Synthesis and antidepressant activity of novel 1-(1-benzoylpiperidin-4-yl) methanamine derivatives selectively targeting SSRI/5-HT1A.

A series of novel 1-(1-benzoylpiperidin-4-yl) methanamine derivatives were synthesized and evaluated for the serotonin reuptake inhibitory abilities and binding affinities to the 5-HT1A receptor. The metabolic stabilities of these compounds were measured in vitro using human or mouse liver microsomes and the antidepressant activities were explored In vivo using the forced swimming test (FST) and tail suspension test (TST) in mice. The results indicated that the compound 12a exhibited strongest serotonin reuptake inhibition (IC50 = 8.2 nM) and marked 5-HT1A receptor affinity (Ki = 0.069 nM), which were significantly superior to lead compounds Ⅰ and Ⅱ. Meanwhile, compound 12a showed good metabolic stability in vitro and exhibited potential antidepressant-like effects in the FST and TST in mice.