Synthesis and Evaluation of Antidepressant‐like Activity of Some 4‐Substituted 1‐(2‐methoxyphenyl)Piperazine Derivatives

A series of new derivatives of N ‐(2‐methoxyphenyl)piperazine have been synthesized for their affinity toward serotonergic receptors and for their potential antidepressant‐like activity. They have been evaluated toward receptors 5‐HT 1A , 5‐HT 6 , and 5‐HT 7 , as well as in vivo in the tail suspension, locomotor activity, and motor co‐ordination tests. All the tested compounds proved very good affinities toward 5‐HT 1A and 5‐HT 7 receptors. The most promising compound was 1‐[(2‐chloro‐6‐methylphenoxy)ethoxyethyl]‐4‐(2‐methoxyphenyl)piperazine hydrochloride, exhibiting affinity toward receptors K i <1 n m (5‐HT 1A ) and K i  = 34 n m (5‐HT 7 ). Antidepressant‐like activity (tail suspension test) was observed at 2.5 mg/kg b.w. (mice, i.p.), and the effect was stronger than that observed for imipramine (5 mg/kg b.w.). Sedative activity was observed at ED 50 (locomotor test, mice, i.p.) = 17.5 mg/kg b.w. and neurotoxicity was observed at TD 50 (rotarod, mice, i.p.) = 53.2 mg/kg b.w.