Discovery of Novel Indolealkylpiperazine Derivatives as Potent 5-HT_1A Receptor Agonists for the Potential Future Treatment of Depression

Abstract

Depression is a severe psychiatric disorder that affects over 100 million people worldwide. 5-HT1A receptor agonists have been implicated in the treatment of a variety of central nervous system diseases, especially depression. In this study, based on FW01, a selective potent 5-HT1AR agonist discovered via dynamic pharmacophore-based virtual screening, a series of indolealkylpiperazine derivatives with a benzamide moiety were designed and synthesized by the modification of the amide tail group as well as indole head group of FW01. Among all tested compounds, 13m displayed potent agonistic activity towards 5-HT1AR with an EC50 value of 1.01 nM. Molecular docking studies were performed to disclose the mechanism of its potent agonistic activity and high selectivity. Finally, the activation model of 5-HT1AR induced by 13m was proposed.

Keywords

• 5-HT_1A receptor agonist
• depression
• drug design
• molecular dynamics