolol,3 16
Brompheniramine,242
Atracurium,
332
Buclizine,242
Atrialfibrillation,
281
Butenolides,
286
Atrialflutter,28'l
peptide,321
Atrialnatriuretic Bufotalin,
284

Atrioventricularblock,
281 Bufotenine,
230

Atrophicvagnitis,374 Buprenorphine,
206,216,400
Atropine,
90 Burimamide,249
Auranofin,
265 Butorphanol,
213,215,216
Aurothioglucose,
268 But ox am in e , 3 l 6
 of MedlclnalChcmlet
46"1
Index
.l66
Cinchocaine,
Cafieine,226 Cinromide,
157
Calcium-channel
blockers.
317 Clemastine,24l
Camazepam,l
97 1gg Clidinium g6
bromide,
Cannabinoids,
221 Clobazam,
191
Captoprit,320 Clofilium,
296
Caramiphen,
Z2l Clonazepam,
191
Carbethyt
saticytate,
260 Clopenthixol,
177
Carbinoxamine,
241 Clopipazan,
17g
Carboloniumbromide,
331 Clorazepate,
191
CardiacAlycosides,
276 Cloxazolam,
197
Cardioselective
13-blockers,
306 Cloxazolam,
19g
Cardiotonic
agents,2g2 Cyprolidot,
190
Carfentanyl,
209 Cypromine,
185
Carisoprodal,
337
Carphenazine,
172,179,174
D-2-amino-5.phosphonovalerate.
156
Carvedilol,
116
Danazol,
360
't76
Centbutinol,
Dantrolene,
334
Celirizine,247
Dazoxiben274
Chlophedianot,
221
Deanolacetamidobe
nzoate,22g
g0
Chlorazepate,l
Debrisoquine,
312
Chlorcycf
izine,Z3g,240,242
Decamethonium
bromide,
331
Chlordiazepoxide,
1g0,191,192 Demoxepam,191
Chlormezanone,1g6,337 11 -Deoxycorticosterone,
353
Chlornaf
trexamine.217
Deprenyl,
17g
Cnlorobutanol,
137,166
Deserpidine,
175
Chloroform,
123
Desogestrel,
363
Chlorotestosterone,
367 Desonide,352
Chlorotrianisene,
356 Dexamethasone,
34g
Chforphenira
mine,329.242 Dextrometho
rphan,
21S, 221
Chlorphenoxamine,91 Dextromoramide,
211
Chlorpromazine,
1g1 Di-isopropylacetamide,
153
Chlorspirane,
173 Di-isopropylftorophosphate,
g7
Chlorzoxazone,
337 Diacetylmonoxime,
gg
Cimetidine,249
Diazepam,
149,154,190,
410,432
 Prlnciplesof MedlclnalChemistry(Vol.lt) __ &. H

Diazoxide,317 Diprenorphine 6
,207,21
Dibutoline,
93 Dipterex,
87
Dichlorisone,
352 Dipyrone,
263
Dichloroisoproterenol,
114,316 Disamide,
150
Diclofenac,
266 Disopyramide,
297
Dicyclomine,
93 Dithiadene,
245
Dienestrol,
357 Diuretics,
321
Diethylstilbesirol,
356 Divinylether,
124
Diethylallylacetamide,
13s DM CM , 1 5 5
Diethylether,
124 Dobutamine,292
Diethylpropion,
226 Doisynolic
acid,358
Diethyltryptamne,230 Domperidone,
180
Diffusion
of ions acrossthemembrane.3 Donepezil,95
Diflunisal,
262 Dopamine,
T4
D gitalisintoxication,
290 Doxapram,225
Digitoxigenin,
284 Doxazosin,
113
Digoxigenin,2S4 '.|88
Doxepine,
Dihydro-2-pyridine gg
aldoxinemethiodide. Doxylamine,
138,241
D hydrocodeine,
204 Dromostalone,
367
Dihydromorphine,204 Droperidol,
176
t
Dihydroprylone,
136 Droxicam,273
4-Dihydropyridines,
318 Drugallergy,
64
Diltiazem,318 Drugpersistence,
63
Dimaprit,250 Drugreceptor
complex,
112
Dimenhydrinate,
241 Duphaston,
362
Dimeprozan,
177 Dydrogesterone,
364
Dimethacrine,
189 Dysmenorrhea,
373
Dimethadione,
146
Dimethindene,
244
Dimethisoquin, Echothiophate,
86
166
Diperodon,
166 Edrophonium
chloride,
85
Diphenhydramine,
239,241 Etletirizine,247
Diphenidol,
296 Electrostatic
bonding,47
D phenoxylate,2l2 Emartazone,272
Diphenylpyratine,
244 Emylamate,337
Dipivefrin,
101 Enalapril,320
 ln&r
Prlnci ler of MedlclnrlGhrmlst Vol.ll

295
Encainide, 138,154
Eromidate,
217
oPioids,
Endogenous 215
Etonitazene,
373
Endometiiosis, 205
Etorphine,

Endorphine,2lT 321
Etozolin,
124
Enflurane, 166
Eugenol,

Enkephalins,2lS
Enprostr\.39O F ac\'\-rtated 3
d-rllusion,
118,120
Epanolol,
Factors
influencing
metabolism,
38
98 105108
Ephedrine,
Famotidine,249
Epinephrine,98
Felbamate197
101
Epinephrylborate,
Felodipine,318
Equilin,
356
Fendosal,262
tetranitrate,
Erythritol 301
Fenfluramine,
226
Erythroidine,
332 Fenoprofen,265
194197
Estazolam,
Fenoterol,
111
198
Estazolam, Fentanyl,
209
Estersof tropicacid,91 Fergusionprinciple,
10
Estradiol,
356 Fexofenadine,
244
Estriol,356 Filtration,
3
Estrone,356 Flecainide,295
154
Etazolate, Floctafenine,
268
360
Ethamoxytriphetol, Fluandrenolone,
348
Ethaverine,
94 Fluclorolone,
352
137
Ethchlorvynol, Fludrocortisone,
353
Ethimivan,225 Flufenamic
acid,266
134
Ethinamate, Flumazemil,191
137
Ethinazone,
Flumethasone,
350
diacetate,
Ethinodiol 363
194,198
Flunitrazepam,
estradiol,
Ethinyl 356
Flunixin,266
Ethisterone,
362
Fluocinolone,
348
145
Ethotoin,
179
Fluoxetine,
150
Ethoxzolamide,
Fluoxymesterone,
367
123
Ethylchloride,
155 173
Fluphenazine,
3-carboline-3-carboxylate,
Ethyl-1
368
Ethylestrenol, 195
Fluprazine,

136
Ethylpicone, Fluprednisolone,
348
Prlnciplesof MedlclnalChemlst Vol. ll h&

Flurazepam,
190,191 H
Flurometholone,
348
factor,255
Hageman
Fluroxene,
i24
191
Halazepam,
Fluspirelene,
178
Halcinonide,350
Flutamide,374
228
Hallucinogens,
Fluvoxamine,
190
Haloperidol,
175176
Formoterol,
111
Fosinopril,
320 Halotestin,
369
144
Fosphenytoin, Halothane,124
Fusidicacid,340 Harmaline,
185,230
G Harmine,
1.85,230

G A B A , 77,15 2 Hexestrol,
257

inhibitor.
GABA.-modulin 154 Hearttailure,283
151
Gabapentin, ]Jellebrin,
?84
Galanthamine,
95 Hemicholinium,
328
Gallamine.332 Heroin,204
Gallopmil,318 96
Hexahydrosiladifenidol,
Genistein.
358 138
Hexapropymate,
n, 28 4
Gitoxigen 125
Hexobarbital,
Glaphenine,268 Hexocyclium,
91
G ucoconicoids,
346 Histamine
release,235
136
Glutethimide. Histamine,233
77
Glycine, HMF,360
Glycopyrrolate,
94 Homoestradiol,
358
Golcicompounds.
268
acid,179
Homovanillic
thiomalate,
Goldsodium 268
HupezineA, 95
Gossypol,
379
145
Hydantoins,
u+ut,270
317
Hydracarbazine,
311
Guanabenz,
Hydralazine,317
sulfate,
Guanadrel 311
204
Hydrocodone,
Guanethidine,
311
Hydrogen 47
bonding,
311
Guanfacine,
312
Guanisoquine, forces,48
Hydrophobic

Guanoclor,312 197
Hydroxyzine,

Guanoxan,312 Hypertension,
305
diseases,
Gyanecological 373 Hypomenorrhea,
373
Prlnclpbsol Medlclnal Ool. ll)
Chemlstry 465

lbogaine,
231 KainicAcid,156
lbotenic
Acid,156,232 Kebuzone,
264
lbuprofen,
265 Ketamne hydrochloride,
126
lbutilide,
296 Ketamine,232
lcotidine,
250 Ketobemidone.
209
ldazoxan,
112
Ketoprofen,
266
lmidolol,120
Ketorolac,272
fmipramine,
171,187
Ketotifen,
245
lmmepip,254
lmpromidine,250
lmpulse
transmission,
67 L-Tryptophan,
138
Indomethacin,
264 'l16,316
Labetalol,
Indoprofen,
266 Lacidipine,
318
Indoramin,
113 Lamotrigine,
155
Induced{it
theory,46 Lansoprazole,
253
Inducers
of drugmetabolism,
38
Laudanosine,
220
Inflammation,
255
Leniquinsin,
Sl3
Inhibitors
of drugmetabolism,
39
Levallorphan,
216
Interceptives,
377
Levonorgestrel,
379
Intra-uterine
device,378
Lidocaine,
295
lonchannel,
56
Lisinopril,
320
lon-dipole
interactions,
47
lonization,
11 Lofentanil,
209

lproniazid,
183,185 Lomotrig
ne, 147

lsofluorphate,
87 LondonDispersion
forces,48
lsoflurance,
124 Loperamide,212
lsoguvacine,
152 Losartan,
320
fsomethadone,
21O Lorazepam,
190,191
lsoprenaline,
98,113,117,316 Lorcainide,
295
lsopropamide,94 Losartan,307
lsosorbide
dinitrate,
301 Lovastatin,
307
lsosterism,
49 Loxapine,
178
lsoxaprolol,
120 Lupitidine,
250
lsoxazole,272 Lynestrenol,
364
lsoxsuprine,
111 Lysergic
acid,113,231
 Principlesof MedlclnatChemist
Vol.ll
rE
M
Methadone,2l
0,400
Macromolecular
penurbation
theory,46 Methallenestril.
377
Malidione,
145 Methamphetamine,
226
Malindone
hydrochlorid
e, 127 Methantheline,
94
Mannitohexanitrate,
30.1 Methapyrilen
e, 240
Maprotilne.1 8 9 ,1 9 0
Metharbital,
143
Mazindo
,227 Methdilazine,
243
Mebulamate,
322 Methenolone,36g
Mechzine,24Z
Methocarbamof
, 337
Meclobemide,
1gS Methohexital
sodium,125
Mectofenamic
acid,266 Methoxaflura
ne, 124
Mecloqualone,
137 Methoxyambenonium g6
chloride,
Medazepam,
190 6-Methoxyharmalan,
230
Medroxyprogesterone,
362 Methytdopa,
gOg
Medrysone,
350 Methylsaiicytate,
260,261
Mefenamic
acid,266 Methylergonovine,
113
Megestrolacetate,
362 Methytpentynot,
137
g6
Melathion,
Methylphenidate.
227
Melitracene,
188 Methylprednisolone,
347
Melperone,
296 Methylsergide,
113
Menopause,373
Methyltestosterone,
366
Me\lprylone,136

eperidine,207 \Jletram\de,249

Mephenesin,337 Metocurine.
331

Mephenytoin, Metoprolol,
115
144
Metrifonate,
95
Mephobarbital,
144
Metrorrhagia,
373
Meprobamate,
197,33
Mexiletine,
157,158,
297
Mepyramine,239
Mianserin.
190
Mescaline,
228
Midazolam,
150,194
Mesoridazine,
174
Mifentidine,
250
Mestranol,
357
Mifepristone,
378
Metabolic
biotransformation,
20 Milrinone,292
Metalol,
116,316 Mineralocorticoids,
353
Metazocine,2l4 ni-pills,376
Methacholine,
82 M noxidil,
317
 Prlnclplesof MedlclnatChemlst Vol.
ll

Miotine,85,
86
Nicotinic
actions,72
Misoprostol,
390
Nifedipine,3lS
Morphi
nan,212,216
Nigutdipine,3l8
Morphine,200
Nikethamide,225
Muscarine,
79,96
Nimodipine,3lS
Muscarinic
actions,
72
Nisotdipine,3lS
Muscimol,232
Nitrazepam,
190,191
Myocardial
cell,276
Nitrendipine,
319
Myosin,277
Nitroglycerin,
301
N Nivaldipine,3lS
N-alkyl
trimethyl
ammonium salts,83 Nizatidine,
250
N-Methyt-D-Asparatate,
I 56 Nomifensine,1gg
Na+K+ATpasepump,279 Nonoxynol-9,
377
Nabilone,
232 Nordazepam,
191
Nadolol,
116 Norepinephrine,
75,98,100
Nafoxidine,
360 Norethandrolone,
36g
Nalbuphine,
206 Norethisterone,
363,364
Naloxone,
206 Norgestrel,
363
Naltrexone,
206,216 Norgestimate,
363
Namoxyrate,265 Normetanephrine,
101, 1g2
Naphazoline,
10g Normethadone,
211
Naphthyridine,
272 19-Norprogesterone,
363
Naproxen,
265 19-Noflestosterone,
361, 364
Narcotic
analgesics,
199, Noscapine, ZOO,ZZ1
Narcotic
antagonists,
220 Nylicirin,
111
Narcoticreceptor,
200 o
Nedocromil,245
Obidoxine
chloride,89
g5
Neostigmine,
Occupation
theory,45
Nephopam,221,937
Oestrogens,
354
Nervegases,g7
Ofigomenorrh
ea,37S
Neupaverine,
94
Olopatadine
HCL 244
Neuromuscular
blockers,
325 Omepyazole,253
Nialamide,
185
Ondansetron,
17g
Nicordanil,322
Opioidantagonists,
220
Nicotine,
82,95
Opticalisomers,
50
 Prlnciplesof MediclnalChemist (Vol.ll

Oralcontraceptives,
374 Par aox on, 8 7 , 2 2 .
Oripavine,
206,216
Parapendide,
175
Orphenadrine,
96
g6
Parathion,
Otoxynol
- 9,977
Pargyline,
1BS,186
Ouabagenin,2g4
Paroxysmalsupraventricular
tachycardia,
Ovulation
stimulants, 292
359 PearlIndex,3g0
Ovulation,
370
Paroxetine,
190
Oxanamide,
136
Pemolinemagnesium,
22g
Oxandrolone,
36g
Penicillamine,
269
Oxatomide,245
Pentaerythritol
tetranitrate,
301,31g
190,.l91
Oxazepam,
Pentazocine,214
Oxazolapam,
197,1gg
g3
Penthienate,
Oxazolidinediones,
146
Pentobarbital,
129,131,132,154,155
Oxycarbazepine,
153
Pentylene
tetrazole154,225
Oxephenbutazone,
263
Perhexilenc,
3C1
Oxepinac,
266
Periactin,244
Oxidation-reduction
potentials,
1 tr
Perphenazine,
174
Oxiforphan,
219,216
Petrichloral,
13g
Oxindole,272
Phagocytosis
and pinocytosis,
B
Oxotremorine,
73,96
Phenacaine,
166,262
Oxyprenolol,
115
Phenadoxone,2l0
Oxycodone,
204
Phenaglycodol,
337
Oxymesteron
e, 367
Phencyclidine,
126,232
Oxymetholone,
367
Phendimetrazine,
227
Oxymorphone,206
Phenelzine,
184,1g5
Oxypurinol,
271
Pheneridine,46g
Phenindamine,
244
Pancuronium Pheniprazine,
1g5
bromide,
332,340
Pancuronium,332 Pheniramine,242
Papaverine,
94 Phenmetrazin
e, 107,227
Pantoprazole, Phenobarbitat,
142
253
Paracetamol, Phenothiazines,
170,171
262
Phenoxybenzamine,
112,246
Paraldehyde,
13g
Phentermine,226
Paramethadione,
146
Phenthiopyridine,
272
Paramethasone,
34g
Phentolamine,
112,113,
313,314
 Principles
of Mediclnal
ChemistryOol. il) 460 ilIE

Phenylsalicylate,
260 Premature
ventricular 2gj
contractions,
Phenylbutazone,
263 Premenstrual
syndrome,
373
Phenylethyl
hydantoin,
145 Prenylamine,
301
Phenylethylmalondiamide,
144 Primidolol,
118
Phenylpropanolamine,
105 Prizidolol"
120
Phenyramidol,
337 Probenecid,
271
Phenytoin,
144,297 Procainamide,
297
Physostigmine,
85 Processes
of drugabsorption,
3
Picoprazole,
253 Prochlorperazine,
173,4OZ
Picrotoxiri,
225 Prodilidene,
208
Piflutixol,178 Prodine,209
Pilocarpine,
82 Progestasert,
378,
Piminodine.208 Progesterone,
361
Pimozide,
171,178 Progestins,
361
Pinacidil,
322 Promethazine,
243
Pinazepam,
198 Pronethalol,
114,316
Piperidolate,
93 Propafenone
, 295,297
Piperoxan,311,238,401 Propanidid,
126
Pipradol,227 Propantheline,
91, 94
Pirbuterol,
110 Propofol,
126
Pirenzepine,
73,96 Propoxyphene,2l l, 221
Piretanide,
321 Propranolol,
114,295,296,316,412
Piroxicam,
265,268 Prostaglandins,
255,383
Poldine
methylsulphate,
94 Psilocybin,
230
Polymenorrhea,
373 Psilocyn,
230
phosphate,
Polyphloretin 389 Psychodelics,
228
Poretransport,
3 Psychotomimetics,
229
pills,377
Postcoital Purines,
226
Potass
u mchannel
modulators.
322 Pyrazolopyridines,
196
Potassium
prorenoate,
340 Pyridine
aldoxime
methiodide,
88
Practolol,
115 Pyridine
aldoxime,
88
Pralidoxime
chloride,
88 Pyridostigmine
bromide,
86
Pramoxine,
166 Pyridostigmine,
85
Prazepam,190,
191,192 Pyrilamine,
138,240
Prazosin,
113,313 Pyrogallol,
102
Prednisolone,
347 Pyrrobutamine,
243
Prednisone,
347 Pyruvaldoxime,
88
Princlplesof Mediclnd Index

o Saprisartan,
320
Saralasin,
319
193
Quazepam,
Schradran,
87
Qu n a zosin.3 13
A,284
Scillaridin
Qu ngestanol,
378
Scopolamine,90
Quinidine,295
preparations,
Sequential 376
Quisqualic
acid,156
273
Seratrodast,
Serotonin,
229
Racemoramide.2l
0
190
Sertraline,
Raheprazole,253
124
Sevoflurane,
Ranitidine.249
Sexhormones,
354
RateTheory,
46 281
Sicksinussyndrome,
Rauwolscine,
113
Silentreceptors,
54
phenomenon,
Re-entry 282 Sildenafil,
396
Receptor
sitetheories,
45
Simplediffusion,
3
Remoxipride,
178
281
Sinusbradycardia,
Renininhibitors,
324 Sinustachycardia,
281
Rescinnamine,
175
nitrite,301
Sodium
Reserpine,
175,311
301,317
Sodiumnitroprusside,
Respiratory
stimulants,
224 114,296,316
Soltalol,
Retroprogesterone,
363
Sparereceptors,
53
Rioprostil,390
agents,377
Spermicidal
Ritodrine,
111
e, 321, 354
Spironolacton
Rivastigmine,95
175
Spiroperidol,
Rocastine,
238
Spotting,
373
Ropizine,
157
Stanozolol,
368
R o p izine,158
Stericleaturesof drugs,49
Roxatidine,
250
stiripentol,
158
Rufinamide,
157
284
Strophanthidin,
Slrychnine,
224
111
Salbutamol, Styramat6,
337
Salicylamide,
260 146
Succinimides,
Salicylic
acid,259 330
Succinylcholine.
Salmeterol,
111 Sudoxicam,267
Salolprinciple,
262 Sufentanyl,
209
Salsalate,
262 Sulfinpyrazone,
263
 of liledlclnelChcmlst

9uFrn. 106 Thiorphan,

221
e ro l,1 1 1 Thiothixene,
177
S.trac,265, 405 Thonzylamine,
240
Srfiride,178,179 Thromboembolic
diseases,
279
149
S.rtthiame, Tiaprofenic
acid,273
13
Surface-activity, Tifluadom,221
Suxethoniumbromide,
330 Timegadine,2T2
Timolol,
116 ,
Timoprazole,253
Tacrine,95
Tocainide,295
Tamoxifen,360
Tolamolol,316
Tarpane,245
Toiazoline,
112
Taurine,TT
Tolmetin,
265,268
Teflutixiol,
176
Tonazocine,2l4
Temazepam,
193
Topiramate,
157
Tenoxicam,273
Toxogenin,
S9
Terazosin,
113
Tranylcypromine,
185
Terbutaline,
111
Trasentine,
93
Terfenadine,245
Trazodone,
190
Terrazepam,
198
Triamcinolone,
347
Tesicam,267
Triazolam,
191,194
Testolactone,
369
pyrophosphate, 124.
Trichforoethanol,
Tetraethyl 86
Trichloroethylene,
123
Tetrahydrocannabinol,
232
Triethylcholine,
328
Tetrahydropapaverine,
94
Trifluperazine,
173
Tetrazepam,
197
'176
Trifluperidol,
Thebaine,
200206
Trimazosine,3l3
Theobromine,226
Trimeperidine,
212
Theophylline,
211
Trimeprazine,
243
Thiamylalsodium,
125
Ttimethadione,
145
188
Thiazesim.
Trimethaphan,
96
173
Thioethylperazine,
Trimethobenz-glycine,
136
Thiomuscarine,
83 Trimoprostil,
390
Thiopental 125,131
sodium, Tripellenamine,
240
Thioperamide,
254 Triprolidine,
243
Thioridazine.
174 phosphate,
Trolnitrate 301
9-.*

Princi ilesof MedlclnalChemlst Vol.ll &

gl
Tropicamide, Ventriaslar
ffi.*ler,282,294
Tropolone,
102 301,318
Verapamll,
Tropomyosin,2TT
Vearnicol,73
Troponin,277
Vigabatrin,
153.
Tropylcholine,
79
Viloxazine,
188
Tubocurarine,
331
Tybamate,
197
Typesof receptor,
44 Xamoterol,
118
Xorphanol,
2',t4

Ureidestructure,
142 Y
v Yohinibine,
231,311
Vagnalcandidiosis,
374
Vaginalcontraceptives,
377 !
ZafirluV,ast,273
Vaginairings,379
Zaltidine,250
Vaginitis,
374
Zearalenone,3SS
Valdice,
153
Zileulon,273
Valnoctamide,
136
Zimelciine,
188
Valorphine,22l
Zolantidine,250
Valproicacid,
149,153
Valpromide, Zomepirac,265
153
Valsartan,
320 Zonisamide,
157
Vasodilators,
317 Zopiclone,
197
Vecuronium.332 ooo

frJo, -1
.ll
d
&ar""r