Synthesis and pharmacological evaluation of new arylpiperazines N-{4-[4-(aryl) piperazine-1-yl]-phenyl}-amine derivatives: Putative role of 5-HT1A receptors

In an attempt to design novel 5-HT1A agonists/partial agonists, based on an arylpiperazine nucleus, a series of N-{4-[4-(aryl)piperazine-1-yl]-phenyl}-amine derivatives were synthesized and biologically tested. The anxiolytic effect of the compounds was investigated employing the Elevated plus Maze (EPM) task. On the basis of in vivo functional test, compound 1c (3 mg/kg) and 4c (3 mg/kg) induced significant increments in open arm entries and time on EPM as compared to Buspirone. The anxiolytic effects of compounds 1c and 4c were effectively antagonized by WAY-100635, a 5-HT1A receptor antagonist (0.5 mg/kg). Furthermore, we have also evaluated the concentration of 5-HT in the brain tissue using HPLC with fluorescent detection. Our result showed that serotonin levels were significantly decreased by ∼38% (p < 0.001) and ∼32% (p < 0.001) after acute administration of compounds 1c and 4c, respectively. These findings suggest that the anxiolytic like activity of these new arylpiperazines is mediated via 5-HT1A receptors in the brain.

A series of N-{4-[4-(aryl)piperazine-1-yl]-phenyl}-amine derivatives(1c–4e) were synthesized and evaluated for their anxiolytic activity. Serotonin levels were also determined by HPLC for possible involvement of 5-HT1A receptors. Compounds 1c and 4c were found to be good anxiolytics.Figure optionsDownload as PowerPoint slide