Discovery of aryl-biphenyl-2-ylmethylpiperazines as novel scaffolds for 5-HT7 ligands and role of the aromatic substituents in binding to the target receptor

It has been reported that 5-HT₇ receptors are promising targets of depression and neuropathic pain. 5-HT₇ receptor antagonists have exhibited antidepressant-like profiles, while agonists have represented potential therapeutics for pain. In the course of our ongoing efforts to discover novel 5-HT₇ modulators, we designed an arylpiperazine scaffold with a substituted biphenyl-2-ylmethyl group. A series of biphenyl-2-yl-arylpiperazinylmethanes were then prepared, which showed a broad spectrum of binding affinities to the 5-HT₇ receptor depending upon the substituents attached to the biphenyl and aryl functionalities. Among those synthesized compounds, the compounds 1–24 and 1–26 showed the best binding affinities to the 5-HT₇ receptor with K_i values of 43.0 and 46.0 nM, respectively. Structure–activity relationship study in conjunction with molecular docking study proposed that the 5-HT₇ receptor might have two distinctive hydrophobic binding sites, one specific for aromatic 2-OCH₃ substituents within the arylpiperazine and the other for biphenyl methoxy group.