DRUGS ACTING ON CNS- ANTI PSYCHOTICS

ANTIPSYCHOTICS [TRANQUILIZERS (OR) NEUROLEPTICS]

Antipsychotic drugs are also CNS depressants. Anti psychotic drugs are drugs which are used in the treatment of mental disease that are characteristic of the psychoses which is a behavioral disorder.
These agents have the capacity to sedate or tranquilize the emotional expressions , aggressive and impulsive behavior and influence being free to mind from disturbance and thus calms the mind with out inducing sleep.
Psychosis: The psychoses are inhibition of sharpens or alter the behavioral, mood and emotional responses.
Psychiatric illness can be divided in to neuroses and psychoses.
A neurotic patient usually retains sufficient insight to realize that he is ill. But the psychotic patient have difficulty understanding reality and their own conditions, they lives in a world of his own. They are often hallucinations and delusions (paranoid in nature), thought disorders and with drawel from social contacts and flattering of emotional responses.

The most important types of psychosis are
i) Schizophrenic :
It is neurological as well as psychological disorder. So fundamental and characteristic distortions of thinking and perception.
ii) Affective (mood) disorders :
Disorders in fundamental disturbance is a change in mood to depression associated by a change is the overall activity
iii) Organic psychosis :
Mental disturbances caused by head injuries, alcoholism, or other kind of organic diseases.

Classification :

1. Rauwolfia alkaloids : Reserpine, deserpidine
2. Phenothiazine derivatives : Chlorpromazine hydrochloride, Triflupromazine, Thioridazine hydrochloride, Mesoridazine hydrochloride, Piperacetazine hydrochloride,Prochlorperazine maleate, Trifluoperazine hydrochloride.
3. Ring analogues of phenothiazines :
   i) Thioxanthines – Chlorprothixene, thiothixene
   ii) Dibenzoxazepines – Loxapine succinate
   iii) Dibenzodiazepines – Clozapine
4. Butyrophenones : Haloperidol, Droperidol, Resoperidone
5. Diphenyl methane derivatives : Pipradrol, captodiame, Hydroxyzine, benactyzine
6. beta - Aminoketones : Molindone, Ondansetron
7. Benzamides : Sulperide, Remoxipride.
8. Miscellaneous : Buspirone, Meprobamate, Tybamate

Phenothiazine derivatives :

Synthesis of chlorpromazine:

Synthesis of prochlorperazine:

Ring analogues of phenothiazines :

1. Chlorprothxene

2. Thio thixene

3. Loxapine succinate SAR for Phenothiazine derivatives :

I. Modification in tricyclic systems :

1. Most of the compounds have either a six membered central ring (6-6-6)
   (Example : phenothiazine) classes for good antipsychotic activity.
   
2. Compounds having larger central ring Example : Imipramine (7 membered) and smaller central ring Example : carbazole (5 membered ring) are lack in antipsychotic activities and produce only antidepressant activity.
   
3. Analogues of tricyclic compounds that lock a central ring (Example :Rimozide) generally devoid of antipsychotic activity.

II. Modifications of alkyl side chain at R10 :

1. The maximum potency is obtained when the nitrogen of phenothiazine and basic amino group is connected by a three carbon side chain, because it permits maximum resemblance with that of most preferred conformational form of dopamine.
   
2. Introduction of methyl group at position 1, 2 or 3 of 3 – amines propyl side chain decrease the antipsychotic activity and may result Imipramine like activity.
   
3. If the side chain may be cyclopropane ring decrease neuroleptic activities and produce potent imipramine like activity.
   
4. If oxygen is introduced in to the 1st position of 3 – amino propyl chain results potent anti depressant activities (example : Chlorthiazine).
   
5. Bridging of position 3 of side chain to position 1 of phenothiazine nucleus reduces neuroleptic activity.

III. Modifications of basic amino group :

1. Maximum neuroleptic potency is obtained in amino alkyl substituents having 30 amines group than 20 and 10 amines group containing compounds.
   
2. Alkylation of basic amino group with groups larger than methyl group decreases neuroleptic potency. Example : Diethylamine analogues.
   
3. Replacement of dimethylamine group with Pyrrolidine, morpholine groups decreases the neuroleptic potency.
   
4. The activity is retained or increased if the amino group is replaced with piperidyl or Piperazine groups. Example : Mesoridazine, carphenazine.
   
5. Bridged piperidine derivatives retains the neuroleptic activities.
   
6. Introduction of hydroxyl , methyl, hydroxy ethyl groups of piperidine and Piperazine moieties increase the potency.
   
7. N4-Piperazine substituents with phenyl ethyl, p – amino phenyl ethyl or estirified long chain fatty acids increases the activity.

IV. Phenothiazine ring substituents at R2 :

1. Substituents at position 2 is optimal for neuroleptic potency, In general, potency increases in the following order of position of ring substitution 1<>
   
2. 2 – substitution is an electron withdrawing group increases the neuroleptic activity, the potency increases in the following order OH <>
   
3. Oxidation of sulfur at 5 – position decrease the neuroleptic activity.


4. 1,2,3,4 – Azo phenothiazines are more effective. 1-Azo phenothiazine is more potent than parent compound. Example: Prothioperdyl.

Butyrophenones :

1. Haloperidol

2. Droperidol 3. Risoperidone

SAR for Butyro phenone derivatives :

1. The 4- fluro phenyl group is necessary for optimal anti psychotic activity.


2. Reduction of carbonyl group and replacement of oxygen, sulphur or sulphone decreases the neuroleptic potency.


3. The bridge between benzoyl and amino group is propyl for good activity. If lengthening, shortening or branching the propylene chain of 4-amino Butyrophenones decreases neuroleptic potency.


4. The amino group is in tertiary form or part of six membered ring like piperidine, Piperazine for good neuroleptic activity.


5. Replacement of six membered ring by larger, smaller or uncyclized diminishes neuroleptic potency.


6. Neuroleptic potency is generally associated with 4,4- disubstituted piperidine. Substitution of 2 or 3 position of piperidine decreases potency

Mechanism of action

1. The neuronal activity in brain is mediated by neuro transmitter. Dopamine is a precursor of adrenaline and nor adrenaline and also function independently as a neurotransmitter. The dopamine have been found in thalamus, hypothalamus and basal ganglia and has depressant action.


2. The control of emotional responses, the hypothalamus is closely associated with reticular and limbic system which incorporates a balanced complex of excitatory(acetyl choline) and inhibitory (dopamine) components.


3. The psychoses associated with the presence of dopamine is greater than the normal level at central synopses in striatum and other brain regions.


4. The anti psychotic drugs act by increasing metabolic rate of dopamine or blocking dopamine (D2) receptors. This results an increasing concentration of excitatory (acetyl choline) and decreasing concentration of inhibitory (dopamine) components.


5. Since anti psychotic drugs shift the balance in favour of acetyl choline. Hence all the anti psychotic drugs are always associated with extra pyramidal effect.


6. The superimposibility of the conformations of dopamine ad phenothiazine derivatives blocks the dopamine receptors, because it possess 3 carbons in side chain separating two nitrogens.