CNS - Antipsychotics

MEDICINAL CHEMISTRY II
B. PHARMACY II/IV (SECOND SEM.)
ANTI PSYCHOTICS
Dr. K. Purna Nagasree
M.Pharm. (BITS, Pilani), Ph.D., PDF (DST, WOSA)
EX-BITS, Pilani Faculty

Anti Psychotics/ Major tranquillizers/
Neuroleptics/ psychotropics
 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

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.
 (due to excess dopamine in mesolimbic pathway)

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.
(due to shortage of dopamine in
mesocortical pathway)
In addition, many of these drugs also act as
skeletal muscle relaxants,
antihypertensives, antiemetics, and
antiepileptics.

Antipsychotics: MOA
All antipsychotics except cloazapine have potent
dopamine (D2) receptor blocking action.
Phenothiazines and thioxanthenes 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.

Antipsychotics : MOA
 Clozapine, Risperidone, Sulpiride and
Fluorobutyrophenones and other atypical
antipsychotics have significant 5-HT2 and α1
blocking action and are relatively selective for D4
receptor.

Mechanism of action
 All typical antipsychotic agents currently employed clinically
block post-synaptic dopaminergic D 2 receptors in the
mesolimbic and prefrontal cortex regions of the brain, and act as
a competitive antagonist of dopamine.
 The blockade of D 2 receptors is responsible for decreasing the
positive symptoms of schizophrenia.
 For example, drugs of the phenothiazine series are non-selective,
competitive D 1 and D 2 antagonists.
 Unlike phenothiazines, antipsychotics of the butyrophenone
series such as haloperidol display selective action only on D 2
receptors

Side-effects
 Classical antipsychotic agents do not selectively block D2
receptors present in the mesolimbic and prefrontal cortex
regions of the brain; it also blocks dopamine D2 receptors in the
nigrostriatal region of brain, which controls the motor function.
 Because of the inhibition of D2 striatal receptor, it causes:
1. Extra-pyramidal side-effects (EPS) that include acute dystonic
reaction characterized by spasm of the tongue, face, and neck,
and akathesia characterized by restlessness
2. Tardive dyskinesia, involving movement of the lips, tongue, and
mouth, and purposeless motions of the extremities
3. Increase in prolactin levels by a block of dopamine receptors in
the hypothalamus and leads to galactorrhea

classification
 Typical antipsychotics/first generation/Classical
1. Phenothiazines 2.Thioxanthines
3. Butyrophenone derivatives: Haloperidol, Droperidol
4. Diphenylbutyl piperidines: Pimozide
5. Dibenzoxazepine: Loxapine
6. Dihydroindole: Molidone 7. Newer drugs
 Atypical antipsychotics/second generation –eg. clozapine

classification
1. Phenothiazine derivatives
Piperacetazine

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

3. Fluorobutyrophenones
 Benzisoxazoles - Risperidone

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

6. Benzodiazepines – Chlordiazepoxide, lorazepam,
oxazepam
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

Promazine HCl
 It has low clinical potency, medium
extrapyramidal toxicity, high sedative
effect, and high hypotensive action.
 It is used as dopamine receptor
antagonist and neuroleptic.
N,N-dimethyl-3-phenothiazin-10-yl
propan-1-amine;hydrochloride

Chlopromazine HCl*
 Metabolism: It is demethylated, sulphoxidized,
hydroxylated, and glucuronidated to yield 7-o-glu-nor
chlorpromazine
 The drug has significant sedative and hypotensive
properties
 Used as dopamine receptor antagonist and
neuroleptic.
3-(2-chlorophenothiazin-10-yl)-N,N-
dimethylpropan-1-amine

Triflupromazine
 It has lower sedative and hypotensive
effects than chlorpromazine, and greater
potency as an antipsychotic
 used as dopamine receptor antagonist
and neuroleptic.
N,N-dimethyl-3-[2-(trifluoromethyl)phenothiazin-10-yl]propan-
1-amine

Thioridazine HCl
 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 of psychotic disorders, used as
Dopamine receptor antagonist and neuroleptic.
10-[2-(1-methylpiperidin-2-yl)ethyl]-2-
thiomethyl-phenothiazine;hydrochloride

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

Prochlorperazine maleate
 It is more potent than chlorpromazine because of the
high 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.
2-chloro-10-[3-(4-methylpiperazin-1-
yl)propyl]phenothiazine

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)-10-phenothiazine
hydrochloride

Phenothiazines:
SAR
 Examination of X-ray structures of dopamine and chlorpromazine
 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.
 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.

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/cyclopropane
decreases antipsychotic activity and produces
imipramine-like activity.
 When oxygen is introduced into C-1 results in potent
antidepressant effect.

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
pyrrolidinyl, morpholinyl, or thiomorpholinyl groups. However,
piperidine or piperazine is more potent than dimethylamino
group.
 Introduction of OH, CH3, CH3CH2 OH at C-4 of piperazine results
in increased activity.

Phenothiazines: SAR
3. Phenothiazine ring
 Substitution at C-2 position is optimal for neuroleptic
activity. potency at different positions/groups increases in
the following order 1 < 4 < 3 < 2……… 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.
 Oxidation of the sulphur at 5th position decreases activity.

Ring analogues of
phenothiazines

Chlorprothixene
2-Chloro-9-(3’-dimethylaminopropylidene) thioxanthene
It is used in the treatment of acute and chronic schizophrenia
Metabolism: Thioxanthenes are closely related to the
phenothiazine in their pharmacologic effects most of the
thioxanthine do not form ring hydroxylated derivatives.

Thiothixene
 The substituent in the second position produces Z
and E isomers. The Z isomers are the more active
antipsychotic isomers.
 An antipsychotic agent useful in the management
of schizophrenia and other psychotic states.
It also shows antidepressant property
N,N-Dimethyl-9-[3-(4-methyl-1-
piperazinyl)propylidene thioxanthene-2-
sulphonamide

Loxapine succinate
 It must be employed with great caution in patients
with glaucoma or urinary retention problems.
 Dibenzoxazepine
 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.

Clozapine Atypical Antipsychotic
 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.
8-Chloro-11-(4-methyl-1-piperazinyl)-5 H -dibenzo[b,e]
[1,4]diazepine
D 4 receptor antagonist
Dibenzodiazepines

 Clozapine has been beneficial in the treatment
of so-called ‘ treatment-resistant ’ cases – the
30% to 60% of cases where traditional
neuroleptics have not been successful.
 also relieves many of the negative symptoms,
while lacking many of the extra-pyramidal
side-effects associated with the
phenothiazines.

Fluoro butyrophenones
atypical antipsychotic

Haloperidol
 It is a drug of choice forTourett’s syndrome.
 Haloperidol is an effective neuroleptic and
antiemetic
 It is metabolized by oxidative N-dealkylation. The
principal metabolites are 4-flurobenzoyl propionic
acid and 4-fluro phenylaceturic acid
4-[4-( p -Chlorophenyl)-4-hydroxypiperidino]-4’-fluorobutyrophenone

Droperidol
1-{1-[3-( p -Fluorobenzoyl)propyl]-tetrahydro-4-pyridyl}–2-benzimidazolinone
The drug exhibits relatively low therapeutic potency, medium
extrapyramidal toxicity, high sedative effect, and high hypotensive
action.
It is frequently used in combination with the narcotic agents pre-
anaesthetically.
It is a neuroleptic used as an adjunct to anaesthesia to produce
sedation and reduce incidence of nausea and vomiting.

SAR of Butyrophenones
 Antipsychotic activity is seen when Ar group is an aromatic system in which
fluoro-substituents at para-position enhances the activity.
 When X = carbonyl ( C = O) optimal activity is seen, although other groups
C(H)OH, C(H) aryl (pimozide) also afford good activity.
 When n = 3 activity is optimal, longer, or shorter chains decrease the activity.
 Aliphatic amino nitrogen is required and highest activity is seen when it is
incorporated into a cyclic form
 Ar1 group should be an aromatic and is needed; it should be attached directly to
the fourth position
 or occasionally separated from it by one intervening atom.
 TheY group can vary and assist the activity.
 The empirical SARs could be constructed to suggest that the 4-aryl piperidino
moiety is super imposable on the 2-phenyl ethyl amino moiety of dopamine and
accordingly could promote affinity for D2 and D3 receptors.
 The long N-alkyl substituent could help to promote receptor affinity and produce
receptor antagonism activity (or) inverse agonism.

Risperidone
Mixed D 2 and 5HT 2A antagonist
It is a uniquely balanced serotonin/dopamine antagonist (SDA)
that offers considerable advantages in the first-line treatment of
schizophrenia
It is a typical antipsychotic, effective against the negative
symptoms of schizophrenia
Its adverse effects include nasal congestion, orthostastic
hypotension, insomnia, and possible EPS. May cause weight gain
and an increased tendency for glucose intolerance.
3-[2-[4-(6-fluoro-1,2- benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-
methyl-pyrido pyrimidin-4-one.

Beta amino ketones
Molindone HCl
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.

Benzamides:
Sulpiride
 It has a role as an antidepressant, an
antiemetic, an antipsychotic agent and a
dopaminergic antagonist.
N-[(1-ethylpyrrolidin-2-yl)methyl]-2-methoxy-5-sulfamoylbenzamide
atypical antipsychotic

bioisosteres
 The requirement for bioisosteres to have similar spatial and
electronic character is illustrated below.
 The phenothiazine ring system, on the left, is commonly found
in anti-psychotic drugs such as chlorpromazine.
 The phenothiazine ring is planar due to the two aromatic rings
and the intervening sulphur, which has 4 π electrons.
 If the sulphur is replaced by a double bond, the ring retains its π
character, and the resulting dibenzazepine retains anti-
psychotic activity.
 When the double bond is reduced, the ring is no longer planar,
as shown below left.
 These compounds do not act as neuroleptics, and in fact have
no CNS activity.
 They are mainly used as antihistamines.

CNS - Antipsychotics

More Related Content

What's hot (20)

Similar to CNS - Antipsychotics (20)

More from Purna Nagasree K (9)

Recently uploaded (20)

CNS - Antipsychotics

Editor's Notes