Design, Synthesis and Biological Evaluation of New 3-[(4-Aryl)piperazin-1-yl]-1-arylpropane Derivatives as Potential Antidepressants with a Dual Mode of Action: Serotonin Reuptake Inhibition and 5-HT1A Receptor Antagonism.

Abstract It has been suggested that the combination of a selective serotonin reuptake inhibitor (SSRI) and a 5-HT 1A receptor antagonist may facilitate the onset of the SSRIs antidepressant action. Accordingly, we describe the synthesis of a series of new 3-[(4-aryl)piperazin-1-yl]-1-arylpropane derivatives with structural modifications performed in Ar 1 , Ar 2 and Z (Z is different functional groups) to obtain the sought dual activity. Compounds were evaluated for in vitro affinity at 5-HT 1A receptors and 5-HT transporter. The antidepressant-like activity of derivatives with the higher affinity was assessed initially using the forced swimming test (FST). Compound 1-(2,4-dimethylphenyl)-3-[(2-methoxyphenyl)piperazin-1-il]-1-propanone ( III . 1 . a ) showed the best antidepressant-like activity which was further confirmed in the learned helplessness test.