Design synthesis and evaluation of arylamino propoxyphenyl indoles for potential atypical antipsychotic activity.

Abstract

<h4>Introduction</h4>A series of substituted indole derivatives have been synthesized and evaluated for their atypical antipsychotic activity Compared to traditional neuroleptics, second-generation or "atypical" antipsychotics offer a more favorable therapeutic profile against both positive and negative symptoms of schizophrenia.<h4>Methods</h4>The compounds were designed based on their physicochemical similarity studies to standard drugs and <i>in silico</i> (docking studies) with 5-HT_2A and D₂ receptors. The prepared compounds were evaluated for atypical antipsychotic activity in animal models of dopaminergic (apomorphine-induced mesh climbing behavior and stereotypy) and serotonergic antagonism (1-(2,5-dimethoxy-4-iodophenyl)-2 aminopropane (DOI) induced head twitch assay). All the test compounds showed. 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.<h4>Results</h4><i>In-silico</i> (docking studies) suggested good binding of the test compounds to the 5-HT_2A and D₂ receptors and a hypothetical binding model for the target compounds was postulated. The prepared test compounds, designated as <b>8 to 15</b>, exhibited an atypical antipsychotic profile in the pharmacological assays with a mechanistic profile of combined 5-HT_2A and D₂ antagonism.<h4>Conclusion</h4>The study has afforded novel indole-based lead molecules with potential atypical antipsychotic effect.