Phenothiazines: Structural Activity Relationship (SAR)

Phenothiazine is a anti-psychotic, which are not CNS depressants. Long term use of Phenothiazine do not cause dependence and addiction.

Structural Activity Relationship of Phenothiazine:
1) Substitution at the second position of phenothiazine nucleus by electron withdrawing substituent increases antipsychotic activity.
Ex: Chlorpromazine
2) Maximum antipsychotic potency observed when the nitrogen of the phenothiazine ring and side-chain nitrogen are connected by a three carbon side chain.
3) Branching at the β-position of the side chain with small methyl group decreases antipsychotic potency but enhances antihistaminic activity.
4) Substitution at the 3-position of phenothiazine nucleus increases antipsychotic activity than unsubstituted derivatives but not by substitution at 2-position.
5) Substitution at 1 and 4 positions of phenothiazine nucleus reduces the antipsychotic activity.
6) The side chains are either aliphatic, piperazine, or piperidine derivatives. Piperazine side chains confer the greatest potency and the highest pharmacological selectivity.
7) Fluphenazine and long chain alcohols form stable, highly lipophilic esters, which possess markedly prolonged activity.
8) Substitution on the side chain with large or polar groups such as phenyl, dimethylamino or hydroxyl results in loss of tranquilizing activity.
9) The phenothiazines produce a lesser degree of central depression than the barbiturates or benzodiazepines.

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