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Autonomic Nervous System Cholinergic Drugs and Adrenergic Agents 25
Table 2.1: Action of ANS on various effectors
Effector Sympathetic Parasympathetic
1. Eyes
Pupil Dilation Constriction
Ciliary Muscles Constriction Constriction
2. Glands
Sweat Secretion —
Salivary Secretion Secretion
Bronchioles Relaxation Constraction
3. Heart
Sinus nodal rhythm Acceleration Slowing
Atrial contraction force Increase Decrease
Ventricular contraction force Increase Decrease
4. Blood Vessels Muscle Dilation —
Salivary gland Constriction Dilation
5. Gastrointestinal muscles tract Relaxation Constriction
6. Urinary Bladder Relaxation Contraction
7. Liver Glycogenolysis —
2.2.2 Cholinergic Receptors
On the basis of bound by naturally occurring alkaloids nicotine and muscarine.
(a) Nicotinic Receptors (N): (Ligand gated ion channels)
(b) Muscarinic Receptors (M): (G-protein coupled receptors)
Nicotinic receptors coupled directly to ion channels, the major role of nicotinic receptors is to
control hypertension. Whereas muscarinic receptors play an essential role in stimulating secretion
of salivary gland, sweat gland, contraction of gut, relaxation of smooth muscles and heart muscles.
N
H
N
CH
3
N
O
+
CH
3
CH
3
CH
3
HO
HC
3
Nicotine Muscarine
Fig. 2.3
2.2.3 Biosynthesis of Ach
Hypothetical model of synthesis, storage and release of Ach.
26 A Textbook of Medicinal Chemistry
Step 1: Ach released from the granules under the influence of action potential and in the presence of
Ca
++
.
Fig. 2.4
ChAT
LA
Choline
Phosphoryl
— choline
ChAT
AchE
Pyruvate
Glucose
Acetyl
carrier
Ach
Ach
Ach
5
Choline
+
Acetyl-CoA
AchE
6
1
3
Ach
Direct Action
Ca
++
R
2
Synaptic
cleft
Ach
AchE
HA
Choline
+
Acetate
R
b
4
Choline
7
Indirect
action
Step 2: Ach acts on postsynaptic cholinergic receptors.
Step 3: Hydrolysis of Ach by AcetylcoE (AchE) in synaptic cleft.
Step 4: A high affinity uptake system returns choline to cytosole.
Step 5: ChAT synthesizes Ach in cytosol and stores in granules
Step 6: Glucose is converted to Ach by pyruvate intermediate in mitochondria and release by acetyl
carrier.
Step 7: With low affinity uptake system choline is taken up in neurons.
2.2.4 Classification
1. Cholinergic Receptor Agonist: These agents have direct or indirect effects on muscarinic
receptors on the organ system (smooth muscles, heart)
Autonomic Nervous System Cholinergic Drugs and Adrenergic Agents 27
1. Direct acting cholinomimetics
(a) Acetylcholine chloride
HC—N —CH —CH —O—C—CH Cl
+
–
322 3
O
CH
3
CH
3
2-acetoxy – N, N, N - trimethylethyl ammonium chloride
Fig. 2.5
(b) Methacholine chloride
HC—N —CH —CH—O—C—CH Cl
+
–
32 3
O
CH
3
CH
3
CH
3
1-acetoxy-2-(N, N, N-trimethyl) propyl ammonium chloride
Fig. 2.6
(c) Carbachol chloride
HC—N —CH —CH —O—C—NH Cl
+
–
322 2
O
CH
3
CH
3
2-carbamoyloxy-N, N, N-trimethylethyl ammonium chloride
Fig. 2.7
(d) Batanechol
HC—CH—CH — N—CH Cl
–
323
+
OCONH
2
CH
3
CH
3
2-carbamoyloxy-1-(N, N, N-trimethyl) propyl-ammonium chloride
Fig. 2.8
(e) Carbachol
HC— N—CH —CH —O—C—NH Cl
322 2
+–
CH
3
O
CH
3
2-carbamoyloxy-N, N, N-trimethylethylammonium chloride.
Fig. 2.9
28 A Textbook of Medicinal Chemistry
(f) Naturally occurring muscarinic alkaloids
HC—N —
+
3
C
CH
3
CH
3
O
CH
3
OH
Cl
–
H
2
Fig. 2.10
(a) Muscarine
(b) Pilocarpine
O
H
C
2
O
N
N—CH
3
HC
52
3-ethyl-4-(1-methyl-5-imidazolymethyl)-tetrahydrofuran-2-one.
Fig. 2.11
(g) Naturally occurring nicotinic alkaloids
(a) Nicotine
N
N
|
CH
3
1-methyl-2-(3-pyridyl)-pirrolidine
Fig. 2.12
(b) Lobeline
N
|
CH
3
HC —C—HC
56 2
O
CH — CH — C H
265
OH
1-methyl-2-(β-hydroxy-β-phenylethyl)-6-phenacylpiperidine
Fig. 2.13
2. Indirect Acting Cholinomimetics
These drugs or chemical agents inhibit cholinesterase enzyme to build-up acetylcholine in neuro-
effector compounds. They are reversible and irreversible cholinesterase inhibitors.
1. Reversible cholinesterase inhibitors
These inhibitors are directed to eyes, skeletal muscles, neuromuscular junction, GI-tract and urinary
tract, heart.
Autonomic Nervous System Cholinergic Drugs and Adrenergic Agents 29
(A) Carbamates
(a) Physostigmine
N
|
CH
3
N
|
CH
3
CH
3
HC—NH—C—O
3
O
1, 3a, 8-trimethyl-2, 3, 3a, 8a-tetrahydropyrroloindol-5-yl-N-methylcarbamate.
Fig. 2.14
(b) Neostigmine
HC—N
+
3
O — C — N(CH )
32
O
CH
3
HC
3
SO
4
– –
N, N, N-trimethyl-meta-(dimethylcarbomoyloxy)-phenylammonium methyl sulfonate.
Fig. 2.15
(B) Quaternary Amines
(a) Edrophonium
HC —N
+
52
OH
CH
3
HC
3
Cl
–
Ethyl-(3-hydroxyphenyl)-dimethylammonium chloride.
Fig. 2.16
(b) Demecarium
HC—N
+
3
O—C—N—(CH) —N—C—O
210
CH
3
HC
3
+
3
N—CH
CH
3
CH
3
O
CH
3
O
CH
3
N, N’-Decamethylene-bis-[meta-(N-methylcarbamoyloxy)-Phenyl-trimethylammonium] hydroxide.
Fig. 2.17
30 A Textbook of Medicinal Chemistry
2. Irreversible Cholinesterase Inhibitors
These are basically organophosphates and are made up of organophosphorus compounds. They act
by forming a complex with hydroxyl group of serine of cholinesterage enzyme with covalent bonding.
(a) Isofluorophosphate
P
(CH ) HC — O
32
F
(CH ) HCO
32
O
(di-iso-propylester of fluorophosphoric acid)
Fig. 2.18
(b) Echothiophate
P
CH —O
25
S — CH — CH — N(CH )
22 33
O
+
CH —O
25
S-(2-trimethylaminoethyl) O, O-diethyl thiophosphate.
Fig. 2.19
2.2.5. Action of Cholinesterase Inhibitors
It is another means to produce an autonomic response to interfere with the synthesis of acetylcholine
by which action of the neurotransmitter is terminated in the parasympathetic nervous system.
However, action of Ach is terminated by its rapid hydrolysis by acetylcholine esterase enzyme to
acetic acid and choline moiety. Inhibition of AchE therefore increases the conc. of Ach in the
synapse and results in generation of both muscarinic as well as nicotinic responses.
O
C
HC
3
O
H
C
2
CH
2
N—CH
3
CH
3
CH
3
H C — COOH + OH
3
CH
2
CH
2
N—
CH
3
CH
3
CH
3
+
HO
2
AchE
Acetic acid
Choline
Ach
Fig. 2.20
2.2.6 Structural Activity Relationship (SAR) of Musarinic Agonist/Cholinomimetics
There are three components in the lead structure of cholinomimetics shown below to examine the
effects of chemical modification of each group.
(A) Modification of Acyloxy Group
(i) It has been observed that introduction of higher homologus of methyl groups like propionyl
or butyryl groups are less active.
Autonomic Nervous System Cholinergic Drugs and Adrenergic Agents 31
(ii) Esterification of aryl acids shows cholinergic antagonist activity.
(iii) Methyl esters of acyloxy group are rapidly hydrolysed by cholinesterase to choline and
acetic acid. To avoid from hydrolysis, carbamate esters of choline (carbachol) were synthesized
and found to be more stable than esters that can be administered orally.
O
C
HN
2
O
CH
2
CH
2
N — (CH ) Cl
33
+
–
Carbachol
Fig. 2.22
(iv) Replacement of ester group with ether or keton generate chemically stable and potent
compound.
(B) Modification of Ethylene Bridge
(i) It has been observed that increase in the chain length results in decreasing the muscarinic
activity. No more than five atoms are required between nitrogen atom and terminal hydrogen
for maximal muscarinic activity.
(ii) Introduction of a methyl group on carbon beta to quaternary nitrogen atom afford methacholine
(acetyl-b-methylcholine), which is equipotent to Ach. While at a carbon to quaternary nitrogen
atom, reduces the activity at nicotinic receptor as well as muscarinic receptor.
(C) Modifiction of Quaternary Ammonium Group
(i) It is essential for activity.
(ii) If nitrogen is replaced by arylring, phosphorus and sulfur it results in less active compounds.
(iii) Replacement of methyl group by ethyl or large alkyl group produces inactive compounds.
2.2.7 Cholinomimetic Agents
(1) Methacholine (Provocholine
®
): Methacholine is marketed as recemic mixture. It is selective
muscarinic receptor agonist its S-(+)-enantiomers is 240 times more potent than R-(-) isomers at
muscarinic receptor.
Uses: Methacholine is used in the treatment of asthma as bronchodilators.
Fig. 2.21: Lead structure.
H C — C— O — CH — CH — N(CH ) Cl
32233
a
b
+–
AB
C
Acyloxy
group
Ethylene
bridge
Quaternary
ammonium
group
O
32 A Textbook of Medicinal Chemistry
(2) Carbachol (Isoptocarachol)
®
: Carbachol is 2-carbamoyloxy-N, N, N-trimethyl ethylammonium
chloride. It increases hydrolytic stability compared to Ach due to having carbamates which are
more stable than esters.
Synthesis:
N
+
Cl
CH
2
CH
2
OH
+ COCl
2
Cl
CH
2
CH
2
O
NH
2
C
O
Cl(H C)
33
CH
2
CH
2
O
O
C
NH
2
–
Cl
CH
2
CH
2
O
NH
2
C
O
N(CH )
33
Trimethyl amine
HCl
2-chloroethanol
Phosgene
NH OH
4
Carbamoyl choline
Fig. 2.24
Carbamol is used in the treatment of glucoma.
(3) Pilocarpine (Isoptocarpine)
®
: Pilocarpine is a natural product obtained from the leaves of
pilocarpus jaborandi. It is muscarinic agonist. It is marketed as an ophthalmic preparation like
solution, gel, tablet and ocusert delivery system. It is chemically unstable to alkali (hydrolysis) and
due to epimerization in the lactone ring to isopilocarpine.
(4) Physostigmine: Physostigmine is assumed to be a classical AchE inhibitor. It is an alkaloid
obtained from the seed of calabar beans, Phystostigma venenosum.
It acts as an antidote for atropine poisoning and in the treatment of glucoma.
Fig. 2.23
HO — CH — CH — Cl + N(CH )
233
HO — CH — CH — N(CH )
233
CH
3
CH
3
+
H C — C — O — CH — CH — N(CH )
3233
CH
3
O
+
Acetic Anhydride
(CH CO) O
32
Propylene
Chlorhydrine
Trimethyl
amine
Addition
Methacholine
HCO
52
NH
|
CH
3
+Br—C—CH—CH
3
OC H
25
N
|
CH
3
CH
3
O
(i) ClCH CN
(ii) [H]/CH I
2
3
P-ethoxymethylaniline
a-Bromopropionyl
bromide
O
Br
AlCl
3
Synthesis:
Synthesis:
Autonomic Nervous System Cholinergic Drugs and Adrenergic Agents 33
(5) Neostigmine (Prostigmine)
®
: It is also an AchE inhibitor like physostigmine. Neostigmine is
indicated for prophylaxis of post-operative abdominal distension, urinary retention and neuromuscular
disorders.
Synthesis:
Fig. 2.25
HO
N
|
CH
3
CH
3
N
|
CH
3
HCO
52
N
|
CH
3
CH
3
O
CH — CH — NHCH
22 3
[H]
HBr
HCNH — C — O
N
|
CH
3
CH
3
N
|
CH
3
O
(Physostigmine)
CH NCO
3
N(CH )
32
OH
+
N — COCl
N(CH )
32
O — C — N(CH )
32
O
KOH
HC
3
HC
3
CH Br (Alkylation)
3
N(CH ) Br
33
O — C — N(CH )
32
O
Neostigmine
Dimethyl carbamoyl
chloride
3-Dimethyl
aminophenol
+
Fig. 2.26
2.2.8 Anticholinergic/Cholinergic Blocking Agents/Parasympatholytics/Antispasmodics
Agents/Muscarinic Receptors Antagonist
Definition
Muscarinic antagonists are those compounds which have high binding affinity for muscarinic
receptors but have no intrinsic activity at the smooth muscles, secretory cells, and certain central
synapses.
Mechanism of Action
There are two approaches to treat the condition characterized by overstimulation of cholinergic
nerves, one is to inhibit the synthesis or release of Ach and second to block the Ach from with the
receptors competitively. These agents cause decreased gastric secretion, dry mouth and mucous
membrane, mydriasis, loss of accommodation, urinary-retention, bronchial and biliary dilation.
34 A Textbook of Medicinal Chemistry
2.2.9 Classification of Anticholinergic Agents
(1) Tertiary Amine Series
(A) Atropine (Atopinol)
®
: D, L-8-Methyl (-8-Azabicyclo-[3, 2.1]-oct-3-yl ester of hyroxy methyl
phenylacetic acid.
N—CH
3
O — C — CH — C H
65
O
CH — OH
2
Fig. 2.27
(B) Cyclopentolate: 2-(dimethylamino) ethylic ester of 1-hydroxy cyclopentane-α-phenylacetic
acid.
CH — COO — CH — CH — N
22
OH
CH
3
CH
3
Fig. 2.28
(C) Tropicamide: N-(4-Piridinylmethyl)-N-ethyl-β hydroxy-α-phenylpropionamide.
O
CH—C—N
|
CH
|
OH
2
CH
2
CH
25
N
Fig. 2.29
(D) Dicyclomine: Diethylaminoethyl ester of 1-cyclohexyl-cyclohexane carboxylic acid.
C — O — CH — CH — N(C H )
22 252
O
Fig. 2.30