Studies toward the discovery of the next generation of antidepressants. Part 6: Dual 5-HT 1A receptor and serotonin transporter affinity within a class of arylpiperazinyl-cyclohexyl indole derivatives

Abstract

Based on the previously reported discovery lead, 3-( cis-4-(4-(1 H-indol-4-yl)piperazin-1-yl)cyclohexyl)-5-fluoro-1 H-indole ( 2), a series of related arylpiperazin-4-yl-cyclohexyl indole analogs were synthesized then evaluated as 5-HT transporter inhibitors and 5-HT 1A receptor antagonists. The investigation of the structure–activity relationships revealed the optimal pharmacophoric elements required for activities in this series. The best example from this study, 5-(piperazin-1-yl)quinoline analog ( trans- 20), exhibited equal binding affinities at 5-HT transporter ( K i = 4.9 nM), 5-HT 1A receptor ( K i = 6.2 nM) and functioned as a 5-HT 1A receptor antagonist.