The document provides an overview of the cholinergic nervous system, focusing on the neurotransmitter acetylcholine (ACh) and its effects on the parasympathetic nervous system. It details the biosynthesis and release of ACh, its interactions with various types of receptors (nicotinic and muscarinic), and chemical characteristics essential for receptor activity. Additionally, it discusses modifications to ACh that can alter its pharmacological effects and the stability of cholinergic agents.

1. PARASYMPATHETIC NERVOUS SYSTEM
OR
CHOLINERGIC NERVOUS SYSTEM

2. AUTONOMIC NERVOUS SYSTEM
• Part of nervous system that controls and
regulate the internal organs.
Two types
• Sympathetic Nervous System: Release
Adrenaline
• Parasympathetic Nervous System: Release
Acetylcholine

3. Cholinergic Neurotransmitter
Acetylcholine
• Pre & post ganglionic fibres of
parasympathetic nerves liberate Ach.
• Important Responses of Ach
1. Contraction of Smooth muscles
2. Cardiac Inhibition
3. Peripheral Vasodilation

4. Biosynthesis of ACh
• Ach is major neurotransmitter of post
ganglionic synapses of cholinergic or
parasympathetic nerve ending.
C
H3
C
O
O
CH2 CH2 N
+
CH3
CH3
CH3

5. • Ach is biosynthesized in nerve terminal.
• Ach is synthesized by Choline and Acetyl
coenzyme with the help of Acetycholine
transferase.
• Active transport system involves picking up of
choline molecule from extrasynaptic fluid.
• This transport is dependent upon intracellular
conc. of Na+ & K+ ions.

6. • Choline is acetylated in the cytoplasm by
acetyl coenzyme A which is biosynthesized in
mitochondria present in the nerve terminal.
• Ach is stored in synaptic vesicles
• When impulse reaches to nerve terminal
depolarization causes activation of Ca
ionophore , allows influx of Ca ions, rupturing
of storage vesicles to release of Ach.

9. Ach gets quickly hydrolysed by
Acetylcholinesterase (AChE), upon hydrolysis
Ach is converted into acetic acid and Choline.
C
H3
C
O
O
CH2 CH2 N
+
CH3
CH3
CH3
Choline + Acetyl Co
-
A
Chloineacetylase Acetylcholine Release of ACh
Acetylcholinesterase
Choline + ACetic acid
O
H CH2 CH2 N
+
CH3
CH3
CH3
Choline
CH3COOH
Acetylcholine
Acetic acid

10. Cholinergic Receptor
• Acetylcholine acts on more than one type of receptor.
• Henry Dale, a British physiologist working in London in 1914,
found that two foreign substances, nicotine and muscarine,
could each mimic some, but not all, of the parasympathetic
effects of acetylcholine.
• It was found that Nicotine stimulates receptors on skeletal
muscle however, muscarine stimulates receptor sites located
only at the junction between postganglionic parasympathetic
neurons and the target organ.

11. • Dale therefore classified the many actions of acetylcholine
into nicotinic effects and muscarinic effects.
• nicotinic receptors cause sympathetic postganglionic neurons
and parasympathetic postganglionic neurons to release their
chemicals and skeletal muscle to contract.
• Muscarinic receptors are associated mainly with
parasympathetic functions and stimulates receptors located in
peripheral tissues (e.g., glands, smooth muscle).
• Acetylcholine activates all of these sites.

13. Muscarinic Receptors

14. Nicotinic Receptors
• N1 - These are found at the skeletal muscle endplate and are
responsible for mediating skeletal muscle contractions. They
are activated specifically by phenyltrimethyl ammonium and
inhibited by tubocurarine.
• N2 - Found in ganglionic cells, adrenal medullary cells, the
spinal cord, and specific parts of the brain. They are
predominantly activated and inhibited by
dimethylphenylpiperazine and hexamethonium.

15. Muscarinic Actions Nicotinic Actions
Cardiac Inhibition
Peripheral Vasodilation
Constriction of eye pupil
Increased salivation
Contraction of peristaltic action
on GIT and urinary tract
Stimulation and maintainance
of tone of skeletal muscles

16. Chemical Features of ACh
C
H3
C
O
O
CH2 CH2 N
+
CH3
CH3
CH3
Acetyl Group Ethylene bridge Quaternary Ammonium group

17. Chemical Features of ACh
• Chemically Ach is an ester of acetic acid and choline
• On the structural basis, it offers 3 sites for molecular
modification,
1. Acetyl group
2. Ethylene bridge
3. Quaternary ammonium group
• Quaternary ammonium group is linked by ethylene
bridge to an ester group.
• Free ACh is rapidly hydrolysed to acetic acid and
choline molecule by cholinesterase enzyme.

18. SAR
• Any change in the ethylene bridge may affect the chemical
stability of ACh.
• Cationic ammonium group is essential for manifestation of
both muscarinic and nicotinic receptor activities.
• Quaternary nitrogen may be replaced by arsenic, antimony,
phosphorous or sulphur without loss of ACh like activity.
• For maximal muscarinic activity there should not be more
than 4 atoms between N and terminal C atom.
C
H3
C
O
O
CH2 CH2 N
+
CH3
CH3
CH3
Acetylcholine

19. • If bulky substituents are placed on terminal
carbon atom of acetyl group, these
substituents block the access of ACh to the
receptor. This results in antimuscarinic activity.
Eg. Benzilylcholine, Tropylcholine.
CH C
H5C6
H5C6
O
O CH2 CH2 N
+
CH3
CH3
CH3
CH C
H5C6
HOH2C
O
O CH2 CH2 N
+
CH3
CH3
CH3
Benzilylcholine Tropylcholine

20. Cholinergic Receptor
 From SAR studies structure of cholinergic receptor is predicted as
 Quaternary ammonium group forms electrostatic bond with
anionoic site.
 Ester forms H- bond at the esteratic site.
 Methyl group present on N atom along with terminal –CH3 are
bound to the receptor by both hydrophobic and van der waal forces
C
H3 C
O
O
+
CH2 CH2 N CH3
CH3
CH3
OH
-
Esteratic site Anionic site
+

21. • The binding assures a close fit of the molecule to
the receptor as shown below.
1.Region of Hydrophobic binding (Van der waals
forces)
2.Region of H- bonding
3.Region of ionic bonding
C
H3 C O CH2 CH2 N
+
CH3
CH3
CH3
O
O
N
H
H
1
1
2
1
3
CO2
-

22. SAR of Parasympathomimetic agents
1. Modification at Quaternary ammonium group
 The trimethylammonium group is the optimal
functional requirement for the activity. There are
following exceptions.
O
O
H5C2
CH2
N
N
CH3
Pilocarpine
N
H
COOCH 3
Arecoline
N
N
CH3
Nicotine

23. 2. Modification of Ethylene bridge
• There should not be more than 4 atoms between nitrogen and
terminal carbon atom.
• Replacement of H atom of ethylene bridge by alkyl group produces
far less active compound.
• Presence of methyl group beta to the quaternary nitrogen atom
increases muscarinic activity.
• Added methyl group hinders the attack of esterase enzyme thus
slows down enzymatic hydrolysis.
• Methyl group alpha to the N increases nicotinic activity.
C
H3
C
O
O
CH CH2 N
+
CH3
CH3
CH3
CH3
Methacoline

24. 3. Modification of the Acyl group
• When the acyl group is substituted by its higher homologues
(propionyl, butyryl etc.), less active compounds are formed.
• Choline esters of aromatic or higher molecular weight acids
are cholinergic antagonist rather than agonists.
• When terminal methyl group is replaced by –NH2 group, is
potent cholinergic agent with both muscarinic and nicotinic
activities.
N
H2
C
O
O
CH CH2 N
+
CH3
CH3
CH3
CH3
Cl
-
Bethanechol chloride
Cl
-
N
H2
C
O
O
CH2 CH2 N
+
CH3
CH3
CH3
Carbachol chloride

25. • Carbachol is stable to hydrolysis and has right size to fit the
cholinergic receptor.
• In carbachol terminal –CH3 of ACh is replaced by –NH2 group,
while the size of the moecule remains same as that of Ach. So,
the size of the molecule may be imp. to its activity.
• Similarly ether oxygen appears to be of primary importance
for high muscarinic activity. As a result of these ethers of
choline is examined for high muscarinic activity.
Cl
-
O CH2 CH2 N
+
CH3
CH3
CH3
CH2
C
H3
Choline ethyl ether

26. • The reduced biological activity of compounds in which oxygen
is replaced by sulphur. Eg. Thiomuscarine. Because S atom has
less ability to form H- bond with the receptor.
N
+
CH3
CH3
C
H3
S
C
H3
O
H
Thiomuscarine
X
-