Synthesis and Evaluation of Aryl Substituted Propyl Piperazines for Potential Atypical Antipsychotic Activity.

BACKGROUND: Schizophrenia is a disorder with complex etiology with hyperdopaminergia as the leading underlying cause. Atypical antipsychotics are the agents which do not give rise to significant extrapyramidal side effects and are more effective against negative symptoms of schizophrenia. INTRODUCTION: A new series of chloro-substituted substituted aryloxypiperazine derivatives and their indole based derivatives was designed and evaluated for atypical antipsychotic activity based on established models for combined dopaminergic and serotonergic antagonism. METHODS: The present series of compounds were designed based on 3D similarity studies, synthesized and evaluated for atypical antipsychotic activity in animal models for combined dopaminergic and serotonergic antagonism. The blood-brain barrier penetration potential was assessed from theoretical log BB values computed through an online software program. RESULTS: Theoretical ADME profiling of the designed compounds based on selected physicochemical parameters suggested excellent compliance with Lipinski's rules. The log BB values obtained for the compounds suggested a good potential for brain permeation. Indole substitution contributed towards an improved efficacy over aryloxy analogs. Lead compounds showed a potential for combined dopaminergic and serotonergic antagonism. CONCLUSION: The 5-methoxy indole based compounds 16 and 17 were identified as the lead compounds displaying a potential atypical antipsychotic profile.

Synthesis, docking and pharmacological evaluation of novel indole based potential atypical antipsychotics.

A series of substituted indole derivatives have been synthesized and the target compounds evaluated for atypical antipsychotic activity in apomorphine induced mesh climbing and stereotypy assays in mice. The compounds 11 and 12 have emerged as important lead compounds showing potential atypical antipsychotic profile. In silico (docking studies) have been carried out to postulate a hypothetical binding model for the target compounds with respect to the dopaminergic D2 and 5-HT2A receptors. Theoretical ADME profiling of the compounds based on selected physicochemical parameters has suggested an excellent compliance with Lipinski's rules. The potential of these compounds to penetrate the blood brain barrier (log BB) was computed through an online software program and the values obtained for the compounds suggest good potential for brain permeation.