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

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-HT 7 . The results exhibited that compound 5a showed strong binding to 5-HT 1A and 5-HT 7 (K i of 0.46 nM, 2.7 nM, respectively) and a high level of serotonin reuptake inhibition (IC 50 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.