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Autonomic Nervous System Cholinergic Drugs and Adrenergic Agents 35
2. Quaternary Amine Series
(A) Methscopolamine: 7-(3-hydroxy-1-oxo-2-phenyl propoxy)-9, 9-dimethyl-3-oxa-9-azoniticyclo
nonane nitrate.
HC—N
3
O — C — CH — C H
65
O
CH OH
2
CH
3
–
NO
3
–
Fig. 2.31
(B) Propnantheline: N-methyl-N-(1-methylethyl)-N-[2-[(9H-Xanthen-9-yl carbonyl) oxy]ethyl]-2-
Propanaminium bromide
O
O
C—O—CH —CH —N—CH
22 3
+
Br
CH(CH )
32
CH(CH )
32
Fig. 2.32
(C) Isopropamide: (3-carbamoyl-3.3-diphenyl propyl)-di-iso propylmethyl ammonium iodide.
C — CONH
2
CH — CH — N — CH
22 3
CH(CH )
32
CH(CH )
32
+
Fig. 2.33
36 A Textbook of Medicinal Chemistry
2.2.10 Structural Activity Relationship (SAR) of Anticholinergic Agent
R — C X — (CH ) — N
22n
—
R
1
R
3
Quaternary
ammonium salt
Ester
(Carbocyclic, Heterocyclic (ring)
(H, OH, carboxamide)
Fig. 2.34: Lead structure of antimuscarinic agents.
(i) Substituents R
1
and R
2
should be carbocyclic or heterocyclic rings for maximal antagonist
activity. However, they may be fused aromatic tricyclic ring system.
(ii) Substitution of naphthalene ring for R
1
and R
2
resultant compounds would inactive due to
steric hindrance.
(iii) R
3
substituents may be H, OH, –OHCH
3
or carboxamide makes the compound more potent.
However, –OH group increases however the potency of binding to receptor.
(iv) X substituents in the most anticholinergic is an ester. It may also be substituted by ethereal
oxygen.
(v) N substituents is a quaternary ammonium salt. Presumably binding to the receptor in cationic
form.
(vi) The alkyl substituents may be methyl, ethyl, propyl or isopropy for anticholinergic activity.
2.2.11 Anticholinergic Agent
(A) Atropine (Atropinol
®
): Atropine is an alkaloid obtained from the solanaceous plant belladonna
(A tropa belladonna) Dubosia, Hyoscyamus. Atropine and its analogue scopolamine are most important
antimuscarinic drugs. These are esters of tropoyl acid-tropine and scopine respectively. Scopine
differs from tropine in that it has an expoxide ring bridge between carbon atoms C
6
and C
7
of
tropine. Atropine is used during anesthesia in surgery, in ophthalmic preparation, for the treatment
of Parkinsonism. Atropine is also used as an antidote with combination of other drugs for poisonous
anticholinesterase agents like organophosphorus insecticides.
Synthesis:
CH
3
N
O
CH — CHO
||
CH — CHO
+ CH NH + HOOC — CH — C — CH — COOH
32 2 2
CH COONa
3
O
Methylamine
Acetone dicarboxylic acid
Tropinone
Maleylaldehyde
Autonomic Nervous System Cholinergic Drugs and Adrenergic Agents 37
(B) Scopolamine: Scopolamine is used for the treatment of Parkinsonism symptoms, stomach
ulcer, spasm of urinary tract and bronchial asthma.
N—CH
3
O — C — CH —
O
CH OH
2
O
Scopolamine
Fig. 2.36
(C) Glycopyrrolate (Robinul
®
): glycopyrrolate prevents the secretion of digestive juices and restores
normal stomach functions. It is used for the treatment of stomach ulcer, inflammed intestine.
(D) Dicyclomine (Bentyl
®
): Dicyclomine is an antispasmodic drug which exhibits direct antispastic
action on smooth muscles and inhibits the action of acetylcholine on smooth muscles. It is used in
the treatment of stomach ulcer, colic in children and for treating irritable bowel syndrome.
Fig. 2.35
N—CH
3
OH
[H]
Reduction
N—CH
3
OH
N—CH
3
HO—C—CH—
O
CH OH
2
O—C—CH—
O
CH OH
2
TropineTropinol
Atropine
Tropic acid
LiAlH
4
38 A Textbook of Medicinal Chemistry
Synthesis:
CH — CH — CH — CH — CH — Br
22222
— 2HBr
CN
C — O — CH — CH — N
22
Br
O
CH
25
CH
25
COOH
Saponification
CH CN
2
+
1, 5-dibromopentane
(i) HO — CH — CH — N
22
CH
25
CH
25
HCl
(i) N, N,-Diethylethanola
mine · HCl
(ii) reduction
Phenylacetonitrile
Dicyclomine hydrochloride
HCl
Fig. 2.37
Synthesis: (Glycopyrrolate)
COH+CH OH
3
COOH
C—OH
COCCH
3
HCl
a-phenylcyclopentane
glycolic acid
(Methyl ester)
1-methyl-3-pyrrolidinol
(ii) CH Br
3
N
CH
3
OH
(i)
N
CH
3
O—C—C—
HC
3
O OH
·Br
+
–
Glycopyrrolate
Fig. 2.38
Autonomic Nervous System Cholinergic Drugs and Adrenergic Agents 39
2.2.12 Newer Drug
1. Donepezil (Aricept)
®
: 2-[(1-benzyl-4-piperidyl) methyl]-5, 6-dimethoxy-2, 3-dihydroinden-1-
one
N
O
O
O
HC
3
HC
3
Fig. 2.39: Donepezil.
Donepezil is non-classic centrally acting, reversible non-competitive AchE inhibitor. It is clinically
useful in the treatment of mild to moderate AD and dementia.
2. Rivastigmine (Exelon)
®
: (S)-N-Ethyl-N-methyl-3-[1-(dimethylamino)ethyl]-phenyl carbamate.
CH
3
O
CH CH
23
CH
3
O
C
N
N
HC
3
HC
3
H
Fig. 2.40: Rivastigmine.
Rivastigmine is centrally acting arylcarbonate AchE inhibitor. It is also suggested for the treatment
of Alzheimer’s disease (AD).
3. Galantamine (Razadyne)
®
: Galantamine was obtained from the plant of family amaryllidaceae.
It is an alkaloid. Galantamine is an reversible AchE inhibitor. It is used in the treatment of mild to
moderate Alzheimer’s disease.
2.3 ADRENERGIC AGENTS
2.3.1 Introduction
Adrenergic agents or drugs are exhibit their pharmacological action by their enhancing or reducing
the activity of the various components of sympathetic division of autonomic nervous systems. The
chemical agents that produce the similar effects to stimulation of sympathetic system are known as
sympathomimetics or adrenergic stimulants. On the other hand, these decrease the effect called
sympatholytics or antiadrenergics or adrenergic blocking agents.
40 A Textbook of Medicinal Chemistry
2.3.2 Mechanism of Action
Norepinephrine is a neurotransmitter of the post-ganglionic sympathetic neurons. It is released
from the sympathetic nerve ending into the synaptic cleft, cause sympathetic nerve stimulation. It
interacts with specific adrenergic receptors (α, β). It is synthesized and stored in Adrenal medulla
from which it is released via circulation. Epinephrine is suggested as a neuro-hormone. In certain
area of CNS, NE and Epinephrine serve as neurotransmitters. Both belong to the chemical class
catecholamines (aromatic ring having two hydroxyl groups situated ortho position to each other).
2.3.3 Biosynthesis of Catecholamines
Biosynthesis of catecholamines takes place in adrenergic and dopaminergic neurons, in sympathetic
neurons in ANS and in adrenal medulla. Enzymes which are responsible for synthesis of
catecholamines, are synthesized in cell bodies at neurons and are transported to the axons to their
nerve terminals. The amino acid L-tyrosin is the main precursor for the catecholamines biosynthesis
which is given below.
Fig. 2.41: Biosynthesis of catecholamines.
CH — CH — COOH
2
NH
2
CH — CH — COOH
2
NH
2
CH — CH — COOH
2
NH
2
HO
HO
HO
CH — CH — NH
222
HO
HO
CH — CH — NH
22
OH
HO
HO
CH — CH — NH — CH
23
OH
HO
HO
1
2
3
5
4
L-norepinephrine
L-phenylalanine
L-tyrosine
L-dopa
L-dopamine
L-epinephrine
1
2
3
4
5
Enzymes involved:
Phenylalanine hydroxylase
Tyrosine hydroxylase
Dopa-decarboxylase
Dopamine- -oxidaseb
Phenlethanolamine methyl transferase
2.3.4 Pharmacological Action
(i) Adrenergic agents exhibit excitatory effects on smooth muscles of blood vessels, salivary
glands and sweat glands.
(ii) Also show inhibitory response to smooth muscles of GI tract, bronchial tract and skeletal
muscles.
Autonomic Nervous System Cholinergic Drugs and Adrenergic Agents 41
(iii) These increase the force of contraction (+ ionotropic effect)
(iv) Increase level of catecholamines in CNS leads to respiratory stimulation and decreased appetite.
(v) Catecholamines promote glycogenolysis in liver as well as in muscles.
2.3.5 Adrenergic
Receptors: There are two main adrenergic receptors:
A. α-Adrenoceptors: α
1
and α
2
in which α
1
is responsible for smooth muscles stimulation,
sweating and salivation. It is located in post-functional of effector organs while α
2
inhibits
the presynaptic release of nor-epinephrine and postsynaptic activation of adenylate cyclase.
I
Tyrosine
Dopa
Dopamine
II
Synaptic
vesicle
NE
–
NE
MAO
NE
III
Ca
++
Presynaptic
cleft
Supporting
tissue
Inhibited by
metanephrine,
corticosteroids
Synaptic
cleft
Direct action
Postsynaptic
cleft
Response
Uptake-1
IV
Indirect
action
Inhibit by
cocaine,
desipramine
H -antagonist
1
Phenylalanine
Tyrosine
a
1
b
1
b
2
b
3
NE
Uptake-2
Glial cell
a
2
COMT
Fig. 2.42: Schematic projection of adremergic neurotransmission.
Step I – Synthesis of catecholamines
Step II – Storage of CAs
Step III – Release of CAs by Exocytosis
Step IV – Reuptake of CAs
COMT – Catechol-O-Methyl
transferase
MAO – Monoamine oxidase
Uptake-1 – Axonal uptake (higher
rate) and granular uptake
Uptake-2 – Extraneuronal uptake
42 A Textbook of Medicinal Chemistry
B. β-Adrenoceptors: β
1
and β
2
β
1
-Adrenoceptors are located in heart. They affect cardiac stimulation and lipolysis.
β
2
-Adrenoceptors are meant for smooth muscles relaxation like vasodilation, bronchodilation,
intestinal and uterine relaxation and glycolysis.
2.3.6 Classification
Adrenergic drugs are classified according to their mode of action on adrenoceptors
I. Direct Acting Agonist
1. α and β-adrenoceptors agonist: Chemically these agents belong to phenylethanolamines derivatives
A. Epinerine: L-1-(3, 4-Dinhydroxy Phenyl)-2-Methyl-aminoethanol
HO
HO
CH — CH — NH — CH
23
OH
Fig. 2.43
B. Norepinephrine: L-1-(3, 4-Dihydroxy phenyl)-2-amino-ethanol.
HO
HO
CH — CH — NH
22
OH
Fig. 2.44
2. Selectively
ββ
ββ
β
-adrenoceptors agonist
A. Isoproterenol: 1-(3, 4-dihydroxyphenyl) 2-isopropylaminoethanol
HO
HO
CH — CH — NH — CH
2
OH
CH
3
CH
3
Fig. 2.45
B. Isoetharine: 3, 4-dihydroxy-α-[1-(iso-propylamino) propyl] benzylic alcohol.
HO
HO
CH — CH — NH — CH
OH
CH
3
CH
3
CH
25
Fig. 2.46
Autonomic Nervous System Cholinergic Drugs and Adrenergic Agents 43
C. Terbutaline: α-[(tert-butylamino) methyl]-3, 5-dihydroxy-benzylic alcohol.
HO
CH — CH — NH — C(CH )
233
OH
HO
Fig. 2.47
D. Metaproterenol: α[(isopropylamino) methyl]-3, 5- dihydroxy benzylic alcohol.
HO
CH — CH — NH — CH
OH
CH
3
CH
3
CH
25
HO
Fig. 2.48
E. Salbutamol or albuterol: 2-tert-butylamino-1-(4-hydroxymethylphenyl) ethanol
HO—H C
2
HO
CH — CH — NH — C(CH )
233
OH
Fig. 2.49
3. Selectively
αα
αα
α
Adrenoceptors agonist:
A. Clonidine: 2-(2, 6-diochlorophenylamino) Imidazoline
NH
N
N
|
H
Cl
Cl
Fig. 2.50
4. Antiedema Sympathomimetics: (Imidazoline Derivative)
A. Naphazoline: 2-(1-Naphthylmethyl)-2-Imidazoline
CH
2
N
H
|
N
Fig. 2.51
44 A Textbook of Medicinal Chemistry
B. Oxymetazoline: 6-tert butyl-3-(2-Imidazolin-2-yl(methyl) -2, 4-dimethylphenol
CH
2
N
H
|
N
HO
(CH )
33
C
CH
3
CH
3
Fig. 2.52
C. Xylometazoline: 2-(4-tert butyl -2,6-dimethyl benzyl) -2-imidazoline
CH
2
N
H
|
N
(CH )
33
C
CH
3
CH
3
Fig. 2.53
II. Indirect Acting Agonist
A. Tyramine: 4-(2-aminoethyl) phenol
CH — CH — NH
222
HO
Fig. 2.54
III. α and β adrenomimetics (Indirect-mixed Action)
A. Dopamine: 2-(3, 4-dihydroxyphenyl)-ethylamine
CH — CH — NH
222
HO
HO
Fig. 2.55
B. Epherine: L-erythro-1-phenyl-2-methyl amino propanol
CH — CH — NHCH
3
CH
3
OH
Fig. 2.56