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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5726_Библиотеки_им_академика_М_И_Перельмана.pdf
Antidepressant Drugs 185
Synthesis:
Styrene
+ N CHCOOC H
225
Ethyldiazoacetate
COOC H
25
2-Phenylcyclopropane-carboxylic acid ethyl ester
CHOH|OH
25
+
Hydrolysis
H
H
COCl
H
H
COOH
1. NaN
3
2. HCl
(Sodium azide)
H
H
NH
2
Tranylcypromine
SOCl
2
Trans-isomer
CH
2
CH
Fig. 11.16
11.7 SELECTIVE SEROTONINE REUPTAKE INHIBITORS (SSRI)
5HT is a major neurotransmitter in depressive illness and serotonergic pathway is very close to the
mental disorders like depression. Therefore SSRIs drugs affecting the levels of 5HT and serotonergic
pathways in neuronal spaces of synapse lead to effective therapy of depressive illness.
SSRIs are clinically proved in the treatment of which depression, obsessive-compulsive disorders
and panic disorders as well. The most substantial advantage of SSRIs over TCAs are to have lower
incidence of side effects and better tolerability. The meaningful differences between the individual
drugs of SSRIs are largely associated to their pharmacokinetics, metabolism of active metabolites,
inhibition of CYP isoforms and drug-drug interaction behaviour as well as half life of drugs.
11.7.1 Mechanism of Action
SSRIs epinephrine preferentially inhibit the reuptake transport of 5HT (SERI) with minimum or no
affinity to nor-epinephrine and Dopamine transporters respectively. SSRIs have higher affinity for
SERT therefore block 5HT from binding to SERT and being absorb into presynaptic cells, because
excess of 5HT cause over-activation of post-synaptic receptors.
186 A Textbook of Medicinal Chemistry
11.7.2 Structure Activity Relationship (SAR) of (SSRIs)
X
[Z]
O
Y
H
CH
3
CF
3
Y=CF
3
Pheno
Aryl ring
substitution
Halogen
Chiral carbon
X=F
(CH ) — N
22
Fig. 11.17 Phenoxy propylamine structure.
1. There are marked racemic mixtures of SSRIs R and S forms.
2. Potency depends on phenoxy ring substituents.
3. Introduction of electron withdrawing group at p-position of phenoxy ring leads to selective
inhibition of 5HT reuptake, other changes in the ring may lead to decrease the activity.
4. Trans-isomers are more potent than cis-isomers, e.g., MDL-28618A.
5. Trans-isomers of famoxatin has 10% affinity of fluoxentine for SERT. While paroxentine
has two chiral atoms, (–) isomere is active of paroxentine.
6. N-demethylation of faxmoxetine to secondary amine leads to enhance potency by 10 times.
7. Conversion of secondary amine of piperidine heterocylic ring to tertiary amine with alky
group decrease the activity for 100 times.
8. Introduction of 4-fluoro is essential for SERT affinity, replacement of 4-fluoro substituent
with hydrogen or alkyl group leads to sudden decrease in activity.
11.7.3 Specific Drugs
1. Fluoxantine (Prozac
®
): 3-phenoxy-3-phenyl propyl-3-[p-(trifluoro methyl)-phenoxy]-N-methyl-
3-amine is the derivative of phenyl propylamine. Fluoxantine is active drug of SSRIs. Its S isomer
is more potent for SERT. Its N-demethyl derivative is more potent than parent compound and more
selective for SERT. Fluoxantin inhibits the re-uptake of 5HT in the presynatic cleft and increase the
abundance in an anxious state.
Synthesis:
CH — (CH ) — NHCH + F C
22 3 3
Cl
FC
3
OH
P-trifluoromethyl phenol
3-(chloro)-N-methyl-3-
Phenylpropylamine
C — (CH ) — NHCH
22 3
H
O
Fluoxantine
Fig. 11.18
Antidepressant Drugs 187
2. Paroxetine (Paxil
®
): (3S, 4R)-3-[2H-(1, 3-benzodiazol-5-yl oxyl) methyl]-4-(4-fluorophenyl)
piperidine
Paroxetine is a potent SSRIs antidepressant drug. It has β-Aryl amine like structure with extra aryl
group. Paroxetine is highly selective towards SERT. Paroxetine is suggested in the treatment of
various etiological depressive illnesses.
O
O
OCH
2
F
N—H
Fig. 11.19
3. Citalopram (celexa
®
): (RS)-1-[3-(dimethylaminopropyl)]-1-(4-fluorophenyl)-1, 3-
dihydroisobenzofuran-5-carbonitrile, citalopram is available in racemic mixture. It is highly selective
for SERT. Its N-mono demethylated derivative is less potent than parent compound. Its aryl moiety
makes the compound more potent. It is used in the treatment of various types of depressions.
O
(CH ) — N
23
F
CH
3
CH
3
NC
Fig. 11.20
11.8 NEWER ATYPICAL ANTIDEPRESSANTS
Newer atypical antidepressant agents are second generation antidepressant drugs. It is very likely
that their mechanism of action is due to their ability to inhibit the re-uptake of norepinephrine or
serotonine.
11.8.1 Specific Drugs
1. Bupropion (Wellbutrin
®
): 1-3-(chlorophenyl)-2-[(1, 1-dimethylethyl) amino]-1-propanone.
Bupropion is structurally similar to amphetamine because of having α-amino ketone. Bupropion is
a dopamine re-uptake inhibitor via dopamine transporter (DAT).
188 A Textbook of Medicinal Chemistry
Synthesis:
CN
(Ethyl magnesium
bromide)
C H MgBr
25
Cl
C—CH —CH
23
Cl
O
Br
2
C—CH—CH
3
O
Br
(CH ) C — NH
33 2
(tert-Butylamine)
C — CH — NH — C(CH )
33
Cl
O
CH
3
Cl
3-chlorobenzo
nitrile
(Bromination)
Bupropion
Fig. 11.21
2. Trazodone (Thrombran®): 2-[3-[4-(m-chlorophenyl)-1-piperazineyl]-propyl]-S-triazolo [4,
3-a]-piperazinyl-3-(2H)-one trazodone is a potent atypical antidepressant drug. It is believed that it
has the ability to inhibit neuronal reuptake of serotonin but minor effect on NE and Dopamine.
Synthesis: (Semicarbazide)
Cl
2-Chloropyridine
HN—HN—C—NH
22
N—H
N
N
Cl — CH — CH — N
22
Cl
N
O
Alkylation
Trazodone
(A) = (3-chlorophenyl propyl)-4-(3-
chlorophenyl piperazine
N
N
N — CH — CH — N
22
Cl
N
O
(A)
O
Fig. 11.22
11.9 NEWER AGENTS
1. Escitalopram: Escitalopram is (S) isomer of citalopram. It has higher affinity for the human
serotonin transport (SERI). It is suggested for the treatment of several anxiety and depressive
states, in panic disorder and obsessive compulsive disorder.
Antidepressant Drugs 189
O
NC
(CH ) — N
23
CH
3
CH
3
Fig. 11.23
2. Things to come: Drugs acting on Neuropeptide receptors
(i) Substance P-NKI receptor antagonists: e.g., MK-0869.
(ii) CRF antagonist (corticotrophin releasing factor antagonist) e.g., CP-614, 526, DMP-696.
EXERCISE
1. Classify antidepressant drugs. Give their mechanism of action.
2. What are trycyclic antidepressants? Discuss in detail.
3. Write SAR on tricyclic antidepressant with various illustrations.
4. Write the synthesis, MOA and uses of the following drugs:
(i) Imipramine
(ii) Amitriptyline
(iii) Doxepine
(iv) Protrypyline
5. Discuss in detail the monoamine oxidase inhibitors. Write any one synthesis of this class.
6. Discuss in details the SAR of SSRIs compounds.
7. Write a note on a typical antidepressant. Give the chemistry of bupropion.
190 A Textbook of Medicinal Chemistry
12
Antianxiety Drugs
12.1 INTRODUCTION
Anxiety is the phenomenon that is directly associated with emotional condition. It is an essential part
of adaptive response to stressful or threatening stimulation that can heighten to the dangerous or
stressful condition. Anxiety is a condition that is clinically difficult to define but may be described as
a sense of unpleasant unwanted anticipation and excessive mental tension. However, anxiety is very
close to the condition of depression to some extent. Nowadays anxiety is an integral part of our life.
It may be chronic, uncontrollable and completely out of proportion to the generating stimulus.
There are so many factors such as social factors, pathophysiological factors serve as initiating state
of anxiety. Somatic symptoms includes tachycardia, palpitation, sweating, dizziness, nausea, insomnia,
irritability and impaired concentration as well.
The anxiety disorders are the following:
1. Generalized anxiety disorders (GAD): Symptoms are restlessness, fatigue, impaired
concentration, irritability and muscles tension.
2. Social phobia (SP) or social anxiety disorder (SAD) pertaining social aspects.
3. Obsessive compulsive disorder (OCD).
4. Post-traumatic stress disorder (PTSU): Symptoms includes extreme fear or terror associated
with social threatening (war or rape), insomnia, night mares, etc.
According to the clinical studies, monoamine oxidase inhibitors (MAOIs) for illustration
iproniazide and phenelzine are the suitable candidates of drugs that are useful in the treatment of
anxiety disorders. Another classes of antidepressants drugs are TCAs (tricylic antidepressants) for
example, imipramine used to panic disorders of anxiety. Apart from that Benzodiazepines (BZs)
discovered in 1950s play a very important role in the treatment of anxieolytic disorders.
Antianxiety Drugs 191
12.2 CAUSES OF ANXIETY
Neurotransmitters, neuromodulators and neuropeptides (for illustration, cholecystokinin,
corticotropin- releasing factors, neuropeptides Y) are involved in the pathophysiology of anxiety.
12.2.1Receptor Involve
1. GABA receptors :- GABA
A
and GABA
B
as well as GABA
C
receptors are utilizing the neurotrans-
mitters for intracellular communication. GABA
B
receptor is (G-protein couple receptor)
2. Serotonergic Receptors:- 5HT
1
, 5HT
2
and 5HT
3
receptors
3. Neuropeptides (CCK Receptors) :- CCK-A and CCK-B receptors
12.3 CLASSIFICATION
1. Benzodiazepines
Fig. 12.1 (Contd.)
N
N
O
Cl
CH
3
N
N
NH
3
Cl
O
–
N
H
N
O
COOK
Diazepam (Valium )
®
Chlordiazepoxide (Librium )
®
Chlorzepate (Tranxene )
®
N
H
N
O
Cl
OH
Lorazepam (Ativam )
®
N
N
Cl
Alprazolam (Xanax )
®
N
N
CH
3
N
H
N
O
Cl
OH
Oxazepam (Serax )
®
Cl
192 A Textbook of Medicinal Chemistry
Derivatives R
1
R
2
R
3
X
Clonazepam H NO
2
HCl
Diazepam CH
3
Cl H H
Clorazepate H Cl COOK H
Flurazepam (CH
2
)
2
N(C
2
H
5
)
2
Cl H F
Halazepam CH
2
CF
3
Cl H H
Oxazepam H Cl OH H
Temazepam CH
3
Cl OH H
Fig. 12.1
Fig. 12.2: Basic structure of benzodiazepine.
Y
N
O
R
2
R
1
X
R
3
9
8
7
6
5
1
2
3
4
N
H
N
O
ON
2
Clonazepam (Klonopin )
®
Cl
N
O
N
N
N
N
Buspirone (Buspar )
®
Cl
Cl
Sertaline (Zoloft )
®
O
Benzodiazepines (Class-A)
Antianxiety Drugs 193
2. Triazolobenzodiazepines: (Class-B)
N
N
N
Y
X
R
Cl
Fig. 12.3: Basic pharmacophore of triazolobenzodiazepines.
Derivatives R X X
Alprazolam CH
3
HN
Midaxolam CH
3
FCh
Estazolam H H N
Triazolam CH
3
Cl N
3. Non-benzodiazepines Drugs:
A. β Carbolines (9H-Pyrido-[3,4-b]-indole) (Norharmane)
N
H
X
N
Fig. 12.4
x = COO E + (β-CCE)
x = COO CH
3
(β-CCM)
x = COO–n–Pr
x = Alkoxy
N
Cl
O
C
O
N
N
CH
3
N
O
N
N
(Zopiclone)
Fig. 12.5 (Contd.)
B. Cyclopyrrolones
194 A Textbook of Medicinal Chemistry
B. Cyclopyrrolnes
4. Newer Agents
A. Imidazopyridines:
R
1
N
N
N
R
1
HC
3
CH
3
O
Zolpidem (Ambien )
®
H
Fig. 12.6
B. Pyrazoloquinolines:
NN
R
O
H
R = H, OCH , Cl
3
N
Fig. 12.7
N
O
O
N
N
CH
3
N
S
Cl
[6-(7-chloro-1,8-Naphthyridin-2yl)-5-oxo-3,7-
dihydro-2H-[1,-4]-dithinopyrrol-7-yl]-4-methyl-
piperazine-1-carboxylate
N
O
N
O
O
O
Panizoclone
N
Cl
N
O
Surizoclone
N
N
Fig. 12.5