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

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 = 1.9-74 nM). Some derivatives tested additionally showed also high affinity for alpha(1)-adrenergic receptors (Ki = 2.9-101 nM) 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. (c) 2005 Elsevier Ltd. All rights reserved.