This ppt gives an insight about the antipsychotics drugs mechansim of action, SAR and individuals drugs usage from medicinal chemistry point of view

1. MEDICINAL CHEMISTRY I
B. PHARMACY II/IV (FIRST SEM)
Dr. K. Purna Nagasree
M.Pharm. (BITS, Pilani), Ph.D., PDF (DST, WOSA)

2. Antipsychotics
 Tranquillizers are used primarily for the
treatment of symptoms of mental diseases.
 They cause sedation without inducing sleep.
They are essentially used in the symptomatic
treatment of psychosis, such as schizophrenia
and organic psychosis.
 The symptoms of schizophrenia can be divided
into two types, positive and negative.
 Positive symptoms are those that are not
normally found in healthy individuals, including
hallucinations, delusions, and thought disorder.

3. Antipsychotics
 Negative symptoms represent the loss of
qualities normally present in healthy
individuals, including impoverishment of
thought, blunted emotion, attention
deficit, and lack of motivation or initiative.
In addition, many of these drugs also act as
skeletal muscle relaxants,
antihypertensives, antiemetics, and
antiepileptics.

4. Anti Psychotics
 Phenothiazines: SAR, Promazine HCl, Chlopromazine
HCl*, Triflupromazine, Thioridazine HCl, Piperacetazine
HCl, Prochlorperazine maleate,Trifluoperazine HCl
 Ring analogues of phenothiazines: Chlorprothixene,
Thiothixene, Loxapine succinate, Clozapine
 Fluorobutyrophenones: Haloperidol, Droperidol,
Risperidone
 Beta amino ketones: Molindone HCl
 Benzamides: Sulpiride

5. classification
1. Phenothiazine derivatives
Piperacetazine

6. 2. Ring analogues
of phenothiazines
 Thioxanthenes
 Dibenzoxazepines
Loxapine succinate
 Dibenzodiazepines
Clozapine
Xanthene

7. 3. Fluorobutyrophenones
 Benzisoxazoles - Risperidone

8. 4.Beta amino ketones:
Dihydroindolones-Molindone HCl
5.Benzamides: Sulpiride

9. 6. Benzodiazepines – Chlordiazepoxide, lorazepam
7. Rauwolfia alkaloids – Reserpine, Reserpidine
8. Diphenyl butyl piperidines – Pimozide
9.Thienbenzodiazepines
a. Olanzapine
10. Propanediol carbamates
a. Meprobamate
11. Miscellaneous
a.Oxypertine
b. Quetiapine
c. Seretindole

10. Antipsychotics: MOA
All antipsychotics except cloazapine have potent
dopamine (D2) receptor blocking action.
Phenothiazines and thioxanthanes also block D1, D3,
and D4 receptors and have correlation with
antipsychotic or tranquillizing property.
Blockade of the dopaminergic projections to the
temporal and the prefrontal area constitutes the limbic
system, and in the mesocortical area, it is probably
responsible for antipsychotic action.

11. Antipsychotics : MOA
 However, over a period of time, this subsides and gives away
diminished activity, especially in the basal to ganglia
corresponding to the emergency of Parkinsons disease.
 Clozapine, Flurobutyrophenones and sulpiride and other
atypical antipsychotics
have significant 5-HT2 and α1 blocking action and are relatively
selective for D4 receptor.
 Thus, antipsychotic property depends on a specific profile of
action of the drugs on several neurotransmitter receptors.

12. Promazine HCl
 It is a white or almost white crystalline
powder, slightly hygroscopic in nature.
 well soluble in water, alcohol, and
methylene chloride.
 It has low clinical potency, medium
extrapyramidal toxicity, high sedative
effect, and high hypotensive action.
 It is used as dopamine receptor
antagonist and neuroleptic.

13. Chlopromazine HCl*
 Metabolism: It is demethylated,
sulphoxidized, hydroxylated, and
glucuronidated to yield 7-o-glu-nor
chlorpromazine.
 Properties and uses: It is a white or almost
white crystalline powder, freely soluble in
ethanol and well soluble in water.
 The drug has significant sedative and
hypotensive properties, possibly reflecting
central and peripheral α1-noradrenergic
blocking activity and also effects the
peripheral anticholinergic activity
 Used as dopamine receptor antagonist and
neuroleptic.

14. Triflupromazine
 It is a white to pale yellow, crystalline
powder, hygroscopic in nature, soluble in
alcohol and freely soluble in water.
 It has lower sedative and hypotensive
effects than chlorpromazine, and greater
milligram potency as an antipsychotic
 used as dopamine receptor antagonist
and neuroleptic.

15. Thioridazine HCl
 It is a white or almost white crystalline powder,
soluble in ethanol, freely soluble in water and in
methanol.
 The drug exerts minimum antiemetic activity and
there by gives rise to minimal extrapyramidal
stimulation.
 The drug has sedative and hypotensive activity in
common with chlorpromazine.
 It is effective in the management and
manifestations of psychotic disorders, used as
Dopamine receptor antagonist and neuroleptic.

16. Piperacetazine HCl
 Piperacetazine is an antipsychotic prodrug,
most notably used for schizophrenia
1-[10-[3-[4-(2-hydroxyethyl)-1-piperidinyl]propyl]-2-
phenothiazinyl]ethanone

17. Prochlorperazine maleate
 It is a white or pale yellow crystalline powder, well
soluble in water and alcohol.
 It is more potent on a milligram basis than its
alkylamino counterpart, chlorpromazine because of
the high prevalence of extra-pyramidal symptom
(EPS).
 It is mainly used for anti-emetic effect, not for its anti-
psychotic effect, used as dopamine receptor
antagonist and neuroleptic.

18. Trifluoperazine HCl
 A phenothiazine with actions similar to
chlorpromazine. It is used as an
antipsychotic and an antiemetic.
10-[3-(4-methylpiperazin-1-yl)propyl]-2-(trifluoromethyl)-10H-phenothiazine
dihydrochloride

19. Chlopromazine HCl* Synthesis

20. Phenothiazines:
SAR
 It is presumed that phenothiazines (neuroleptic) mediate their
pharmacological effect mainly through interaction at D2 type
dopamine receptors.
 Examination of X-ray structures of dopamine and chlorpromazine
 substituted with chlorine shows that these two structures can be partly
superimposed.
 Chlorpromazine base could be superimposed on aromatic ring of
dopamine base with sulphur atom aligned with p-hydroxy of dopamine.
 These substances are chemically constituted by lipophilic linearly fused
tricyclic system having hydrophilic basic amino alkyl side chain.
 Activity of phenothazines is determined by the following:
 1. Nature of alkyl side chain at C-10.
 2. Amino group of side chain.
 3. Substituents on aromatic ring.

21. SAR
Phenothiazines
1. Modification of alkyl side chain
 Potency is maximum when there is three carbon between
two ‘N’ atom (ring and side chain N ).
 Introduction of methyl group at C-1 decreases antipsychotic
activity and produces imipramine-like activity.
 If C-1 is incorporated into cyclopropane ring imipramine-like
activity is obtained.
 When oxygen is introduced into C-1 results in potent
antidepressant effect. Example: Chloracizine.
 Addition of –CH3 at C-2 or C-3 has very little effect on
activity.
 Bridging of position 3 of side chain to position 1 of
phenothiazine nucleus decreases neuroleptic activity.

22. Phenothiazines: SAR
2. Amino group modification
 3° nitrogen shows maximum potency and 2° or 1° nitrogen shows
reduced or abolished activity.
 N-alkylation with more than one carbon decreases activity.
 Activity is decreased when dimethylamino group is replaced by
pyrolidinyl, morpholinyl, or thiomorpholinyl groups. However,
piperidine or piperazine is more potent than dimethylamino
group.
 Bridged piperidine derivates retain high degree of activity
although bulky.

23. Phenothiazines: SAR
 Piperazine and phenothiazines may be esterified
with long-chain fatty acids to produce slowly
absorbed long-acting lipophilic prodrugs.
 Due to the slow release from oily deposition, signifi
cant activity is retained
 When N-4 piperazine substituents are as large as
phenyl, ethyl, or p-amino phenyl ethyl
(e.g.Azaspirane, Chlorspirane) are active.

24. Phenothiazines: SAR
3. Phenothiazine ring
 Substitution at C-2 position is optimal for neuroleptic activity. In
general, potency at different positions increases in the following
order 1 < 4 < 3 < 2. Potency of the various groups increase in the
following order OH < H< CN < CH3 < Cl < CF3.
 Disubstitution (or) trisubstitution of the C-2 substituted drugs results
in harmful potency.
 CF3 is more potent than Cl, but EPS appears, hence, chlorpromazine
is much used, rather than triflupromazine.
 The electro-negative chlorine atom at C-2 is responsible for
imparting asymmetry to this molecule and the attraction of the
amine side chain towards the ring containing the chlorine atom
indicate an important structural feature of such molecules.
 Oxidation of the sulphur at 5th position of antipsychotic
phenothiazine decreases activity.

25. Ring analogues of
phenothiazines

26. Chlorprothixene
It is a white or almost white crystalline powder, slightly soluble in
methylene chloride, and soluble in water and alcohol.
It is used in the treatment of acute and chronic schizophrenia,
psychotic and other conditions in which anxiety, agitation, and
tension predominate.
Metabolism: Thioxanthines are closely related to the
phenothiazine in their pharmacologic effects and there seems to be
at least one major difference in metabolism, most of the
thioxanthine do not form ring hydroxylated derivatives.

27. Thiothixene
 White, or nearly white crystalline powder with slight odour, and affected
by light, soluble in water, anhydrous alcohol, or chloroform, practically
insoluble in benzene, acetone, or ether.
 The substituent in the second position produces Z and E isomers. The Z
isomers are the more active antipsychotic isomers.
 It was introduced as an antipsychotic agent useful in the management
of schizophrenia and other psychotic states. It is also helpful in the
management of secondary symptoms of schizophrenia, such as
hallucinations, tension, and suspiciousness.
It also shows antidepressant property.

28. Loxapine succinate
 Exist as white to off-white crystalline powder, slightly soluble in
water or alcohol.
 It may give rise to possible anticholinergic and antiadrenergic
activity. It must be employed with great caution in such patients
who have either a history of glaucoma or urinary retention
problems.
 It has resulted from the expansion of the six-member central ring of
phenothiazine followed by isosteric replacement of one or more
atoms with oxygen.
 Because of its seven-member central ring, the conformation
of loxapine is more twisted than that of the phenothiazine rings.
It is used for symptomatic control of schizophrenia.

29. Clozapine
 It is a yellow crystalline powder, dissolves in dilute acetic acid,
insoluble in water, freely soluble in methylene chloride, and soluble
in alcohol.
 It has more affinity for D1 and less for D2 dopamine receptors.
Selective to D4
 It may have its unique profile due to the blockade of D1 receptors
and M1 muscarinic activity.
 It has high potentially fatal agranulocytosis. Other adverse side
effects include drowsiness, dizziness, and dose related seizures.
 It is effective in individuals suffering from disorganization. For
example, loose associations, inappropriate affect, incoherence, and
reduction in rational thought processes.

30. Fluorobutyrophenones

31. Haloperidol

32. Droperidol

33. Risperidone

34. Beta amino ketones:
Molindone HCl
Exists as white crystals, freely soluble in water or alcohol
It is a potent antipsychotic as trifluoperazine and all the side
effects resemble those of the phenothiazines.
It is used in the treatment of schizophrenia and other psychosis.

35. Benzamides: Sulpiride
N-[(1-ethylpyrrolidin-2-yl)methyl]-2-methoxy-5-
sulfamoylbenzamide
A dopamine D2-receptor antagonist. It has been used therapeutically
as an antidepressant, antipsychotic, and as a digestive aid.