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-HT1A, 5-HT6, and 5-HT7, 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-HT1A and 5-HT7 receptors. The most promising compound was 1-[(2-chloro-6-methylphenoxy)ethoxyethyl]-4-(2-methoxyphenyl)piperazine hydrochloride, exhibiting affinity toward receptors K-i <1nm (5-HT1A) and K-i=34nm (5-HT7). Antidepressant-like activity (tail suspension test) was observed at 2.5mg/kg b.w. (mice, i.p.), and the effect was stronger than that observed for imipramine (5mg/kg b.w.). Sedative activity was observed at ED50 (locomotor test, mice, i.p.)=17.5mg/kg b.w. and neurotoxicity was observed at TD50 (rotarod, mice, i.p.)=53.2mg/kg b.w.