Design, synthesis, and biological evaluation of aralkyl piperazine and piperidine derivatives targeting SSRI/5-HT1A/5-HT7

Abstract

Serotonin reuptake inhibition combined with the action targeting 5-hydroxytryptamine receptor subtypes can serve as a potential target for the development of antidepressant drugs. Herein a series of new aralkyl piperazines and piperidines were designed and synthesized by the structural modifications of the previously discovered aralkyl piperidine compound 1, targeting SSRI/5-HT_1A/5-HT₇. The results exhibited that compound 5a showed strong binding to 5-HT_1A and 5-HT₇ (K_i of 0.46 nM, 2.7 nM, respectively) and a high level of serotonin reuptake inhibition (IC₅₀ of 1.9 nM), all of which were significantly elevated compared to 1. In particular, compound 5a showed weaker inhibitory activity against hERG than 1, and demonstrated good stability in liver microsomes in vitro. The preliminary screening using FST indicated that orally administered 5a, at a high dose, could reduce immobility time in mice markedly, indicating potential antidepressant activity.

Keywords: 5-HT(1A); 5-HT(7); Antidepressant; Selective Serotonin Reuptake Inhibitor (SSRI); hERG.