Structure–intrinsic activity relationship studies in the group of 1-imido/amido substituted 4-(4-arylpiperazin-1-yl)cyclohexane derivatives; new, potent 5-HT1A receptor agents with anxiolytic- like activity

Abstract: Introduction of 1,4-disubstituted cyclohexane ring in the structure of flexible long chain arylpiperazines resulted in linearly constrained, potent serotonin (5-HT)1A ligands. In order to trace structure–intrinsic activity relationships in this group, a new series of 1-substituted 4-(4-arylpiperazin-1-yl)cyclohexane derivatives with different cyclic imide/amide termini, and their flexible, tetramethylene analogues were synthesized and pharmacologically evaluated for 5-HT1A receptors. In vitro binding experiments revealed that all the compounds were potent 5-HT1A receptor agents (K i =1.9–74nM). Some derivatives tested additionally showed also high affinity for α1-adrenergic receptors (K i =2.9–101nM) and for 5-HT7 receptors. Functional in vivo examination revealed that rigid ligands with o-OCH3 group in the aryl moiety and cyclic imide system in the opposite terminal behaved like postsynaptic 5-HT1A receptor antagonists. On the other hand, unsubstituted, m-Cl, or m-CF3 substituted derivatives as well as those with cyclic amide group in the terminal fragment exhibited agonistic or partial agonistic activity. Three out of four derivatives tested, that is, postsynaptic 5-HT1A antagonists 9 and 10, and partial agonist 16, showed anxiolytic-like activity in the conflict drinking (Vogel) test in rats. [Copyright &y& Elsevier]