Cholinergic neurotransmitters: Biosynthesis and catabolism of acetylcholine. Cholinergic receptors (Muscarinic & Nicotinic) and their distribution. Parasympathomimetic agents: SAR of Parasympathomimetic agents Direct acting agents: Acetylcholine, Carbachol*, Bethanechol, Methacholine, Pilocarpine. Indirect acting/ Cholinesterase inhibitors (Reversible & Irreversible): Physostigmine, Neostigmine*, Pyridostigmine, Edrophonium chloride, Tacrine hydrochloride, Ambenonium chloride, Isofluorphate, Echothiophate iodide, Parathione, Malathion. Cholinesterase reactivator: Pralidoxime chloride. Cholinergic Blocking agents: SAR of cholinolytic agents Solanaceous alkaloids and analogues: Atropine sulphate, Hyoscyamine sulphate, Scopolamine hydrobromide, Homatropine hydrobromide, Ipratropium bromide*. Synthetic cholinergic blocking agents: Tropicamide, Cyclopentolate hydrochloride, Clidinium bromide, Dicyclomine hydrochloride*, Glycopyrrolate, Methantheline bromide, Propantheline bromide, Benztropine mesylate, Orphenadrine citrate, Biperidine hydrochloride, Procyclidine hydrochloride*, Tridihexethyl chloride, Isopropamide iodide, Ethopropazine hydrochloride.

1. Para Sympathomimetic
Mr. Mote Ganesh D
Asst. prof, Annasaheb Dange College of B.Pharmacy,
Ashta

3. Biosynthesis , Storage, Release and Catabolism of Acetyl
Choline

4. Choline is transported inside the nerve by depolarization of nerve cell
choline acetyltransferase transfer the acetyl CoSA group from
mitochondria to Choline and choline esterifies into Acetyl choline
The majority of the Ach stored in nerve endings 100 um vesicles
The release of ACh occurs through Ca2+ stimulated docking, fusion, and
fission of the vesicle with the nerve terminal membrane
ACh binds only briefly to the pre- or postsynaptic receptors to show
biological response
After biological respose it dissociated from the receptor and ACh is rapidly
hydrolyzed by the enzyme acetylcholinesterase (AChE) into choline and
acetyl CoA
Biosynthesis, Storage, Release ,Action and Metabolism of Acetyl Choline

5. Biosynthesis of Acetyl Choline
CH3 C
O
SCoA
Acetyl CoA
+ OH CH2 CH2 N
CH3
CH3
CH3
Choline Acetyl Transferase
CH3 C
O
Acetyl Choline
O CH2 CH2 N
CH3
CH3
CH3
Choline
OH CH2 CH2 NH2
Choline
OH CH2 C
H
NH2
Serine
COOH
Serine Decarboxylase
Choline N-Methyl Transferase

6. Catabolism of Acetyl Choline
CH3 C
O
Acetyl Choline
O CH2 CH2 N
CH3
CH3
CH3
CH3 C
O
SCoA
Acetyl CoA
+ OH CH2 CH2 N
CH3
CH3
CH3
Choline
Acetyl Choline esterase
H-OH

16. Choline Esters
N
CH3
O
O
H3C
2-acetoxy-N,N,N-trimethylpropan-1-aminium
Methacholine
N
O
O
H3C
Acetyl choline
N
CH3
O
O
H2N
carbachol
2-(carbamoyloxy)-N,N,N-trimethylpropan-1-aminium
Bethanechol
N
O
O
H2N
2-acetoxy-N,N,N-trimethylethanaminium
2-(carbamoyloxy)-N,N,N-trimethylethanaminium

17. Cholinomimetic alkaloids
O
HO
H3C
N
Muscarine
(4-hydroxy-5-methyl-tetrahydrofuran-2-yl)-N,N,N-
trimethylmethanaminium
O
O
Pilocarpine
N
N
H3C
3-ethyl-4-((1-methyl-1H-imidazol-5-yl)methyl)-dihydrofuran-2(3H)-one
N
O
O CH3
Arecholine
methyl 1-methyl-1,2,5,6-tetrahydropyridine-3-carboxylate

19. N
N
O
HN
O
CH3
N
O
O
N
CH3
CH3
Br-
Physostigmine
neostigmine bromide
3-(dimethylcarbamoyloxy)-N,N,N-
trimethylbenzenaminium bromide
N
O
O
N
CH3
CH3
CH3
Pyridostigmine O
O
N
CH3
CH3
H3C
N
CH3
CH3
Rivastigmine
3-(1-(dimethylamino)ethyl)phenyl dimethylcarbamate
3,4,8b-trimethyl-2,3a-dihydro-1H-pyrrolo[2,3-b]indol-7-yl] N-
methylcarbamate;2-hydroxybenzoic acid
3-[(dimethylcarbamoyl)oxy]-1-methylpyridinium
Reversible Cholinesterase Inhibitors

20. N
N
H
2
5
,
6
,
7
,
8
-
t
e
t
r
a
h
y
d
r
o
a
c
r
i
d
i
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-
9
-
a
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T
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R
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s
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s
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a
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n
h
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T
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e
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D
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a
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Reversible Cholinesterase Inhibitors

21. OH
N
N-ethyl-3-hydroxy-N,N-dimethylbenzenaminium
Endrophonium
O
N
O
N
CH3
(CH2)10
N
O
O
N
Demecarium
Trimethyl-[3-[methyl-[10-
[methyl-(3-
trimethylammoniophenoxy)
carbonyl-
amino]decyl]carbamoyl]ox
yphenyl]ammonium
N
H3C
CH3
H
N
O
O
N
H
N
CH3
H3C
Cl
Cl
N-(2-chlorobenzyl)-2-(2-(2-((2-chlorobenzyl)diethylammonio)ethylamino)-2-oxoacetamido)-N,N-
diethylethanaminium
ambenonium
Reversible Cholinesterase Inhibitors-Quaternary ammonium salt

23. H3C
H3C
O P
O
O
F
Isofluorphate
diisopropyl phosphorofluoridate
3HC
O P
S
O
S
O
O
O
O
diethyl 2-(dimethoxyphosphorothioylthio)succinate
malathion
H3C
O P
O
O
S
H3C
O P
S
O
O
Parathion
N
I-
2-(ethoxy(isopropoxy)phosphorylthio)-N,N,N-
trimethylethanaminium iodide
Echothiophate iodide
NO2
O,O-diethyl O-4-nitrophenyl phosphorothioate
Reversible Cholinesterase Inhibitors-Organophosphates

24. Classification

25. MOA of Cholinergic Drugs

26. MOA of cholinergic Drugs:
Acetyl Choline, Methacholine, Carbachol, Bethanechol,, arecholine,
Muscarine, Pilocarpine:
At M1, M3, and M5 Receptor: Acetylcholine binds with Gq coupled receptor and activates
Phospholipase C, converts IP2 to IP3, activates, increases entry of calcium inside the cell,
depolarizes the cell, hence it shows excitatory response such as:
Salivary gland(M1): Increases the secretion
Bronchial Muscle(M3): Contracts the bronchial muscle,
CNS(M5): Increases the secretion of dopamine
At M2 & M4 Receptor: When ACH and Its analogs bind with M2 or M4 receptor
coupled with G protein, It inhibits the adenylate cyclase enzyme, Hence decreasing
the conversion of ATP into cAMP and deactivating the protein kinase and
phosphorylase enzyme, hence it shows inhibitory response such as
Heart(M2): relaxation of the heart,
Auto receptor(M4) : Inhibit the release of the acetylcholine release

27. MOA of cholinergic Drugs:
Acetyl Choline, Methacholine, Carbachol, Bethanechol,, arecholine, Muscarine,
Pilocarpine, Phenyl trimethyl ammonium,
At Nm(N1) Receptor: Acetylcholine or Phenyl trimethyl ammonium binds with Ion
gated receptor and activates Nicotinic ion channel receptors, increase the entry of
calcium inside the cell, and decrease the out flux of potassium leading to
depolarization of the cell, cell is contracted and shows excitatory response.
Skeletal Muscle (Nm): Contracts the skeletal muscle
At NN(N2): When ACH or tetramethyl ammonium and Its analogs bind with the N2
receptor coupled with an ion-gated channel, increase the entry of calcium inside the
cell and decrease the out flux of potassium leading to depolarization of the cell, cell
contacted and shows excitatory response.
Autonomic ganglion (NN): Depolarization and contraction of pre-ganglion for release
of adrenaline.

28. MOA of reversible acetyl Cholinesterase Inhibitors:
Neostigmine, Pyridostigmine, Physostigmine, rivastigmine, Endrophonium,
demecarium, and Ambenonium
bind reversibly with acetylcholine esterase
It phosphorylate the enzyme of cholinesterase
Then deactivate the enzymes
hence acetylcholine esterase enzyme does not take part in the hydrolysis of
acetylcholine.
The ester group of drugs takes part in the binding with acetylcholine esterase
enzyme
and blocks the action of acetylcholine esterase.
Hence hydrolysis of acetylcholine is reduced,
Acetylcholine will be available for a longer period for cholinergic action by avoiding
its hydrolytic metabolism.

29. MOA of irreversible acetyl Cholinesterase Inhibitors:
Parathion, Malathion, Echothiopate, Isofluorphate
it bind irreversibly with acetylcholine esterase
It phosphorylate the enzyme
It deactivates the enzymes hence acetylcholine esterase enzyme does not take
part in the hydrolysis of acetylcholine.
The Phosphate group of drugs takes part in the binding with the acetylcholine
esterase enzyme,
it phosphorylates the acetylcholine esterase enzyme and blocks the action of
acetylcholine esterase.
Hence hydrolysis of acetylcholine is inhibited, Acetylcholine will be available
for a longer period for cholinergic action by avoiding its hydrolytic metabolism.

58. Synthesis of Carbachol
C
H2
C
H2
+ Cl C
HO
Cl
O
Cl C
H2
C
H2
O
Cl
C
O
Cl
NH3
C
H2
C
H2
O
Cl
C
O
H2N
N
CH3
CH3
CH3
C
H2
C
H2
O
N
C
O
H2N
H3C
H3C
CH3
Carbachol
2-chloroethanol
phosgene
2-chloroethyl carbonochloridate
2-chloroethyl carbamate

59. Synthesis of Neostigmine
N
CH3
CH3
OH
+ Cl C
O
N
CH3
CH3
N
CH3
CH3
O
C
O
N
CH3
CH3
CH3Br
N
CH3
CH3
O
C
O
N
CH3
CH3
H3C
Neostigmine(Acetyl Choline esterase inhibitor)
3-(dimethylamino)phenol
dimethylcarbamic chloride
3-(dimethylamino)phenyl dimethylcarbamate