pharmaceutical chemistry

1. Antipsychotic agents
There is no cure for Schizophrenia just symptomatic control is done
BY – Miss Priya S Hargunani.
Assistant Professor
Department of PHARMACEUTICAL CHEMISTRY.
Venue: DD Vispute College of Pharmacy & Research Centre .

2. Antipsychotics/neuroleptic agents/tranquilizing
agents/ drugs for schizophrenia…..
Introduction
Classification
Mechanism of action of Phenothiazine derivatives
Structure activity relationship of Phenothiazine
Phenothiazine derivatives
Thioxanthene derivatives
Miss Priya S Hargunani 2Antipsychotic agents

3. Introduction…
The psychoses (eg: schizophrenia) are among the most severe mental
illnesses .
Positive symptoms: abnormality of normal function leading to presence
of inappropriate behaviors – Delusions (false belief)and hallucination
(false perception), speech disturbances
Negative symptoms: loss of normal function leading to absence of
appropriate behaviors – lack of motivation, social withdrawal, lack of
interest in fun activity, doesn’t respond to questions
SCHIZOPHRENIA IS FOR LIFE
Schizophrenia – Increase dopamine
Antipsychotic drugs: Decrease dopaminergic neurotransmission
Miss Priya S Hargunani 3Antipsychotic agents

4. Introduction…
Pathway Significance Associated disease
The Nigro-straital pathway Movement Low dopamine causes
EPS (Extra Pyramidal symptoms)
The Mesocortical pathway Motivation, pleasure,
socialization
High Dopamine causes
negative symptoms of
schizophrenia
The Mesolimbic pathway Speech, grasp of reality High dopamine causes
positive symptoms of
schizophrenia
The Tubero
infundibular pathway
Prolactin Hormone release Prolactin Hormone deficiency
Ideally we would want dopamine blockade only in Mesocortical and Mesolimbic pathway but that
has not been realized till now
Miss Priya S Hargunani 4Antipsychotic agents

5. Introduction…
Extrapyramidal nigrostrial pathway –consist of neurons which plays
important role in locomotor coordination.
Degeneration of these neurons is a key hallmark in Parkinsons
deseases.
Mesolimbic and mesocortical pathway: involves emotions, behaviours
and higher thoughts process
Antipsychotic drugs act majorly on D2 receptor in both extrapyramidal
and limbic brain region that can be located presynaptically and
postsynaptically both.
D2 presynaptic autoreceptors activation: other hetroreceptors such as
adenosine A2, histamine H1,
Serotonic 5HT1a located near presynaptic dopaminergic nerve terminals
in stratium can modulate synthesis
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6. Introduction…
Side effects: sedation , hypotension, sexual dysfunction , antagonism of
muscarinic ach receptor, parkinsonism like movement side effect
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7. Introduction…
Mechanism of action:
The antipsychotic mechanism of action of neuroleptics involves
modulation of dopamine neurotransmission in the mesolimbic-
mesocortical pathway.
This may achieve via direct D2 receptor interaction and include
functional spectrum antagonism, inverse agonism and/or partial agonism.
 These drugs clinical efficacy however not only depends on D2 receptor
interaction , other CNS system receptors are also involved (ach,
histamine, norepinephrine and serotonin) appears to be involved ,
specially for the atypical drugs.
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8. Classification of the antipsychotic drugs…
A) TYPICALANTIPSYCHOTICS
(more EPS, D2 blokage)
B) ATYPICALANTIPSYCHOTICS
(less EPS, D2 and 5HT2a blokage)
C) BOTH (TYPICALAND
ATYPICAL)
ANTIPSYCHOTICS
1) PHENOTHIAZINE:
a) ALIPHATIC:
CHLORPROMAZINE,
TRIFLUPROMAZINE,
b) PIPERIDINE: THIORIDINE,
c) PIPERIZINE: FLUPHENAZINE
1) DIPHENYLBUTYLPIPERIDINE:
PIMOZIDE
1) DIHYDROINDOLONES:
MOLINDONE
2) THIOXANTHENES:
CHLORPROTHIXENE
2) BENZIOXAZOLE:
RESPERIDONE
2) BENZAMIDE: SULPIRIDE
3) FLUOROBUTYROPHENONES:
HALOPERIDOL, DROPERIDOL
3) DIBENZODIAZEPINE:
LOXAPINE, CLOZAPINE
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Miss Priya S Hargunani 8Antipsychotic agents

9. P
O
T
E
N
C
Y
Classification of the antipsychotic drugs…

10. Mechanism of action of Phenothiazine
derivatives..
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Drugs found in this class are antagonist.
They work by D2 receptor blocking in the dopaminergic pathway –
decrease effect of dopamine release.
Blocking the D2 receptor in mesolimbic pathway result in
antipsychotic effect

11. Structure activity relationship of
Phenothiazine...
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N
S
H2C
H
C
R3
H2
C N
R1
R1
R2
2
3
4
56
7
8
9
10
1
THE NEUROLEPTIC PROPERTIES OF
PHENOTHIAZINE MAY BE AFFECTED BY
FOLLOWING :
A) NATURE OF THE CHAIN IN POSITION
10
B) NATURE OF THE AMINO GROUP
C) R2 SUBSTITUTION
 Replacement of the h in position 2
 Substitution at position 3
 Substitution at position 1
 Three carbon chain
 Branching with larger groups
 Replacement of terminal alkyl amino group

12. Structure activity relationship of
Phenothiazine...
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• Electron Donating • Electron Withdrawing

13. Structure activity relationship of Phenothiazine...
A)ALKYL SIDE CHAIN:
MAXIMUM POTENCY: Nitrogen of phenothiazine ring and the more basic
side chain nitrogen is connected with THREE CARBON SIDE CHAIN.
branching at the β position of the side chain with small methyl group –
DECREASE IN ACTIVITY.
β position substitution with larger group - LOSS IN ACTIVITY.
Bridging of position 3 of the
side chain to position 1 – LOSS IN ACTIVITY
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N
S
1
N(CH3)23

14. Structure activity relationship of Phenothiazine...
B) BASIC AMINO GROUP:
MAXIMUM POTENCY : amino alkylated phenothiazine having
TERTIARY AMINO GROUP.
DECREASE ACTIVITY: alkylation of basic amino group with groups larger
than methyl group (diethyl amine analogue less potent than chlorpromazine).
 Piperidinyl derivatives are less potent than dimethyl amine derivatives.
Substitution at 4 position of the piperazinyl or piperidinyl propyl substituted
phenothiazine has been varied.
• Hydroxy ethyl –enhances the activity
• Acetoxy group – even more potent
• Decrease in activity – n-methyl and n-propyl derivatives
Antipsychotic agents Miss Priya S Hargunani 14

15. Structure activity relationship of Phenothiazine...
C) PHENOTHIAZINE RING SUBSTITUTION (POSITION 2 –R2):
Potency increases in the following order of position of ring substitution
1<4<3<2
2 substitution of phenothiazine nucleus increases neuroleptic potency in the
following order:
OH , H, METHYL, nC3H7CO, C2H5CO, CH3CO, CL, SCH3, CF3
Oxidation of 5 sulphur – decrease in activity.
1,2,3,4-aza phenothiazine – more potent.
1-aza analogue of promazine –
more potent than parent compound
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N
S
N
N(CH3)2
1

16. Phenothiazine derivatives…
1) Chlorpromazine
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N
S
N(CH3)2
Cl
[3-(2-Chloro-phenothiazin-10-yl)-propyl]-dimethyl-amine
 First phenothiazine derivative in therapy
 Antipsychotic
 Other uses nausea , vomiting, hiccups.
 Extensively metabolised by CYP2D6
 Weak hepatic metabolism
 100 of metabolites possible
 Alteration of GI motility may also contribute
 Sedative and hypotensive properties- central
histaminergic and peripheral alpha 1
noradrenergic blocking activity respectively
 Effects of peripheral anticholinergic activity
are common
 As with other phenothiazine the effect of other
CNS –depressant drugs , such as sedative and
anaesthetics can be potentiated.

17. Phenothiazine derivatives…
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2)TRIFLUPROMAZINE 3) THIORIDAZINE
N
S
N(CH3)2
CF3
Dimethyl-[3-(2-trifluoromethyl-phenothiazin-10-yl)-propyl]-amine
N
S
SCH3
N
CH3
10-[2-(1-Methyl-piperidin-2-yl)-ethyl]-2-methylsulfanyl-10H-phenothiazine

18. Phenothiazine derivatives…
4) FLUPHENAZINE:
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N
S
CF3
O
N
N
OH
3-[4-(2-Hydroxy-ethyl)-piperazin-1-yl]-1-(2-trifluoromethyl-phenothiazin-10-yl)-
propan-1-one

19. Thioxanthene derivatives….
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S
C
R
CH2
H2C NRH
STRUCTURAL MODIFICATION OF
PHENOTHIAZINE DERIVATIVES
 Thioxanthene bioisosteres – derived by replacing N-
CH2 structural feature of phenothiazine with
bioisosteric double bond.(olefinic double bond)
 Cis is more potent than trans isomer.
CHLORPROTHIXENE
S
CH
Cl
CH2
CH2 N
CH3
CH3
[3-(2-Chloro-thioxanthen-9-ylidene)-propyl]-dimethyl-amine

20. Antipsychotic agents Miss Priya S Hargunani 20
Thankyou