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Chem Biol Drug Des. 2015 Mar;85(3):326-35. doi: 10.1111/cbdd.12394. Epub 2014 Aug 14.

Synthesis and evaluation of antidepressant-like activity of some 4-substituted 1-(2-methoxyphenyl)piperazine derivatives.

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Department of Bioorganic Chemistry, Chair of Organic Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688, Krakow, Poland.


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 Ki <1 nm (5-HT1A ) and Ki = 34 nm (5-HT7 ). 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 ED50 (locomotor test, mice, i.p.) = 17.5 mg/kg b.w. and neurotoxicity was observed at TD50 (rotarod, mice, i.p.) = 53.2 mg/kg b.w.


(2-methoxyphenyl)piperazine; 5-HT; antidepressant-like activity; chimney test; locomotor test; neurotoxicity; rotarod; tail suspension test

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