Medicinal Chemistry of Analgesics

ASSOC. PROF. DR. SYED ADNAN ALI SHAH

Department of Pharmacology and Chemistry,Faculty of Pharmacy,Universiti
Teknologi MARA (UiTM),Puncak Alam Campus,42300 Bandar Puncak Alam,Selangor
Darul Ehsan,Malaysia
Atta-ur-Rahman Institute for Natural Products Discovery (RiND),Universiti Teknologi
MARA (UiTM),Puncak Alam Campus,42300 Bandar Puncak Alam,Selangor Darul
Ehsan,Malaysia
 Objectives: Learning outcomes:

• To understand the basic • Explain the molecular

principles of medicinal chemistry
of analgesics.
• To gain knowledge about the
molecular mechanisms
underlying the different types of
Analgesics. pcommon banyak!!
-
mechanisms of pain perception
and the different types of pain.
• Evaluate the SAR of analgesic
drugs and how different
molecular interactions affect
X
their activity.

• To examine the structure-activity • Analyze the pharmacokinetic

relationship (SAR) of analgesic and pharmacodynamic
drugs and the importance of properties of analgesic drugs
molecular interactions for their and their implications for drug
activity. design.
• To explore the pharmacokinetic • Apply the principles of medicinal
and pharmacodynamic chemistry to design novel
properties of analgesic drugs analgesic drugs.

ugwain,caoneem.I!!
A
CD pharmaco-Kinetic
Pharmaco-dynamic A
-

x CD
-

Bond interaction have idea whatare the [basically structure Kend

Xperia hafal).
Basic dipoleinteraction apapamPfahul
UD attleast
metabolites? 2D
tahn
tahn tahap Dah send batal? isindivi
 hydrophobic
us -p penetrate into target
area.

distributed.
up hydrophilic
-

receptors to jugak.
take functional group dekat amino group (the
↳Keno
 Analgesics
Analgesics are the compounds that are capable
of relieving pain.

• Nonsteroidal
Anti-
inflammatory
Drugs (NSAIDs)
• Opioid analgesics
• Local anesthetics
 Nonsteroidal Anti-inflammatory Drugs (NSAIDs)
• The primary effect of the nonsteroidal anti-
inflammatory drugs (NSAIDs) is to inhibit
cyclooxygenase (COX or prostaglandin carbon.

synthase [PGHS]), thereby impairing the -20

ultimate transformation of arachidonic acid to
prostaglandins, prostacyclin, and thromboxanes.
• Prostaglandins are extremely powerful
chemicals and do their jobs at very low
concentrations. They mediate some rather
uncomfortable and unpleasant bodily processes,
such as, pain, inflammation (swelling), fever,
blood pressure regulation, menstrual cramps,
labor, blood clotting, and asthma attacks.
• They have wildly descriptive and romantic-
sounding names like: PGD2, PGE1", and PGE2.
• Understanding of NSAIDs requires O

comprehension of the actions and biosynthesis 9

8
COOH

of prostaglandins-unsaturated fatty acid

12
derivatives containing 20 carbons that include a 11
16

cyclic ring structure. HO

H OH
 +

cylof oxygen
Cring)

Conversion of arachidonic acid to prostaglandins.

• Aspirin, ibuprofen, and other nonsteroidal anti-inflammatory
(NSAI) drugs are each single molecules from a class of chemical
compounds called arachidonic acid pathway inhibitors.
• In 1897, a German pharmacist and chemist named Felix Hoffmann,
working for Bayer, found a solution for that bitter pill and acetylated
salicylic acid, meaning that he replaced the hydrogen on the –OH
groups with a -C(O)CH3. This compound is called acetyl salicylic acid.

of acid
autylation salicylic
 Mechanism of action of NSAIDs
• Aspirin, ibuprofen, and other NSAIs
inhibit the arachidonic acid pathway early
in the process—at the cyclooxygenase
step to be precise. These chemicals are
called competitive inhibitors. They
compete with the arachidonic acid for
cyclooxygenase, binding with it so that
the arachidonic acid cannot. If the
enzyme is busy with the NSAI, it cannot
do its job on the arachidonic acid.
• Three isoform of COX have been
identified: COX-1, COX-2, and COX-3.
• COX-1 & COX-2 are selectively inhibited
by anti-inflammatory drugs while COX-3
is selectively inhibited by
analgetic/antipyretic drugs
• COX-1 is expressed in most tissues, but variably. It is described
as a "housekeeping" enzyme, regulating normal cellular
processes (such as gastric cytoprotection, vascular
homeostasis, platelet aggregation, and kidney function), and
it is stimulated by hormones or growth factors.
• COX-2 is constitutively expressed
acid
in the brain, in the kidney, in
is used
treatmenstrual cramps
bone, and probably in the female reproductive system. Its
expression at other sites is increased during states of
-

inflammation or, experimentally, in response to mitogenic

stimuli.
↳fiferent
-

the
is methyl group,

I:iso.
0 - Vallines.
C ⑧
↳ functional group Kenc tahn dkt base dia
 Anti-inflammatory Drugs
Chemical Classifications of NSAIDs - indomethacin()
- Selindal
acific dislofenac
acid. I
aryl-heteroary)
1) • Salicylates Aspirin. ibuprofen Cibulate
P Prick).
2) • Arylalkanoic Acids uparyl-heteroaryl propionic
acid
Ketoproter.
acid (Structur-
3) • N-Arylanthranilic Acids (Fenamic Acids) anthramilia
->

chos]
• Selective COX-2 Inhibitors (celecoxib (Celebrex®), rofecoxib
(Vioxx®), and valdecoxib (Bextra®))
B
Antipyretic Analgesics
• Acetanilide
• Phenacetin
• Acetaminophen
 acxy:c
&-
Salicylates
O
C a carboxylic
cronati
↓ rirg. O- akobol dimer.

Rena
hafal!!
↓

de 0
O↳ condensed
togethe

↓ Lesters.

salicylic

acetyl
acid t
0
g-thio

8
T

.
-
-

- -
-

& Para substitution).

 anti-inflammatory action!!

oor autolativ
but
2
no
carboxylate
C) present-

still
have the
aut, analgesic

↳ I
↳Dirreversible both cox 2.

carboxylate menting!!!
Structure-activity Relationships: Salicylate (Salicylic acid)

• The active moiety appears to be the salicyclate anion.

important
• Side effects of aspirin, particularly the GI effects, appear
to be associated with the carboxylic acid functional

gi
group.
• Reducing acidity of this group (converting to an amide, 0
salicylamide) maintains the analgesic actions of salicyclic ,&

acid derivatives but eliminates the anti-inflammatory

properties.

↓
• Substitution on either the carboxyl or phenolic hydroxyl
groups may effect potency and toxicity. up important
• Benzoic acid itself has only weak activity. Placing the
phenolic hydroxyl group meta- or para- to the carboxyl Halogen
group abolishes activity. ↑
polry
• Substitution of halogen atoms on the aromatic ring I
to
enhances potency and toxicity.
-Para
position.
city.
• Substitution of aromatic rings at the 25-position of
salicyclic acid increases anti-inflammatory activity (e.g.,
diflunisal) d
-
-

inflam
I
anti
- -
-

para hydroxyl
to group:
 Aspirin USP.
• Acetylsalicylate acid.
• Stable in a dry environment but hydrolyzed to
salicyclic acid and acetic acid under humid or
moist condition.
• Aspirin is unique among NSAIDs since it covalently
modifies both isoforms of COX, thus inactivating
them irreversibly. Its major drawback is a significant
gastrotoxicity; symptoms may range from gastritis to

I
u
peptic ulcer and severe gastrointestinal haemorrhage.

acidic
properties
↓

- 20x 1 inhibitory
effe(7
 Shemetabolites
* of
moston version
the
(majority).

hydrfel hydroxy. Indraxy. - most ofthe salicylic

acid.

will be
glucorinized
~D glucocinidation.

Emono-hydroxylation). dihydroxylation
-De +; Mes

"these tab
 La 7
Arylalkanoic Acids
axid
Carboxy)

0Farauxislin
Day acidi

• Largest group of NSAIDs.

• Produced in 1980s, but withdrawn in 1983
due to several deaths caused by
cholestatic jaundice in Europe and US.
• Nonselective COX inhibitors. acid
⑪ ⑧ acetic
• Aryl-and heteroarylacetic acid O - hetero cyclic

-⑧①
acid.

S
- acetic

(Indometacin, Diclofenac sodium) acetyl

-D
2

⑪ ⑳ propionic daid
• Aryl-and heteroarylpropionic acid
↓
(Ibuprofen, Naproxen) ↓
↓ 3

can be
carbon
-
heteroarylpropionic
can be either.
propionic,

acid propionic acid pun

ada
 OC -

I I
acetic acid.
acefic acid. anyl
hetero-aryl

O -

Gryl

culpyr
dry -
X hetero.
X hetero
0
sc inter

& an
special
 Aryl-and heteroarylacetic
acid: Indometacin
• The chirality introduced in the molecules is important. 08
• Anti-inflammatory activity is displayed only by the (S)(+)- enantiomer. The
confirmation of indomethacin appears to play a crucial role in its anti-
inflammatory actions.
Conformation.
• The preferred confirmation of the N-p-chlorobenzoyl group is one in which the
=
-

chlorophenyl ring oriented away from the 2-methyl group (or cis to the
methoxyphenyl ring of the indole nucleus and is non-coplanar with the indole
ring because of steric hindrance produced by the 2-methyl group and the
hydrogen atom at the 7-position.

less of
O
⑧ OX
O lotof

I↓
-
-

Steric
hindrance

jank
0 O Staric
hindrance.
Ibosars.
2 ↓
[cis methoxy plenyl]
to
Besar activy.
I
 Structure-activity Relationships: Indometacin
C pares
positiv

-
important
*
• Replacement of the carboxyl group with other
0.
•
acidic functionalities decreases activity.
Anti-inflammatory activity generally increases (factivity
I
-
as the acidity of the carboxyl group increases

&awasser
&

and decreases as the acidity is decreased. ~

S

• Amide analogues are inactive. X=>

inflammation para
position
0
• Acylation of the indole nitrogen with with kalan
->
Replace

aliphatic carboxylic acids or aralkylcarboxylic

-

fanctional gron
=x
activity. (import
acids results in amide derivatives that are less
active than those derived from benzoic acid.
• &
N-Benzoyl derivatives substituted in the para-
position with chloro, fluoro, trifluoromethyl or
thiomethyl groups are the most active.
• The 5-position of the indole ring is most ·de
accity: anti-inflam
flexible with regard to the nature of
substituents that enhance activity.
Metabolism of Indomethacin gluronidation
&

glucornidation
O ⑦8
hydroxyl

hydroxylation
Indomethacin

whatare the
metabolism
degradation. ->
a
ofthis
molecules

alkyl group

hydrophobicity. ⑦ ⑧
I
penetrate membrane
e

convert other
to
metabolites. -
 Structure-activity Relationships: Sulindac
SAR
0
• Substituents such as methoxy, fluoro,
dimethylamino, methyl, allyloxy, acetyl are more indole ring.

active than unsubstituted indole ring.

↓ positition.
*

• The presence of an indole ring nitrogen is not

essential for activity because the corresponding I
-

O r
1-benzyldenylindene analogs (e.g., sundilac) are
active. ~D tular indole jadihetero-N
X effect. Inessentially
• Alkyl groups, especially methyl, at the a-position
are more active than aryl substituents.
-
-

• Substitution of a methyl group at the a-position

propionic
acid

of the acetic acid side chainor (to give the

corresponding propionic acid derivatives) leads to
and/
adic
eqiactive analogs.
propionic
-
-

a
t
active analog
equi"same
 Metabolism of Sulindac
8
howanide. gitordation
-
hydroxylation O sulphite
metayl
0 -> gluconnidate.

0 O
->

hydroxy
 -zeklow go
f
Diclofenac Sodium

·
• Diclofenac is synthesized from N-phenyl-2,6-dicloroaniline.
• Diclofenac possesses structural characteristics of both
arylalkanoic acid and the anthranilic acid classes.
• It displays anti-inflammatory, analgetic, and antipyretic
properties. anthramilia aciL
O
->
drylakanoic
• It is six times more potent analgetic than indomethcin and -
acid.

40 times as potent as aspirin in the phenyl benzoquinone.

quilino.
⑧
anillo phenyl
• Diclofenac is unique among the NSAIDs in that it possesses group.

three possible mechanism of action: 1) inhibition of

↓
arachidonic acid cyclooxygenase system 2) inhibition of
Lipoxygenase pathway 3) inhibition of arachidonic acid birding
release. sile

Structure-activity Relationships t

• The function of the two o-chloro groups is to force the anilino-phenyl

ring out of the plane of the phenylacetic acid group portion, this
-

↳
twisting effect being important in the binding of NSAIDs to active site
of the COX.
↳ planar
x
Metabolism of Diclofenac

hydroxylation
- ~ /

Je
2

4)

0
g
O

O
 Nabumetone
↳ acidic
x
↓
↳a Letic
Keaton,
y

• A new class of nonacidic prodrug. acid

• Rapidly metabolized after absorption to form a major active metabolite, 6-
methoxynaphthalene acetic acid.
• It is a classic example of the prodrug approach in drug discovery.
• It is approximately 13 times more potent than aspirin, one-third as active
as indomethacin, and half as active as diclofenac.

produc
↑

active
 Structure-activity Relationships:
Nabumetone
• Introduction of methyl or ethyl groups on the
butanone side chain greatly reduced anti-
inflammatory activity.
-

butanome
-

↓
-
u
• Conversion of ketone functionality into important.
dioxolone retains the activity while
d
C I
converting ketone into an oxime reduced ↑
•
activity.
Removal of methoxy group at the 6-position
Coelmoxyps"
6.
3

mittyl/
reduced activity. etyl
• But replacement of methoxy with a methyl or -

f anti infram
chloro group gave active compounds.
• Replacement of the methoxy with hydroxyl,
acetoxy, or N-methylcarbamoyl groups, or
positional isomer of the methoxy group at
the 2- or 4-positions, greatly reduced activity.
Aryl-and heteroarylpropionic acid
propionic

g acid.

ga"
prapio

·OoO propionic

hetero
- acid

arys.
 ± -IBUPROFEN
Cl
• It was the first NSAID since indomethacin and the first arylpropionic acid
derivative to be marketed in the U.S.
• It is marketed as the racemic mixture although biological activity resides
almost exclusvely in the (S)(+)-isomer.
• The stereochemistry associated with the chiral centre in the arylpropionic
acids, but lacking in the acetic acid derivatives, play an important role in both
the in vivo and in vitro activities of these agents.

droxyl
(R)-Ibuprofen (S)-Ibuprofen
I

I hydroxy,

focus
Da this
 has enditioner
only dings that
being
Structure-Activity Relationships: Naproxen merkeled

Knaphthalene Rigay
memorise lipophili, grave
• In series of substituted 2-naphthylacetic acids,
substitution in the 6-position led to maximum anti-
inflammatory activity.
• Small lipophilic groups, such as Cl, CH3S, and
CHF2O, were active analogues, with CH3O being
the most potent.
• Large groups were found to be less active.
X Ich group beson
↳D
O . ↓
6

↓
• Derivatives of 2-naphthylpropionic acids are more
potent than the corresponding acetic acid
aFlamm
↑

analogues.
• Replacing the carbonyl group with the functional
groups capable of being metabolized to the
carboxyl function (e.g., -CO2CH3, -CHO, or –CH2OH)
led to a retention of activity.
• Naproxen is the only arylalkanoic acid NSAIDs
currently marketed as optically active isomers.
 N-Arylanthranilic Acids (Fenamic Acids)
• The anthranilic acid class of NSAIDs is the result of the application of
classical medicinal chemistry bio-isosteric drug design concept,
because these derivatives are nitrogen isosteres of salicylic acids.

0
-> sameparties

0
->
anthranilic
acid. ·cyliz

& O - al
SPECIFIC DRUGS
 General Structure-Activity Relationships:

• Sunstitution on the anthranilic acid ring

generally reduces activity, whereas substitution
of the N-aryl ring can lead to conflicting results.
patentpole
• 2’-Cl derivative is more potent than the 3’-Cl
analogue.
• The NH-moiety of anthranilic acid appears to be
essential for activity, because replacement of
the NH function with O, CH2, S, SO2, N-CH3, or N- 2

COCH3 functionalities significantly reduces

activity. 2

• Anthranilic acid derivatives are active, whereas 3

meclofenamic acid
the m- and p-aminobenzoic acid analogues are
not. x faham
• Replacement of the carboxylic acid function
with the isosteric tetrazole moiety has little
effect on activity.
tetrazole
Selective COX-2 Inhibitors
Metabolism of Celecoxib

Y hydroxylat
live-
d Oxidation
0 0 I
↓
hy
droxylategran Oxidative

sincantali Carboxylic acid

Metabolism primarily occur in the liver by CYP2C9 and involves
hydroxylation of the 4-methyl group to primary alcohol, which is
subsequently oxidized to carboxylic acid as major metabolite. The
carboxylic acid is conjugated, to a slightly extent, with glucuronic acid
to form the correspond glucuronide.
 Binding Models I heter w
2 Phenyl ring.
, sulphonamide
Limethyl

60
↓anti ↓
Binding models of Binding models of
I faham
indomethacin to COX-1 Celecoxib to COX-2
sugat!!
↓
aryl
alkanoit.
 Selective COX-3 inhibitors

8 piteral

am
 metabolite.

Metabolism of Acetaminophen G

• Both acetanilide and phenacetin

are metabolized to acetaminophen.
• Additionally, both undergo
mydrgsi
hydelyil
·

0
->
hydrolysis to yield aniline derivatives
auiline.
and Hydroxylamine derivatives.

hydroxyla
•O-glucuronide being the primary -
metabolite in adult while O-sulfate
conjugate being primary metabolite
in children.

aniline
 Medicinal Chemistry Of Opioid Analgesics (Multicyclic
opioids)
• Opioids cover all the synthetic, semi-synthetic, naturally occurring, and
endogenous compounds that interact with opioid receptors in the body.
• The first opioids were extracted from opium—the sticky exudate obtained
from the opium poppy (Papaver somniferum).
• Opium is the oldest herbal medicine known to humanity and has been used
for myriad afflictions.
• Opium was also smoked in opium dens, which became widespread around the
world—especially among Chinese communities.
• Opium contains a complex mixture of over 20 alkaloids. The principal alkaloid
in the mixture, and the one responsible for opium's analgesic and sedative
activity, is morphine.
 also proved to be one of the first examples of a drug blood supply revealed that morphine was a potent anal-
Structure of morphine
taken for ‘recreational purposes’. A number of famous gesic and sedative, and was far more effective than opium.
cinal Chemistry of Opioid Analgesics | PharmaFactz

O
2
HO 3 HO MeN

T
1 N
HC
A
Antihistamine
O
4 11 =chiral OH
fertiary
10 centre

Garcia
12 15 16 O
O O D O
14 9 B E
13 NMe NMe
5 H fam.
6 7 8
H C H
OH O
HO HO ↳Sings

FIGURE 24.1 Structure of morphine showing different representations.

• Five rings labelled A–E and has a pronounced T-shape. -

• It is basic because of the tertiary amino group, but it also contains a phenol,
alcohol, aromatic ring, ether bridge, and alkene double bond.
• The nitrogen atom of the amine can undergo inversion, which means that the
Morphine
N-methyl group can slowly interconvert between the axial and the equatorial
numberingsystem
632 positions. bind.
97.indb
N-methyl group is to
11/28

T
0
OH

HO''
Morphine
Eu
grind ⑳ "OH

Morphine's"T-shape"

prearl,
rough the synthesis and/or analysis of several morphine derivatives, several
 the stereochemistry of morphine. Morphine is
Structure–activity relationships: Opioid
634 Chapter 24 The opioid analgesics

Analgesics
2 E

HO HO HO RO O
H

O O O O
NMe NMe NMe NMe 15 16
H
H
H
H
H
H H
H O
6 6 6 6 3.

RO O O HO NHMe
H
Heterocodeine; R = Me 6-Oxomorphine Hydromorphone Dihydromorphine; R = H H
6-Ethylmorphine; R = Et Dihydrocodeine; R = Me Tentrary
6-Acetylmorphine; R = Ac HO amino
RO I

O Analogues of morphine.
van der Waals Lee in
2
NMe Binding H-bonding
H H
6 that groups
functional
I
HO group Ionic
Codeine; R = Me pharmacophore: responsible
for the
3-Ethylmorphine; R = Et
3-Acetylmorphine; R = Ac
binding to the receptor /particulogy activity.
Important functional
FIGURE 24.3 I 0 ②groups for ana
• Important functional groups for analgesic activity are the phenol OH group,
FIGURE 24.2 Analogues of morphine.
the
activity aromatic ring,
in morphine.
and the tertiary amine which is protonated and ionized when the drug interacts with its target
binding site. ③
For additional material see Web article 11: testing molecule containing several asymmetric centres and
methods. exists naturally as a single stereoisomer. When morphine
was first synthesized, it was made as a racemic mixture of
• ThThese functional
ese, and other, groupsthatplay
results led to the conclusion the thean important
naturally roleplusinits mirror-image
occurring enantiomer binding the drug to the binding site by the
important functional groups for analgesic activity are enantiomer (Fig. 24.4). It was noticeable that the activ-
intermolecular
the phenol OH group, the aromatic bonding forcesity of synthetic morphine was half that of natural mor-
ring, and the tertiary
amine which is protonated and ionized when the drug phine and separation of the enantiomers revealed that
Heterocodeine,
• interacts with its target binding site.6-ethylmorphine,
These functional the unnatural6-acetylmorphine,
enantiomer had no analgesic activity.6-oxomorphine,
This
Patrick97397.indb 634 hydromorphone, and
groups play an important role in binding the drug to the should come as no surprise as the macromolecules tar-
dihydromorphine
binding site by the intermolecular bonding structures where
forces indi- geted by drugs the alkene
are themselves or and
asymmetric 6-hydroxy
are able groups have been modified or
Atremoved. Analgesic activity isEpimerization
retained in theseasymmetricstructures, indicating that neither of these
cated in Fig. 24.3. to distinguish between the enantiomers of a chiral drug.
this stage, it is worth making some observations on of a single centre is not
groups isofcrucial
the stereochemistry to activity.
morphine. Morphine is a chiral beneficial for activity either, as changing the stereo-
chemistry of even one asymmetric centre can result
• However, O
analgesic activityinmolecule drops
binds to itssignificantly
target binding site. For for
example, codeine,
a drastic change of shape that could affect how the
dihydrocodeine, and 3-
ethylmorphine, indicating theepimerization
H
importance of thecentre
of the asymmetric phenolic
at position group.
results in a stereoisomer that has only 10% the activity
14

15 16
 converting diamorphine to morphine.
didmorphine
↓ ⑧ 0
here

↑
in
prin
7
0 -
ester
⑧
⑧
⑧
-
↑

lipophilic
↳y hydrophobicity
Tty derivatives
Ofmorphine
• The phenolic –OH is masked as another functional group (i.e. prodrugs such
as diamorphine) which enhance hydrophobicity and hence improve the ability
https://pharmafactz.com/medicinal-chemistry-of-opioid-analgesics/
to cross the blood-brain barrier (BBB), ultimately leading to enhanced
analgesia.
• In the case of diamorphine, both the phenolic hydroxyl and the hydroxyl in
position 6 have been acetylated.
• Through the activity of metabolic enzymes, both the phenolic –OH and
position 6 hydroxyl groups are unmasked by esterase enzymes in the CNS,
converting diamorphine to morphine.
- -
-

-
-
 Activity with respect to morphine = 10% OH

Opioid pharmacophores
FIGURE 24.5 Epimerization of a single asymmetric centre.

MeHN MeHN
8 N
Ionic

pai
OH
Aromatic
Ar
O =

HBD

⑧
OH OH HBA
OH
Skeletal pharmacopore Pharmacophoric triangles

FIGURE 24.6 Opioid pharmacophores for morphine and related opioids.

• Analgesic activity is not only related to the presence of the
sum up,important functional
analgesic activity is not onlygroups,
related to but to theirSimpler,
macophore. relative
moreposition withare believ
flexible opioids
resence of the important functional groups defined to interact with opioid receptors in a different way fro
respect
er, but to their relativeto eachwith
position other—the pharmacophore.
respect to each morphine such that the phenol group becomes redu
r—the•pharmacophore
The molecular (sectiontarget
13.2). Opioid
for phar- dant (see
morphine: sectionsreceptors:
opioid 24.6.3.4 and 24.6.3.5).
There Alternative
are
ophores can be defined in different ways, either by more complex opioids such as the orvinols contain add
three
ing a simple main
skeleton that types
links the of analgesic
important func- or opioid
tional receptor
binding groups thatthat are
can compensate for the mas
l groups activated by morphine:
or by pharmacophoric trianglesthe mu ing
where (μ), kappa
of the phenol(κ), and
group delta
(section (δ)
24.6.4).
orners correspond to functional groups or binding
receptors.
-

Test your understanding and practise your molec

actions (Fig. 24.6).
lar modelling with Exercises 24.2 and 24.3.
nally, a word of caution regarding the importance
-
 target binding site. These functional
the unnatural enantiomer had no analgesic activity. This
portant role in binding the drug to the
should come as no surprise as the macromolecules tar-

Stereochemistry of morphine
he intermolecular bonding forces indi-geted by drugs are themselves asymmetric and are able
to distinguish between the enantiomers of a chiral drug.
is worth making some observations on Epimerization of a single asymmetric centre is not
ry of morphine. Morphine is a chiral beneficial for activity either, as changing the stereo-
• Morphine is a chiral chemistrymolecule containing
of even several
one asymmetric asymmetric
centre can result centres and exists
in a drastic change of shape that could affect how the
naturally as a single stereoisomer.
O molecule binds to its target binding site. For example,
• Changing the stereochemistry epimerizationofofeven one asymmetric
the asymmetric centre
centre at position 14 can result in a drastic
change results in
of shape that could a stereoisomer
affect how the that has only 10%
molecule the activity
binds to its target binding site.
O 15 16 of morphine (Fig. 24.5).
NHMe
H
H
HO HO
O

van der Waals O O

ing NMe NMe

H-bonding H H
ps H H
Ionic HO HO
Natural morphine Mirror image of morphine
portant functional groups for analgesic The molecular target for morphine: opioid receptors 635
activity in morphine. FIGURE 24.4 Morphine and its mirror image.
HO Change of
stereochemistry Original
ring
MeN
O H
NMe OH
H H O

e
Change of 11/28/2012 9:20:07 PM
HO stereochemistry
Activity with respect to morphine = 10% OH
Charger
-
the shape
FIGURE 24.5 Epimerization of achange stereochemisty
single asymmetric
-
centre.
-charge the capabilities.
 ing, is free of euphoric effects, and has a low risk of physi-

Morphine: Pharmacodynamics and

cal dependence. The κ receptor is considered the safest of
the three types of receptor and a lot of research has been
carried out to develop κ-selective opioids. Unfortunately,
Pharmacodynamics refers to the manner in which a drug
binds to its target and produces a pharmacological effect.
The functional groups that are important to the activity

Pharmacokinetics
it has been discovered that activation of the κ receptor
can lead to sedation and psychological side effects, such
of morphine act as binding groups in the following man-
ner (Fig. 24.7):

Ionic bond

0 N

OH

00
O

van der Waals

interactions
Analgesic
receptor OH
H-bond

FIGURE 24.7 Binding interactions of morphine with the hypothetical binding site of an opioid receptor.
• The amine nitrogen is protonated and charged allowing it to form an ionic bond
with a negatively charged region of the binding site.
• The phenol acts as a hydrogen bond donor and forms a hydrogen bond to a
Patrick97397.indb 636 11/28/2012 9:20:09 PM

hydrogen bond acceptor in the binding site.

• The rigid structure of morphine means that its aromatic ring has a defined
orientation with respect to the rest of the molecule, allowing van der Waals
interactions with a suitable hydrophobic location in the binding site.
• Morphine is relatively polar and is poorly absorbed from the gut, and so it is
normally given by intravenous injection.
 R R O R

N-Alkylated morphine N-Acylated morphine N-Alkylated morphine

Morphine analogues
Demethylation and alkylation of the basic centre.

• Drug extension
duration

⑧
O
HO MeO HO
van der Waals interactions
↑
action

/ O
14

OH
H
NMe
O

R
H
NMe
O

H
H
N
H
Extension
M
aft
I
O O HO
X
X -
dOxymorphone i Hydrocodone N-Phenethylmorphine
(2.5 " activity of morphine) (dihydrocodeinone); R=H (14 " activity of morphine)
Oxycodone; R=OH =

target FIGURE 24.9 Extended analogues of morphine.

ethyl phenyl
dre R2 = Me Et Pr Bu Pentyl, Hexyl CH2CH2Ph -substition modify
Agonism decreases Zero Agonists 14 " activity
the
activing.

dagaudat Change in activity with respect to alkyl group size.

Antagonism increases activity

eas
of morphine
-
FIGURE 24.10 Change in activity with respect to alkyl group size.
640 Chapter 24 The opioid analgesics
ziduc HO HO
The opioid antagonists have also proved useful in
HO
habit. As a result, they are more likely to remain absti-
treating addictions. Naltrexone is eight times more active nent. Naltrexone in combination with bupropion (sec-
Cyclopropylmethyl
than naloxone as an antagonist and is given to drug
Allyl tion 23.12.4) is also being considered for the treatment ofAllyl
O who have been weaned off morphineOor heroin.
addicts obesity. Nalmefine (Fig 24.11)Ois a close analogue which
Naltrexone blocks the opioid N receptors, preventing the is currently
N undergoing clinical trials as an oral treatment
N
effects that addicts seekHif they are tempted to restart their for
OH
H
alcoholism. H
It binds more strongly than naltrexone
H to
OH
O X HO
Naloxone Naltrexone (X = O) Nalorphine

L
Emiphin
Nalmefine (X = CH2)

from
-
Otymorphore
Patrick97397.indb 639
FIGURE 24.11 Antagonists
Antagonists to morphine.
to morphine.
11/28/2012 9:20:11 PM

opioid receptors and blocks the effects of natural opioids whether structures with fewer rings and chiral centres
released as a result of drinking. were still active.
 structure and ask whether the complete carbon skeleton As might be expected, the mirror image of l

Simplification or drug dissection

is really necessary. If the molecule could be simplified, it
would be easier to synthesize analogues (section 13.3.8).
The structure of morphine has five rings and five chi-
Removing ring E ral centres (Fig. 24.12) and analogues were made to see
(dextrorphan) has insignificant analgesic act
The same strategy of drug extension alread
for the morphine structures was tried on the m
with similar results. For example, adding an a

important
uent on the nitrogen gives antagonists. Addin
e thyl group to the nitrogen greatly increase
HO HO
Adding a 14-hydroxyl group also increases ac
A A
Oxygen
bring To conclude:
&
A contribute
for ⑧O D
B E
NMe
O D B • morphinans are more potent and longer-a
their morphine counterparts, but they also h
actiring -

C H
C
H H
toxicity and comparable dependence charac
HO HO
• modifications carried out on the morphina
FIGURE 24.12 Removing ring E from morphine. same structure–activity relationship (SAR
Removing ring E leads to complete loss of activity. This emphasizes the importance of
the basic nitrogen to analgesic activity.
↳ form tonic bond.
Removing ring D -
and of -
still
I
have analgesic
Patrick97397.indb 640
Removing the oxygen bridge, as well as the alcohol and alkene functional groups
gives a series of tetracyclic compounds called the morphinans, which have useful -

analgesic activity. This demonstrates that the oxygen bridgeMorphine analogues

is not 641
essential.
HO HO HO

analgesi NMe NMe N N

Ph

activity H
H
H
H
H
H
H
H

N-Methylmorphinan Levorphanol Levallorphan N-Phenethyllevorphanol

(20% activity of morphine) (5 × more potent (Antagonist 5 × more (15 × more potent than morphine)
than morphine) potent than nalorphine)
sting molecule containing several asymmetric centres and
Morphinans
exists naturally as a single stereoisomer. When morphine
was first synthesized, it was made as a racemic mixture of
at the the naturally occurring enantiomer plus its mirror-image
y are enantiomer (Fig. 24.4). It was noticeable that the activ-
rtiary • morphinans are more potent and longer-acting than their
ity of synthetic morphine was half that of natural mor-
drug phine and separation of the enantiomers revealed that
ional morphine counterparts, but they also have higher toxicity and
the unnatural enantiomer had no analgesic activity. This
o the should come as no surprise as the macromolecules tar-
indi- comparable dependence characteristics.
geted by drugs are themselves asymmetric and are able
to distinguish between the enantiomers of a chiral drug.
ns on • modifications carried out on the morphinans have the same
Epimerization of a single asymmetric centre is not
chiral beneficial for activity either, as changing the stereo-
structure–activity relationship (SAR) results as they do with
chemistry of even one asymmetric centre can result
in a drastic change of shape that could affect how the
morphine. This implies that morphine and morphinans are
molecule binds to its target binding site. For example,
binding to the same receptors in the same way.
epimerization of the asymmetric centre at position 14
results in a stereoisomer that has only 10% the activity
of morphine (Fig. 24.5). Morphine analogues 641

HO HO HO HO HO

Ph
O O
NMe NMe N N
NMe H H H H
H H H NMe H H H
H H
HO HO N-Methylmorphinan Levorphanol Levallorphan N-Phenethyllevorphanol
(20% activity of morphine) (5 × more potent (Antagonist 5 × more (15 × more potent than morphine)
Natural morphine Mirror image of morphine
esic than morphine) potent than nalorphine)

FIGURE 24.4 Morphine and its mirror image. FIGURE 24.13 Examples of morphinans.
 and represent the remnants of the C ring. It is important longer duration, has 200 times the activity of morphine,
that these methyl groups are retained in order to obtain appears to have no addictive properties, and does not
Removing rings C and D
good activity.
The same chemical modifications carried out on the
depress breathing.
To conclude:
benzomorphans as described for the morphinans and
Removing both rings C and D gives an interesting group of compounds called the
morphine produce the same biological effects, implying • rings C and D are not essential to analgesic activity;
benzomorphans, which retain analgesic activity.
a similar interaction with the analgesic receptors. For • analgesia and addiction are not necessarily co-existent;
-
3'
X HO HO
4'
7
1'
6 8
4 3

C4D
-

9
R1 5 1 NMe Me NMe Me NCH2CH 2Ph
H H
R2 Me Me
Ring Metazocine Phenazocine
(same potency as morphine) (4 × more potent than morphine)
X contribut HO HO

to
activity Me

Me N Me Et N OH
H H
Me Me Me
Pentazocine Bremazocine
(33% activity of morphine, short duration,
low addiction liability)

FIGURE 24.14 Benzomorphans.

• rings C and D are not essential to analgesic activity;

• 6,7-benzomorphans are clinically useful compounds with reasonable analgesic
activity, less addictive liability, and less tolerance; addictive) I↓ tolerance.
It
• benzomorphans bind to opioid receptors in the same manner as morphine and
Patrick97397.indb 641 11/28/2012 9:20:12 PM

morphinans.
to be analgesics—this is evident if the structure is drawn class of opioids known as the 4-anilinopiperidines and
as shown in Fig. 24.15. Activity can be increased sixfold are among the most potent agonists known for the μ
Removing
by introducing the rings B, group
phenolic C, and and Daltering the ester receptor. These drugs lack a phenolic group and are very
to a ketone to give ketobemidone. lipophilic. As a result, they can cross the blood–brain
•Pethidine
Removing (meperidine) is a weaker analgesic than barrier more efficiently. Fentanyl itself is up to 100 times
rings B, C, and D gives a series of compounds known as 4-
morphine, but shares the same undesirable side effects. more active than morphine as a sedative and analgesic
On thephenylpiperidines.
plus side, it has a rapid onset and a shorter dura- and it is thought that the Russian authorities used it in
• ofActivity
tion action. Ascan be increased
a result, it has been sixfold byanalge-
used as an introducing the phenolic
an attempt groupa group
to incapacitate and altering theduring
of terrorists
sic in ester
childbirth.
to aTh e rapid to
ketone onsetgive and short duration of the infamous cinema siege of recent years. Apparently,
ketobemidone.
action mean that there is less chance of the drug depress- the drug was introduced as a gas through the ventilation
• therings
ing baby'sC,breathing
D, and once
E are it isnot essential
born. for analgesic
The structure was systemactivity;
into the auditorium and succeeded in rendering
discovered in 1939 andring
• the aromatic was theand firstbasic
fully synthetic
nitrogenopioid both terrorists
are essential and hostages
to activity, unconscious.
but the phenol Unfortunately,
group
analgesic to enter clinical practice.
is not; the authorities waited too long to enter the building and
Phenyl
↓
4° centre
4° centre
·
O
HO
A CO2Et Et
=
I 3.

"piperidine
EtO2C NMe
N N
Me Me
Pethidine (or meperidine) Ketobemidone
(20% activity of morphine)

FIGURE 24.15 4-Phenylpiperidines. ↑

HO
↑
x86
H
H
 • piperidine analgesics are faster acting and have a
swaps an addiction to heroin or morphine for an addiction
shorter duration of action than morphine;
Removing rings B, C, D, and E - to methadone. This is considered less dangerous, though.
methadone.
• the quaternary centre present in piperidines is The molecule is a diphenylpropylamine structure con-
usually necessary (fentanyl and its analogues are taining a single asymmetric centre. When the molecule is
The analgesic methadone was discovered indrawn
exceptions); Germany during
in the same manner World War IIwe
as morphine, and is expect
would
• comparable
the aromatic ring in and
activity
basic to morphine.
nitrogen It is orally
are essential to theactive and has
R-enantiomer to beless severe
the more activeemetic
enantiomer. This
activity, but the phenoleffects.
group is not; proves to be the case with the R-enantiomer being twice
and constipation plenyn. -

emetic
I

100
constipation
-

Asymmetric centre
R 2 ! more potent than morphine
O -

S Inactive
Me NMe2 H 1-
= *
Ph Ph H O
Me Ph Me NMe2

CH 2CH 3

FIGURE 24.18 Methadone. *

x-meting
.indb 643 11/28/2012
 Rigidification
target
↳X meettang anadding site
Lotter
R
Morphine analogues

• The strategy of rigidification is used to H 20

Me
OH O

limit the number of conformations that a

MeN MeN
N

OH O
OMe

molecule can adopt and retain the active O O O

conformation for the desired target. Morphine

OH OH
Oripavines
O

• increase activity, improve selectivity, and Comparison of morphine and orvinols.

FIGURE 24.20

decrease side effects. HO HO HO

Etorphine is 10,000 times more potent

analgesics ever reported. Dihydroetorphine is used in and pentazocine in that it has analgesic activity
• China as a strong analgesic and as a treatment for opi- very low risk of addiction. It is a particularly sa
O O O
oid addiction. because it has very little effect on respiration, an
than morphine. This is a combination 24.20 of
The presence of lipophilic groups at C20 (R in Fig. NMelittle effect it does have actually NMedecreases at high
) is found to improve activity dramatically,Hindicat- Therefore, the risks ofHsuffocation from a drug ov

its high hydrophobicity which allows it ing

into
the existence of an extra hydrophobic binding region are much smaller than with morphine. Bupreno
MeO MeO MeO

C
the receptor binding site.* The group best H able to inter- has been used in H hospitals to treat patients rec
20 20
cross the blood–brain barrier 300 times
act with this region is a phenethyl substituent, and the from surgery, as well as those suffering from ca 20
product containing this group isMe even moreOH active than has alsoMe been used OH as an alternative to methad
Me
CH CH CH CH CH CH
etorphine. As one might imagine, these highly active weaning addicts off heroin. Its drawbacks inclu
2 2 3 2 2 3

more easily than morphine, allied to a compounds

times higher affinity for the analgesic
receptor due to better
20 have to be handled very carefully in the effthatectsit cannot
laboratory.
such as nausea and vomiting, as well as
be taken orally.
Etorphine Dihydroetorphine Dipren
has
Test your
lar modellingmore
understanding and practise your molecu-
with Exercises 24.7–24.11.
- Buprenorphine Agonists
has unusual and antagonis
receptor binding
ties with respect to other opioids. It has a stron
FIGURE 24.21 Etorphine and r
HO binding HOfunctional HO
ity for the μ receptor where it acts as a partial a
HO
Because of their rigid structures, these compounds whereas it acts as an antagonist at the κ and δ

O
are highly selective agents for the analgesic recep- tors. Normally, one would expect compounds tha
interactions. group
tors. Unfortunately, the increased
↓
at lower analgesic
doses activity is antagonists
than morphine, μ receptor
butatifthethe are at the κ
and agonists
pain levels
O O
also accompanied by unacceptable side effectsOdue to tor to be safer analgesics, and
high, buprenorphine is not as effective 24.
O so the clinical prope
as morphine.
• Adding a cyclopropyl group gives a H very
strong
NMeinteractions
X conformation
with the μ receptor.
decided to see whether N-substituents,
NMe
Nevertheless,
It was, therefore, buprenorphine
buprenorphine N areanother
provides
quite surprising. It is thought
example
such as an allyl lackHof serious side effects is related in some H way
↓
H
of an opioid
↓ or Ha nalorphine—an MeO
or cyclopropyl group, would give analogue
the oripavine where
equiva- rateanalgesia has been
at which buprenorphine interacts withWe
separated r
the re
powerful antagonist called diprenorphine
MeO H lent of aMeO
pentazocine
as an antagonist at the μbind
20
agent acting
fromtodangerous side effects.
receptor 20
It
H is slow to bind, but MeO
once it has bound,
and an agonist at the and is slow to leave. As the effects of binding are
it binds
H lem r
s
easily 20 20
phin
Me OH κ receptor. Me OH
receptor.
CH2CH2CH3 Adding a cyclopropyl
CH2CHgroupCH gives
KEY3POINTS
2 a very
Me
powerful Me
OH
levels. Buprenorphine
antagonist called diprenorphine (Fig. 24.21), which in the orvinol series of compounds
cyclopropyl.
it means that there are no sudden
is the
Me changes
most
Me
OH in tran
repla
lipophilic
andMe
in
enters
com
su
th
d
is 100 times more potent than
• Thenalorphine
addition andof aDiprenorphine
can be very group
14-hydroxyl easily, or
andansoNthe slow onset
-phenethyl
Me
of binding
group an agha
Etorphine Dihydroetorphine
used to reverse the immobilizing effects Diprenorphine
of etorphine. ingato do with Buprenorphine
how easily it reaches (1968)
the receptor. B
Rigidification.
usually
FIGURE buprenorphine
The related compound 24.21
increases
Diprenorphine has no analgesic activity.
binding regions.
Etorphine
activity as
(Fig. and
24.21related
result of interactions
structures.
) to interact
with extra
buprenorphine binds very strongly, less of cule it is r
recep
with a certain percentage of analgesic
“Lipophilicity can impact the extent of oral bioavailability, hepatic penetration on
first pass, and CNS distribution.”

“Most multicyclic opioids provide durations of analgesic action of 4 to 6 hours.”

main Biotransformation ofall sports.
a

“Multicyclic opioids undergo predictable Phase I and Phase II reactions. Common

to most are N-dealkylation and glucuronic acid conjugation or sulfonation of the
phenol. These biotransformations strongly attenuate activity or inactivate the drug,
respectively.”
 Codeine
metabolism

hydroxylation
demethylation, ↓

-
-

1 ↓
Or
sulphon or sulphones
Receptors
otypical μ agonist is (-)-morphine. • Flexible opioids are not conformationally restrained. They can orient their aro
Opioid Receptors Mediating Analgesia
equatorial to the piperidine ring, which permits binding of the former at Trp28
eptor is coupled to Gi and Go proteins. Analgesia is mediated through a
in intracellular cAMP and Ca2+.
receptor.
• Trp238 normally binds with Phe of the enkephalins. Since Phe is nonphenolic, a
OH group is neither required nor desired in flexible opioids.
• All flexible opioids are pure agonists and bind selectively to μ receptors. (See F
with fentanyl as ligand). The 4-phenylpiperidine pharmacophore can be found
envisioned in the flexible opioids (Fig. 12.6).

I,
hydrogen
per

4-phenylpiperidine
Figure 12.5 Mu receptor-fentanyl binding interactions.

Figure 12.6 4-Phenylpiperidine pharmacophore in flexible opioids.

Medicinal)Chemistry)of)Local)Anesthetic)
Agents
A. Hydrophobic-pathway
into-the-nerve-cell
B. Hydrophobic-pathway
to-the-binding-site.
C. Hydrophilic-pathway-
from--the-inside-of-the-
nerve-cell-to-the-binding-
site.-
 SARs%of%Local%Anesthetics%
hydrophorsis hydrophilic
Yester I
a

• The$structure$of$most$local$anesthetic$agents$consists$of$three$parts$as$
shown$above.$
(a)$a$lipophilic$ring$that$may$be$substituted$
(b)$a$linker$of$various$lengths$that$usually$contains$either$an$ester$or$an$
amide
(c)$an$amine$group$that$is$usually$a$tertiary$amine$with$a$pKa between$7.5$
and$9.0.$
 position
-para
1. The Aromatic Ring
• The aromatic ring adds lipophilicity to the anesthetic agents and helps the
molecule penetrate through biological membranes.
• It is also thought to have direct contact with the local anesthetic binding
site on the sodium channel.
• The aromatic ring is believe to interact with the local anesthetic binding
site through a !8! interaction or a !8cation interactions.
• Substituents on the aromatic ring may increase the lipophilic nature of the
aromatic rings.
• Para substituent ester type local anesthetic showed that lipophilic
substituents and electron8donating substituents in para position increased
anesthetic activity. -
-

O
-

O
-

Cocaine -
⑧
↓ d I Procaine

door h
doneg cry
↑length ↑ lipophila
pard
=

-
EDGanesthetic
-
 I

Better/amie
2. The Linker
• The$linker$is$usually$an$ester$or$an$amide$group$along$with$a$hydrophobic$
chain$of$various$lengths.$
• In$general,$when$the$number$of$carbon$atoms$in$the$linker$is$increased,$
the$lipid$solubility,$protein$binding,$duration$of$action,$and$toxicity$
increases.$
• Esters$and$amides$are$bioisosteres$having$similar$sizes,$shapes,$and$
electronic$structures.$ upsas pharmacological effect
-

• Bioisosteres are$substituents or$groups$with$similar$physical$or$chemical$

properties$which$produce$broadly$similar$biological$properties$to$a$
chemical$compound

⑧
d
amide
 halflite
amide
tester yafli
A to
easing bird to--
prokin
L plasma
2. The Linker
• The similarity in their structures means that esters and amides have similar
binding properlies and usually differ only in their stability in vivo and in vitro.
• For molecules that only differ at the linker functional groups, amides are
more stable than esters and thus have longer half@lives than esters.
• Plasma protein binding maybe more prevalent for the amide anesthetics as
-
-
well, contributing to the increased half@life.
-
-

3. The Nitrogen -
hydrophiliz.
• Most local anesthetics contain a tertiary nitrogen with a pKa between 7.5 and
9.5. Therefore, at physiological pH both the cationic and neutral form of the
molecule exists.
• The anesihetic compounds bind to the anesthetic receptor site on the sodium
channel in the ionized form.
• To keep the anesthetic soluble in commercial solutions, most preparations are
acidified.
 electronic cloud
EDG:
t ↑
with
Binding&affinity&with&receptors affing Rezepten
• Electron8donating>groups>on>the>aromatic>ring>created>a>resonance>effect>
between>the>carbonyl>group>and>the>ring,>resulting>in>the>shift>of>electrons>
from>the>ring>to>the>carbonyl>oxygen.>As>the>electronic>cloud>around>the>
oxygen>increased,>so>affinity>of>molecule>with>the>receptor>also>increased.
• Aromatic>ring>substituted>with>an>electron8withdrawing>group>decreased>
the>electronic>cloud>around>the>carbonyl>oxygen>and>the>anesthetic>
activity>decreased>as>well.>
Binding&of&an&ester3type&local&anesthetic&agent&to&a&receptor&site

donating. I polar.
in
electro

t pdar.
>electron withdrawing
 Local&Anesthetic&Products
• The Ester Local Anesthetics
2PB CT
• The Amino Amide Local Anesthetics

The&Ester&Local&Anesthetics around
Cloudcarbonyl

800 000
electron eDU Procaine
- d
Icon And the
-
pfamil
matri
prett

Cocaine DN my Benzocaine

Chloroprocaine Tetracaine
 The$Amino$Amide$Local$Anesthetics

&jyyanna gaming
pain

Lidocaine Mepivacaine uniru

andJama gave 8
Prilocaine
Etidocaine

Bupivacaine Levobupivacaine
 metubolites
mai

⑧
Structure'Activity,Relationship,Comparison,of,Local,Anesthetics
dryl
Linker amino/farting amin

- ester

-
amidi

to amide

estern
->