Cholinergic Antagonists

1
 Cholinergic Antagonists
• What are cholinergic antagonists
– Drugs binds to Ach receptors but do not
activate it
– Prevent Ach from binding
– Antagonists have the opposite clinical effects
from agonists

Ach
Ach Ach

Presynaptic nerver
2
Antagonist
Postsynaptic nerve
Site of action of anticholinergics

3
 I- Muscarinic antagonists
• Pharmacological effects
– Reduction of saliva and gastric secretion
– Reduction of GIT and UT motility
– Dilatation of eye pupils
– CNS effects
• Clinical uses
– Shut down GIT and UT during surgery
– Ophthalmic examination
– Relief peptic ulcer
– Parkinson’s disease
– Anticholinesterase poisoning
– Motion sickness 4
 Cholinergic antagonists
I. Muscarinic antagonists
1. Atropin
2. Scopolamine
3. Ipratropium
II. Nicotinic antagonists
Scopolamine
A. Depolarizing
1. Decamethonium
2. Succinylcholin
B. Non-depolarizing (stabilizing)
1. Tubocurarine
2. Pancurionium
3. Atracurium 5
I. Muscarinic antagonists

1- Atropine
3° amine Me
N

H easily racemised
CH2 OH

O CH
C *

• Racemic form of hyoscyamine

• Source - roots of belladonna (deadly nightshade)
• Used as a poison
• Used as a medicine to
• decrease GIT motility
• antidote for anticholinesterase poisoning
• dilation of eye pupils 6
• CNS side effects – hallucinations An Introduction to Medicinal Chemistry, Patrick, Third Edition
I. Muscarinic antagonists

2- Hyoscine (Scopolamine)
3° amine Me
it is classified as
N “ aminoalcohl ester”

H
O CH2 OH

H O CH
C *
H
O

• Source - thorn apple

• Medical use - treatment of motion sickness
• Used as a truth drug (CNS effects) > Atropine 7
An Introduction to Medicinal Chemistry, Patrick, Third Edition
 Scopolamine
Methylatropine Probanthine

I. Muscarinic antagonists

Homatropine
Ipratropium Atropine 8
I. Muscarinic antagonists

N Me2N Me
N
O
H
CH2CH3 CH
N O O
CH
OH
CH
O
CH2OH

Tropicamide Cyclopentolate Benztropine

(opthalmics) (opthalmics) (Parkinsons disease)
O
HN C

N
N N

C O

CH CH 2

Me

Benzhexol Pirenzepine
(Parkinsons disease) (anti-ulcer) 9
 Muscarinic Antagonists – Atropine
 The prototypical anticholinergic is atropine, an alkaloid isolated from Atropa
belladonna (also called “deadly nightshade”)
 Blocks the effects of electrical stimulation & muscarine on the parasympathetic
nervous system
CH3 N
O
H
CH2OH NCH3 O
it is classified as
O
OH “ aminoalcohl ester”
O O
Atropine (H3C)3N
O CH3
acetylcholine chloride

The major structural difference between atropine and ACh (both compounds
are esters of amino alcohols is the size of acyl portion
 This prompted several studies into the use of large groups

O
R2N R2N
OH O acyl 10
amino alcohol amino alcohol ester
 Muscarinic Antagonists – Atropine
Comparison of atropine with acetylcholine
3° amine Me
N
NMe3

CH2 CH2 H
quaternary
CH2 OH
nitrogen
O
O
O CH 3
(H3C)3N C
C
O CH3 Aromatic ring
O
O
acetylcholine

• Relative positions of ester and nitrogen similar in both molecules

• Nitrogen in atropine is in the balanced of ionised and unionised??
• Amine and ester are important binding groups (ionic + H-bonds)
• Atropine binds with a different induced fit - no activation
• Atropine binds more strongly than acetylcholine
• Aromatic ring of atropine is an extra binding group (vdW) 11
An Introduction to Medicinal Chemistry, Patrick, Third Edition
 Muscarinic Antagonists
(Simplified Analogues of atropine)
Et
Me Me
N
CH
Et CH2 CH2 Me
CH2 CH2 OH O CH2CH2 N CH
HO C CH2 CH2N(Et)3 Br O C Me
O CH Me
C O
Cl
O

Amprotropine Propantheline chloride

Tridihexethyl bromide

Pharmacophore = ester + basic amine + aromatic ring

quaternary
nitrogen
 Note that all the muscarinic
O antagonists have at least one
(H3C)3N aromatic ring, which it is NOT in the
O CH3
agonist?
acetylcholine 12
An Introduction to Medicinal Chemistry, Patrick, Third Edition
 SARs for Muscarinic Antagonists
 The generalised structure of muscarinic
antagonists is shown below

R1

R2 X (CH2)n N R4

R3
 Based on the structure of atropine, the following conclusions
were made in relation to anticholinergic activity
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 Muscarinic Antagonists – SARs (R1 & R2)
R1
R2 X (CH2)n N
R3
• R1 & R2 should be ring systems for maximum potency (may be the same)
• Usually one is aromatic & the other saturated
• They may be fused
• They cannot be too big (e.g.naphthalene), as this results in loss of activity
pyrrole
ring
O CH3
CH3 N N H3C CH3
O CH3 O
H OH N CH3
O
glycopyrrolate H3C
O
Benzotropine CH CH3
(parkinsons disease) O propantheline
O
H2
HN N C C N N CH3

N
14
Pirenzepine
(Anti-ulcer)
 Muscarinic Antagonists – SARs (R3)
R1
R2 X (CH2)n N
R3

• R3 may be:
• Hydrogen
• Hydroxyl
• Part of the R1/R2 system
• Carboxamide
• Hydroxymethyl
• Compounds with R3 as a hydroxyl or hydroxy methyl are the most potent
pyrrole
ring
H3C O
O O
N
(S)
CH3 O
H N H2
H3C CH3
O CH3 HN N C C N N CH3
OH
N Pirenzepine 15
Orphenadrine glycopyrrolate (Anti-ulcer, M1-selective)
 Muscarinic Antagonists – SAR (X)
R1
R2 X (CH2)n N
R3

• X may be:
 In the most potent compounds, X is an ester (but it does not have to be)
• Ester
• Ether
• may be absent
• Compounds with X as an ester are the most potent
pyrrole
ring OH
O H3C O N
CH3 N
N (S)
H
O CH3 CH3
H3C
OH
glycopyrrolate
Orphenadrine Procyclidine
16
 Muscarinic Antagonists – SAR (N)
R1
R2 X (CH2)n N • N may be:
R3
 N is a quaternary nitrogen in the most potent compounds???
 Some tertiary amines are allowed
 Alkyl substituents on N are usually small (Me, Et, Pr, iPr)
pyrrole
ring
H3C
O CH3 N
O
N
OH
(S)
N H
CH3 H3C CH3
O
OH
glycopyrrolate Orphenadrine Procyclidine
Et H3C CH3
N
O
H3C O Et CH2 CH2
N N CH3
(S)
H CH2 CH2 OH O
CH3 H3C
H3C CH3
O CH
C
17
propantheline
Amprotropine O
Orphenadrine
 Muscarinic Antagonists – SAR [(CH2)n]
R1
R2 X (CH2)n N (CH2)n may be:
R3

 Distance between the ring-substituted Carbon (X) and the amino nitrogen (N)
 Not critical
 2 to 4
 The most potent anticholinergic agents have two methylene units
Et
N
H3C O OH Et CH2 CH2 H3C O
N N N
(S) CH2 (S)
H CH2 OH H
H3C CH3 CH3
O CH H3C
C

Amprotropine
O
Orphenadrine Procyclidine Orphenadrine
H3C CH3 pyrrole
O ring

N CH3 O CH3
O N
H3C CH3
O CH3 O
OH 18
propantheline
glycopyrrolate
 Muscarinic Antagonists – SAR
 Based on the structure of atropine, the following conclusions were made in relation to
anticholinergic activity:

• N is a quaternary nitrogen
• R1 & R2 should be ring R1 in the most potent
systems for maximum compounds
potency (they may be the R2 X (CH2)n N
same) • Some tertiary amines are
R3 allowed
• Usually one is aromatic &
the other saturated • Alkyl substituents on N are
• In the most potent
usually small (Me, Et, Pr,
• They may be fused compounds, X is an ester i
Pr)
(but it does not have to
• They cannot be too big (e.g. be)
naphthalene), as this results
in loss of activity • R3 may be hydrogen, a • (CH2)n
hydroxyl, carboxamide,
or part of the R1/R2 • (n=2 to4)
system • 2 the most active
• Compounds with R3 as a
hydroxyl or hydroxy
methyl are the most
potent
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 SAR for Antagonists vs. Agonists
R1 O

Me O CH2 CH2 NMe3

R2 X (CH2)n N
acyloxy quaternary
R3 group ethylene
group
nitrogen

SAR for Antagonists SAR for Agonists

Tertiary amine (ionised) Quaternary nitrogen
or quaternary nitrogen

Ester, ether, absence Ester

N-Alkyl groups (R) can be N-Alkyl groups = methyl

larger than methyl

R1, R2 = aromatic or heteroaromatic R1, R2, R3 = H

Branching of Ar rings important

n= 2-4 carbons n= 2 carbons

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An Introduction to Medicinal Chemistry, Patrick, Third Edition
 Binding Site for Muscarinic Antagonists
 Since antagonists are larger than agonists, it is suggested that R1/R2 bind outside the
binding site of Ach
 Since in the most potent antagonists R1/R2 are hydrophobic, it is probable that the
region surrounding the ACh binding site is quite hydrophobic

van der Waals’

binding regions
for antagonists

Acetylcholine
binding site

RECEPTOR SURFACE 21
An Introduction to Medicinal Chemistry, Patrick, Third Edition
 Binding Site for Muscarinic Antagonists

Me Me
CH
Me
O O CH2CH2 N CH
C
Me
Me
O C O
Cl

O
H 2N Asn
Propantheline CH2
CH2

NMeR2
CO2

22
An Introduction to Medicinal Chemistry, Patrick, Third Edition
 Muscarinic Antagonists
(Simplified Analogues of atropine)
An Introduction to Medicinal Chemistry, Patrick, Third Edition Me
N
N Me2N
H
O
CH2CH3 CH
O
CH
N O
OH
CH

O
CH2OH

Tropicamide Cyclopentolate Benztropine

(opthalmics) (opthalmics) (Parkinsons disease)
O
HN C

N N
N
C O

CH2
CH
Benzhexol N Pirenzepine
(Parkinsons disease) (anti-ulcer)
N 23
Me
 Most Recent-Future of Muscarinic Antagonists
• Need to get selectivity to cretin muscarinic receptors which then will
lead to selective pharmacological response???
O O S

CH3
HN HN
N N
N N

N O N O N
CH3 CH3
Pirenzepine Telenzepine
(Anti-ulcer) (Anti-ulcer)
(shows selective M1 (shows selective M1
antagonist activity) antagonist activity)

Structural changes in these regions tends to promote M2 selctivity

O S
N
CH3
HN
N
N
N O

AFDX-116 24
(shows selective cardiac M2 antagonist activity)
Nicotinic Antagonists

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 Nicotinic Antagonists
 All therapeutically useful nicotinic antagonists are competitive
antagonists (compete with Acetylcholine)
Their effects are reversible with acetylcholine

There are two subclasses of nicotinic antagonists

• Ganglionic blocking agents (N2 blockade, No therapeutic use?)

• Skeletal Neuromuscular Blocking Agents (NM) (N1 blockade)

 Compounds in this group are considered as either “depolarising” or

“non-depolarising”, which refers to whether the compound depolarises
the post-junctional membrane prior to causing a blockade
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 Neuromuscular Blocking Agents

 Skeletal neuromuscular blockers (NM) ( N1 blockade)

– Depolarising
– Bis-trimethylammonium polymethylenes - decamethonium
– Linear bis-choline derivatives eg succinylcholine

– Nondepolarising
• Cyclic, bis-isoquinoline alkaloids eg tubocurarine,
• Aminosteroids eg pancuronium
• Acyclic, bis-isoquinoline alkaloids eg atracurium
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 Depolarising Neuromuscular Blocking Agents
Depolarising
 These compounds have two quaternary nitrogens which are separated by
a distance equal to about 10 to 12 atoms

O Cl O O
N(CH3)3
N(CH3)3
Br Br H H
O
(H3C)3N (CH2)10 N(CH3)3 O Cl
H
decamethonium bromide N(CH3)3 H
O N(CH3)3
O O
Succinylcholine chloride (chloride
succinylcholine suxamethonium)

• The ester groups in this molecule are

 Activity diminishes as
you change the number of
carbons between the two
nitrogens
readily hydrolysed (making it inactive)
• However, this same “feature” means it
has a brief duration of action, so it is
often used clinically to induce rapid
but short-lived muscle relaxation (e.g.
for endotracheal & endoscopic
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procedures)
Non-Depolarising Neuromuscular Blocking Agents
None-depolarising

 Curare
• Extract from ourari plant
• Used for poison arrows
• Causes paralysis (blocks acetylcholine signals to muscles)
• Active principle = tubocurarine
MeO

Me
N
HO Me
H CH2
O

CH2
H
Me

H N
O
Tubocurarine
OH

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OMe
Non-Depolarising Neuromuscular Blocking Agents

 Analogues of tubocurarine R O

O Me
Me
Pancuronium (R=Me)
Vecuronium (R=H) Me H N
N
Me
H H

O
H

O Me

• Steroid acts as a spacer for the quaternary centres

• Acyl groups are added to introduce the Ach skeleton
• Faster onset than tubocurarine but slower than suxamethonium
• Longer duration of action than suxamethonium (45 min)
• No effect on blood pressure and fewer side effects
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Non-Depolarising Neuromuscular Blocking Agents
 Analogues of tubocurarine
MeO OMe
O O
Me H
N C C N
MeO CH 2 CH 2 O (CH 2)5 O CH 2 CH 2 OMe

Atracurium OMe MeO

OMe Atracurium besylate OMe

• Design based on tubocurarine and suxamethonium

• Lacks cardiac side effects
• Rapidly broken down in blood both chemically and metabolically
• Lifetime is 30 minutes
• Administered as an i.v. drip
• Unstable: limits lifetime
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Non-Depolarising Neuromuscular Blocking Agents
 There are several general structural classes, but in reality they all
present two positive charges into a specific relative spatial arrangement
MeO
None-depolarising O
N(CH3)2
MeO
CH3
Me O
O
CH3 Me H N
N
OMe H3C
H H
O
CH3 R3O
N H
CH3
OMe amino steroid-based compounds

metocurine

MeO OMe
Me Me
N O O N
MeO OMe

O O

MeO Atracurium besylate OMe

32
OMe OMe
tetrahydroisoquinoline-based compounds
Ganglionic Blocking Agents (N2 Blockers)

+
+ N
N
N O
+
hexamethonium S N

trimethaphan

33
 SAR for Nicotinic Antagonism
1 Bis quaternary ammonium ions
– nicotinic receptors have 2 anionic binding sites
=> 2 ammonium ions
2 The two ammonium ions separated by
– 5 or 6 carbons (favours N2)
• strong ganglionic block with weak curariform
action
– 10-12 carbons (favours N1) weak ganglionic block
• strong curariform action
• similar to distance between N atoms in
tubocurarine
34
ANY QUESTIONS

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