Anticholinergics

Acetylcholine (Ach)
Drugs that directly inhibit
pharmacological response of Ach
 Muscarine antagonist/antispamodics
• These drugs block the response of Ach in the
muscarine receptor by competitively binding to
it and inhibiting any response.
• They have opposite pharmacological
response of Ach ie if Ach agonist slows heart
rate then Ach antagonist speeds heart rate or
if Ach relaxes bladder then it antagonist
constricts it
• Their medical use is in
– in Sooth muscle spasm
– in cold n flu (to reduce nasal secretion)
– previously in ulcer (but now replaced by H2
antagonist and proton inhibitors)
– Overactive bladder (to much urination)
– Motion sickness
– Treat organophosphate poisoning (still doesn’t
work in aging and doesn’t treat respiratory failure)
– Parkinson (brain disease where nerves start
degrading and person slowly goes crazy)
 SAR of anticholinergics
• Atropine was the first drug of this type and
was used to generate SAR. It was noted that
unlike Ach, the terminal ester carbon in
Atropine had a bulky substituent. This was
considered important and modifications were
done there
 R1

R2 C X (CH2) N substituent
n
R3
General framework of Anticholinergics
1) The R1 or R2 groups must be carbocyclic or
heterocyclic, but if both are cyclic it gives
maximal antagonist potency. The rings may
be same or different. One of is generally
aromatic and other is saturated ring or olefinic
group (ie it has a C-C double bond)
•Rings may be same or different
•The benzene could be any type
Cyclohexane (non-aromatic carbocyclic
or pyridine (aromatic heterocyclic)
or Pyrrolidine (non-aromatic heterocyclic
 Detect R1-R3 and X
R1

R2 C X (CH2) N substituent

R3
2)The R3 group can be hydrogen, hydroxyl (-OH)
, hydroxymethyl (-CH2OH), amide ( ) or a
component of the R1 and R2 group. Best
potency is seen with hydroxyl or
hydroxymethyl (this hints that the oxygen
group must be participating in H bond)

Amide

Hydrogen Hydroxyl Hydroxymethyl

Component of R2 and R3
3) The X is mostly ester in most potent
derivatives but it can be a ether oxygen or
absent completely

Mostly ester Or else ether Or absent completely

4) The N substituent cab be both quaternary
ammonium salt or tertiary amine with
different alkyl groups. Most potent
derivatives have quaternary ammonium salt.
The alkyl group is not restricted to only methyl
(as in SAR of Ach agonist). It can be ethyl,
propyl or isopropyl.

Quaternary form Alkyl = ethyl Alkyl = isopropyl

is most potent Alkyl = methyl
5) The distance between the ring substituted
carbon and nitrogen is not fixed ie it can vary
The no. of alkyl units between that carbon and
nitrogen can vary from 2-4, with most potency
in case of two CH2 units.(this is also unlike
SAR of Ach agonist where the CH2 units
should not be more than 2).

2 CH2 units is 2 CH2 units (don’t 3 CH2 (don’t count double or

best distance count O or N, just C) triple bonded carbon. Only
count single carbons)
 R1

summary R2 C X (CH2) N substituent

R3
• The R1 or R2 groups must be carbocyclic or
heterocyclic
• The R3 group can be hydrogen, hydroxyl (-OH),
hydroxymethyl (-CH2OH), amide or a component of
the R2 and R3 group
• The X is mostly ester in most potent derivatives but it
can be a ether oxygen or absent completely
• The N substituent cab be both quaternary ammonium
salt or tertiary amine with different alkyl groups
• The distance between the ring substituted carbon and
nitrogen is not fixed but maximum potency requires
about 2 carbon units
• (Note: The SAR does not say anything about selectivity
for muscarinic subtypes)
What happens during muscular spam?
• A muscle spasm, or muscle cramp, is an
involuntary contraction of a muscle. Muscle
spasms occur suddenly, usually resolve quickly,
and are often painful. Both skeletal muscle and
smooth muscle are effected by it.
• Spasms may occur when a muscle is overused
and tired, particularly if it is overstretched or if it
has been held in the same position for a
prolonged period of time. The muscle becomes
hyperexcitable, resulting in a forceful contraction
 Contrast between SAR of Ach agonist
and antagonist
A) Nitrogen group
• In agonist the N can only be quanternary but
• In antagonist N can be both quanternary or
tertiary

Methacholone
B) Ethylene group
• In agonist the no of ethylene is fixed at only 2
but
• In antagonist no of ethylene can range from 2-
4

carbamate

Bethanecol
C) Selectivity
• In agonist the methyl substitution in ethylene
group controls selectivity of muscarinic or
nicotinic but
• In antagonist no such feature is present. Still
It only antagonizes muscarinic only

Methacholone
Muscarinic selective
D) Ester group or X group
• In agonist ester is not needed and can be
removed but an Oxygen must exist in it’s
place
• In antagonist ester is not needed and can be
removed but an Oxygen need not exist in it’s
place
 O Mostly ester

H2N O CH2 CH2 N(CH3)3

Ester

Oxygen in place
on ether
H3C O CH2 CH2 N(CH3)3

Ether

H3C CH2 CH2 N(CH3)3 Oxygen absent

Ketone
E) Rule of five and terminal carbon
In agonist rule of five is followed and terminal
carbon is bonded to Hydrogens
In antagonist, rule of five is not followed and
the terminal carbon is bonded to two bulky
ring groups

Methacholone
Spot the associated functional groups
 Specific Muscarinic antagonists
• Aminoalcohol esters
– Atropine
– Scopolamine
• Aminoamide While all of these are selective to
muscarinic receptor
– Tropicamide they are not selective to a specfic
• Aminoether subtype eg M1, or M2 etc. Only
the last two Solifenacin and
– Benztropine Darifenacin show selectivity to
M3.
– Orphenadrine
• Micellneous
– Solifenacin
– Darifenacin
 O

O C CH
Atropine
NCH3

CH2OH
O

O O C CH Scopolamine
NCH3

CH2OH

Dicyclomine Tropicamide
 O

Atropine NCH3 O C CH

CH2OH
• It is anticholinergic that blocks muscarinic receptors
• It is an alkaloid extracted from Solanaceae plant and was the first
anticholinergic.
• It is an ester of tropine and tropic acid and used as a sulphate Salt
in racemic from
• At therapeutic does it can penetrate the brain and stimulate the
CNS
• Uses
– Treat Bardycardia
– Reduce secretion before surgery
– Treat Iritis (painful inflammation of eye)
– Organophosphate poisoning (only to decrease muscarinic action, not an
antidote like PAM)
• MOA – It competitively binds to muscarinic receptor and
antagonizes it thus blocking all cholinergic effects
 Atropine synthesis
O

H
OH HO C C
NCH3

CH2OH

Tropine Esterification Tropic Acid

with HCl
(-H20)

NCH3 O C CH

CH2OH
Atropine
 O

Scopolamine O NCH3 O C CH

CH2OH
• It is anticholinergic that blocks muscarinic
receptors
• It is an alkaloid extracted from Solanaceae plant
• It is used as salt hydrobromide salt in enantiopure
(-) form
• At therapeutic does it depresses CNS
• Uses
– Treat Iritis (painful inflammation of eye)
– Treat Parkinson
– Treat Motion sickness
• MOA - It competitively binds to muscarinic
receptor and antagonizes it thus blocking all
cholinergic effects
Dicyclomine
• It is an anticholinergic that blocks muscarinic
receptors
• It is a weaker antagonist than atropine and
doesn’t stimulate the brain
• Uses
– treat intestinal hypermotility (causes constipation and
diarrhea and decreased opportunity for the
absorption of nutrients)
– irritable bowel syndrome (a disorder in large intestine
that causes cramping, abdominal pain, bloating, gas)
• MOA - It competitively binds to muscarinic
receptor and antagonizes it thus blocking all
cholinergic effects
 Synthesis
Br

H2C CH2 CH2 CH2 CH2 Br

CH2CN

Phenyl acetonitrile 1,5-Dibromopentane

-2HBr

CN
Cyclohexane derivative
 Saponification

COOH

C2H5
i) HO CH2 CH2 N
HCl
C2H5
ii) Reduction
O
C2H5

C O CH2 CH2 N
.HCl
C2H5

Dicyclomine Hcl
Tropicamide
• It is an anticholinergic that blocks muscarinic
receptors
• Its duration of action is shorter than Atropine
• Uses
– Mydriatic (drug that dilates pupil)
– Cycloplegia (to fix eye movement)
• MOA - It competitively binds to muscarinic
receptor and antagonizes it thus blocking all
cholinergic effects
 COOH O

H3C C Cl
Synthesis CH CH2OH

Tropic acid Acetyl Chloride

Esterifcation

COOH O

CH CH2O C CH3
Tropic acid acetate
SOCl2
O

C Cl O
An acid chloride
CH CH2O C CH3
 C2H5

HN H2C N

O C2H5

C N CH2 N
Tropicamide acetate
C CH2O C
H CH3

Saponification

O C2H5

C N CH2 N
Tropicamide
C CH2OH
H
 Newer Muscarinic Antagonist
• Newer drugs focus on subtype selectivity and
don’t have defined SAR

Older SAR based non-selective drug

Selective to M1 Selective to M2
Observe the use of tri-cyclic ring and how minor modification changed
Selectivity from M1 to M2. This is true not just here in in every case
Acetylcholine and muscle contraction
 Action
Ach binds to AP causes
potential
it’s receptor in Release of
(AP)is
muscle Ca2+ from SR
generated

Myosin cross-
Muscle return AP ends and
bridges with
back to Ca2+ is put
Actin leading
relaxed state back into SR
to contraction

Events during Muscle contraction

 Events during an action potential

Depolarizing blockers
keep maintaining
depolarized state

An action potential is a temporary “all or nothing” changes in cell

membrane potential. During this period cell is taken from polarized to
depolarized state
 Nicotinic antagonist
• Nicotinic Antagonist competitively bind to
nicotinic receptors and block nicotinic response
which results in blockade of skeletal muscle
contraction ie paralysis
• There are two types
– Neuromuscular Blockers (not the same as skeletal
muscle relaxant that work by CNS depression)
– Ganglionic Blockers

(We will only discuss the first)

 Neuromuscular Blockers
• The first Neuromuscular Blockers was
extracted from the plant cucare which
contained Tubocuraine.
• It was noted that given in normal condition,
they cause muscle paralysis.
• Tribesmen of Amazon used it in their arrows
for hunting.
• The poison will cause respiratory failure in the
prey
Therapeutic application
• As an Adjunct to general Anesthetic ,(general
Anesthetic are drugs that makes you
unconscious for surgery) they lower the dose
of Anesthetic thus lowering side effects and
promoting postanesthetic recovery time and
• Tracheal intubation (putting tube inside food
pipe) or endoscopy (putting tube inside
rectum)
• Correct bone dislocation
• 2 types
– Non-depolarizing (desired property)
– Depolarizing (undesired property)
 SAR
• Two quaternary ammonium salts separated by
10-12 carbon units is the only known general
requirement. This follows from the
observation that nicotinic receptor has two
cationic site
H3C CH3

H3C N CH2 N CH3

10
H3C CH3

Decamethonium bromide
 Succinylcholine Chloride
• It is a depolarizing neuromuscular blocker. This
depolarization effect makes the muscle fiber resistant to
further stimulation by Ach. This nature makes it
therapeutically undesirable in comparison to the Non-
depolarizing blockers
• It is a dimer (two same molecules joining each other) of
acetylcholine molecules
• Like Ach, it’s is rapidly metabolized in blood and thus
has short duration of action of about 6 to 8 mins
• Uses
– Endotracheal insertions
– Endoscopy
• MOA – It antagonizes nicotinic receptors at
neuromuscular junction which causes skeletal muscle
paralysis
 Think of modification to improve
duration of action of Succinylcholine
Chloride
Hint- Rapid metabolism is due to hydrolysis of ester
O

O CH2 CH2 N{CH3}3Cl

O CH2 CH2 N{CH3}3Cl

O
 synthesis
O
CH2 C Cl Condensation
2HOCH2CH2N(CH3)2
CH2 C Cl
Dimethyl animo -2HCl
O ethanol
Succinyl Chloride
O O
CH3Cl
CH2 C OCH2CH2N(CH3)3 Methyl CH2 C OCH2CH2N(CH3)2
CH2 C OCH2CH2N(CH3)3 chloride CH2 C OCH2CH2N(CH3)2
O O
.2Cl
Succinyl Choline Chloride
D-Tubocuraine
• It is a Non-depolarizing neuromuscular blocker. It doesn’t
make the muscle fiber resistant to further stimulation by
Ach.
• This nature makes it therapeutically desirable in
comparison to the depolarizing blockers
• It is metabolically stable, only 1 % is degraded by liver, thus
acts for a longer period of about 80-120 mins
• It’s preparation includes bisulfites (an anti-oxidant) which
causes histamine release thus can cause allergic reactions
• Uses
• MOA – It antagonizes nicotinic receptors at neuromuscular
junction which causes skeletal muscle paralysis
 Point to be noted
• Being metabolically allows drug to be active
for longer periods but it also means that the
only way to get rid of their effect is excretion
through the kidney.
• Thus in patients with kidney failure, such
characteristic can cause trouble. An ideal drug
must be readily expelled from body. In such
case does might need to be lowered.
Thank You
 Drugs from Plants and HTS
•Historically, Plants have always been the source of the first drugs in a class. Both
Atropine and Tubocuraine were the first of their kind and notice they were all
alkaloids, along with Physostigmine .
•The only downside to this process is that there are thousands of plants and each
plant typically contain a multitude of compounds, that testing for each and every
one against a receptor/enzyme is a very exhaustive process.
•Thankfully, the industry can test thousands of compounds in few days using High
Throughput Screening(HTS) which are automatic and robotic system. To use it first
we have to design as assay. This is now available in academia too.
Drug Plant Class Chemical
Type
Atropine Solanaceae Antimuscari Alkaloid
nic
Tubocuraine Curare Antinicotinic Alkaloid

Physostigmi calabar Reversible Alkaloid

ne beans AChE
inhibtor
• In these systems drugs/compounds are injected into
plates that contain many hole which actually is a
individual assay that contains receptor/enzyme on
which we desire to find if the drug has any activity or
not
• In each hole different drug concentration is injected
• Successful drugs generally gives some kind of visible
color change (colorimetric assay) or change in
fluroscence reading (florimetric assay) in every hole in
the plate. All the data for every hole can be seen easily
in a computer screen
• The intensity of color change and fluroscence reading
allows to both qualify and quantify drug action at that
concentration
• If a compound is having good activity, medicinal
chemists alter it to improve potency/selectivity
 HTS machine looks like this

For more info:

Watch this video https://www.youtube.com/watch?v=EQC5MViYCtI
Read : http://ajpcell.physiology.org/content/286/3/C465