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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5726_Библиотеки_им_академика_М_И_Перельмана.pdf
Antiparkinsonism Agents 125
8.3 INITIATION OF THERAPY
In the present time, definition of Parkinson’s disease have been changed. Parkinsons disorder is the
consequence of an imbalance between dopaminergic and cholinergic system. Further treatment of
PD may include either blocking excessive stimulation of cholinergic system or normalize the
functional activity of popaminergic system. Figure 8.1 represents the agonist therapy by dopamine
or COMT or MAO inhibitors that are useful in the treatment of PD.
Dopamine agonist
Add Levadopa/Carbidpa
Inadequate control
Inadequate control
Levadopa/Carbidopa
in higher dose
Inadequate control
Add COMT inhibitor or add
MAO-B inhibitor
Levadopa/Carbidopa
Inadequate control
Adjunct therapy
For tremor : Add Ach antagonist
For drug induced dyskinesia:
Approach amantadine
Option
Surgical
Operation
Failure of medical therapy
Failure of
medical
therapy
Fig. 8.1: Schematic diagram of initiation of therapy.
8.4 CLASSIFICATION OF ANTIPARKINSONISM AGENTS
8.4.1 Dopaninergic Treatment
8.4.1.1 Dopamine-D
2
Receptor Agonists
1. Pergolide Mesylate (Permax®): Ergoline-8-(methylthio) methyl)-6-Propyl-8-monomethane
sulfonate.
H
O
S
O
OH
H
CH
2
N
|
H
Fig. 8.2
126 A Textbook of Medicinal Chemistry
2. Cabergoline (Dostinex®): 1-[16-allylergolin-8β-yl)-carbonyl]-1-[3-(dimethylamino)propyl]-3-
ethylurea
H
CH
3
N
|
H
H
N
C
N
C
H
|
N
N
CH
3
O
O
Fig. 8.3
3. Lisuride: 1, 1-diethyl-3-(6aR-9S)-7-methyl-hexahydroindolo-[4, 3 f 9] quinoline-9-yl)-urea.
H
N
|
H
H
N
H
N
N
CH
3
CH
3
CH
3
O
Fig. 8.4
4. Apomorphine
HO
HO
N
H
R = CH Apomorphine
R = n – C H N-propylnora omorphine
3
37
,P
R
Fig. 8.5
Antiparkinsonism Agents 127
8.4.1.2 Di-Receptor Agonists:
1. Dihydrexidine: 5, 6, 6a, 7, 8, 12b-hexahydro-benzo-phenanthridine 10, 11-diol
H
H
NH
HO
HO
Fig. 8.6
2. Dinapsoline: 8, 9-dihydroxy-2, 3, 7, 11b-tetrahydro-1H naphisoquinoline
HO
HO
H
NH
Fig. 8.7
8.4.1.3 Mao inhibitors
1. Phenelgine (Nardil®): (2-phenylethyl) hydrazine
H
N
NH
2
Fig. 8.8
2. Selegiline (Eldepryl®) –N-methyl-N-(2-propionyl)-2-methyl-Phenylethylamine
CH
3
N
HC
3
CCH
Fig. 8.9
3. Tranylcypromine (Parnate®): (±)-trans-2-phenylcyclopropane-1-amine.
NH
2
H
H
Fig. 8.10
128 A Textbook of Medicinal Chemistry
8.4.1.4 Decarboxylase Inhibitors (Peripheral)
(1) L(–) carbidopa (Lodosyn®): (–)–3-(3, 4-dihydroxy phenyl)-L-alanine)
H
HO
HO
COOH
NH
2
HO
HO
COOH
NHNH
2
HC
3
Levodopa
Fig. 8.11
(2) Benserazide (Serazide®): 2-amino-3-hydroxy-N (trihydroxybenzyl)-propane hydrazide.
HO
HO
N
H
H
N
OH
NH
2
OH
O
Fig. 8.12
8.4.1.5 COMT Inhibitors: (Catechol-O-Methyl Transferase Inhibitor)
1. Entacapone: 2-cyano-3-(3, 4-dihydroxy-5-nitrophenyl)-N, N-diethyl-propenamide
HO
HO
N
CN
NO
2
O
Fig. 8.13
8.4.1.6 Dopamine Agonist
1. Levodopa (Sinemet®): Structure mentioned above (–)-3(3, 4-dihydroxy phenyl)-L-alanine.
8.4.2. Agents Action on Nondopaminergic System
8.4.2.1 Anticholinergic Agent
1. Benztropine (Cogentin®): 3-(diphenylmethoxy)-8-methyl-8-azabicyclo [3, 2, 1] octane.
Antiparkinsonism Agents 129
O
H
N—CH
3
Fig. 8.14
2. Biperiden (Akineton®): 1-(6-bicyclo[2, 2, 1]hept-2-enyl)-1-phenyl-3-piperidine-1-yl-propane-
1-ol.
N—CH —CH —C—OH
22
Fig. 8.15
3. Diphenhydramin (Benadryl®): 3-(diphenylmethoxy)-N, N-dimethyl ethanamine
CHO — CH — CH — N
22
CH
3
CH
3
Fig. 8.16
4. Procyclidine (Kemdrin): 1-cyclohexyl 1-phenyl-3-pyrrolidin-1-yl-propan-1-ol.
N—HC—H C—C—OH
22
Fig. 8.17
130 A Textbook of Medicinal Chemistry
5. Trihexyphenidyl (Parkopan®): 1-cyclohexyl-1-phenyl-3-piperidinopropan-1-ol.
C—CH —CH —N
22
OH
Fig. 8.18
8.4.2.2 Glutamate Antagonist
1. Amantadine (Symmetrel®): Adamantan-1-amine
NH
2
Fig. 8.19
2. Memantine: 1-amino-3, 5-dimethyladamantane
NH
2
HC
3
CH
3
Fig. 8.20
8.4.2.3 Serotonin Agonists
1. Sarizotan: 1-[3, 4-dihydro-2H-chromen-2yl]-N-[5-(4-fluorophenyl) pyridin-3-yl]methyl)
methanamine
F
N
H
N
O
Fig. 8.21
8.5 DOPAMINERGIC AGENTS
In the treatment of PD, the compensation of the dopamine deficiency in neostriatum, usually by
direct stimulation of dopamine receptors. Another option is to enhancing the synthesis of dopamine
Antiparkinsonism Agents 131
by decrease its catabolism. Thus, dopaminergic agents are given to the patient during treatment. It
has been proved that parkinsonism produced by MPTP that has ability to prevent MAO-B inhibitors
action therefore selective MAO-B inhibitors or antioxidants are the right choice to slow progressive
of idiopathic PD.
1. Pergolide (Permax®): Pergolide is ergoline derivative.
Synthesis:
N
N—CH
3
COOME
N
N—CH
3
CH OH
2
N
N—CH
3
CH —S—CH
23
LiAlH
(Reduction)
(i) CH SO Cl
methane
sulphonyl
chloride
(ii) CH SH
32
3
Derivative of Ergot
Pergolide
Fig. 8.22
Pergolide is selective D
2
receptors agonist and used in the treatment of parkinsonism.
2. Levodopa (Sinemet®): Levodopa is a levorotatory isomer of dioxyphenylalanine and mainly
used as a precursor of dopamine. Therapy behind the assumption that Levodopa does not cross the
blood brain barrier. While it turns into dopamine and it has ability to normalize the dopamine level in
the brain.
Synthesis:
HO
CH — CH — COOH
2
NH
2
HO
CH — CH — COOH
2
NH
2
CH CO
3
CH COCl/AlCl
33
(Acetylation)
HO
CH — CH — COOH
2
NH
2
HO
H O | NaOH
22
(Deacetylation)
Tyrosine
Levodopa
Fig. 8.23
132 A Textbook of Medicinal Chemistry
3. Selegiline (Eldepryl®): Selegiline is selective MAO-B inhibitor which suppress dopamine
inactivation process and increase the level of dopamine in brain as well as Selegiline is used in the
combination with Levodopa in the treatment of Parkinson disorder. It also oxidizes MPTP to
neurotoxic by-product.
Synthesis:
CH — CH — NH
2
CH
3
CH
3
Br — CH — C CH
2
(Alkylation)
CH — CH — N — CH — C CH
22
CH
3
CH
3
(–) Methyamphetanine Selegiline
Fig. 8.24
4. Carbidopa (Lodosyn®): Carbidopa is DOPA-decarboxylase inhibitor. It is given with the
combination of levodopa concomitantly. Carbidopa falicitate to increase level of levodopa by peripheral
inhibition of DOPA-decarboxylose enzyme whereby it can cross blood brain barrier. (Carbidopa
does not cross BBB).
Synthesis:
O
CH
3
HO
OCH
3
NC
CH
3
HO
OCH
3
OH
(i) NH — NH
22
(ii) HBr
Derivative of propiophenone
HCN
COOH
CH
3
HO
OH
NH·NH
2
Carbidopa
Fig. 8.25
8.6 NON-DOPAMINERGIC AGENTS
Non-dopaminergic agents or anticholinergic agents exert the excitatory effect on GABArgic output
from the striatum in interneurons. Agents that increase the cholinergic neurotransmission (e.g.,
physostigmine and carbachol) would be associated to potentiate Parkinson character in human
while centrally active antimuscarinic agents (e.g., belladonna alkaloids) are concerns to deactivate
cholinergic transmission and manage the deficiency of dopamine release transmission. In the concern
of antimusarinic activity, antihistaminic agents also exert central muscarinic antagonist action but
Antiparkinsonism Agents 133
the adverse effects also put by central antimuscarinic agents like peripheral blocked of parasympathetic
functions (dry mouth, impaired visual accommodation, constipation, urinary retention, tachycardia).
nonpaminergic drugs sometimes given with L-dopa to prevent tremor.
1. Benzotropin (Congentin®): Benzotropin is synthetic anticholinergic drug. Benzotropin is used
in the treatment of Parkinson’s disease.
Synthesis:
CNN
+
+
N—CH
3
OH
CH — O
N
|
CH
3
Diphenyl diazomethane
Tropin
Benzotropine
Fig. 8.26
2. Procyclidine (Kemdrin®): Procyclidine is also synthetic anticholinergic drug. It is to be suggested
in the treatment of Parkinson’s disorder.
Synthesis:
C
CH
3
O
C
CH — CH — N
22
O
HCHO/H — N
MgBr
Benzophenone
2-(1-Pyrrolidino)-Propiophenone)
Cyclohexylmagnesium bromide
C—CH —CH —N
22
OH
Pyrrolidine
Fig. 8.27
3. Biperiden (Akineton®): Biperiden also possesses same properties as the aforementioned agents.
134 A Textbook of Medicinal Chemistry
Synthesis:
C
CH
2
O
H
C
2
N
Cl
(i)
5-chloro-2-norbornene
(ii) Mg
+
2-(1-piperidino)-propiophenone
C — CH — CH — N
22
Biperidine
OH
Fig. 8.28
4. Amantadine (Simmetrel®): Amantadine is an adamantine (cage-like structure). It was initially
developed as an antiviral agent. Amantadine has ability to release dopamine and Nor-adrenaline from
the interneuronal storage place and block-re-uptake of dopamine, therefore the appropriate availability
of dopamine as neuro-transmitter. Amantadine also enhances the effect of L-Dopa, on the other
site, the derivative of Memantine that has been used as spasmolytic agent in the treatment of both
Parkinson’s and dementia disorders.
Synthesis: Ritter Reaction
Br
2
Br
CH CN / H SO
243
(Acetonitrill)
NHCOCH
3
NaOH
NH
2
AmantadineAdamantane
Fig. 8.29
8.7 STRUCTURAL MODELING FOR DOPAMINE RECEPTOR AGONIST/SAR OF
DOPAMINE RECEPTOR AGONISTS
8.7.1. Conformational Aspects
1. Development of selective dopamine receptor proximity are the major concerns according to
QSAR studies of lead molecule.
2. It should be clear that agonist action exerted by the compounds at dopamine D
1
type and
especially D
2
-type receptors properly.