Design, Synthesis and Evaluation of Novel Phenothiazines as Antipsychotic Agents

The present work relates to novel phenothiazines derivatives as antipsychotic agents. The introduction of the Chlorpromazine (a Phenothiazine class drug) in 1952 was positive advance in the treatment of psychosis. Phenothiazines constitute one of the most active classes of compounds possessing diversified biological applications and are the most commonly used class of antipsychotic agents. Phenothiazines mainly act by antagonism of the D₂ receptors and are thus useful for the treatment of the positive symptoms and have very little effect on negative symptoms or cognitive deficits.

In addition, blockade of dopamine D₂ receptors leads to an increase in prolactin secretion and associated neuroendocrine disorders including gynecomastia, amenorrhea, and sexual dysfunction. The antipsychotic efficacy of typical neuroleptics is related to the D₂ receptor blockade. D₂ receptor is one of the G protein coupled receptors family that also includes the D₃ and D₄ receptor subtypes. And it was found that the D₄ receptor density is elevated in schizophrenia.

About six fold increases in the D₄ receptor subtype have been reported in schizophrenic brains, compared with normals. Autoradiographic analyses with the D₄ selective ligand ³H-NGD 94-1 show D₄ sites to be dense in rat and human hippocampus, hypothalamus, and neocortex, among other brain regions, and to be absent in the striatum. These findings suggested that a D₄-specific compound might treat schizophrenia as effectively as Clozapine but without the D₂ antagonist-mediated EPS or the Clozapine constellation of side effects.

We undertook a plan of building pyrazoline ring fused with the nucleus of phenothiazine. The preliminary pharmacological screening of the synthesized compounds revealed that out of the 12 compounds synthesized 6 compound (3a,3c,3d,3f,3j,3l) displayed significant activity.