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

It has been suggested that the combination of a selective serotonin reuptake inhibitor (SSRI) and a 5-HT1A 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-HT1A 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. (C) 2000 Elsevier Science S.A. All rights reserved.