Discovery of Novel Indolealkylpiperazine Derivatives as Potent 5-HT(1A) Receptor Agonists for the Potential Future Treatment of Depression

Depression is a severe psychiatric disorder that affects over 100 million people worldwide. 5-HT(1A) 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-HT(1A)R 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-HT(1A)R with an EC(50) 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-HT(1A)R induced by 13m was proposed.