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Bojarski AJ, Paluchowska MH, Duszynska B, Bugno R, Klodzinska A, Tatarczynska E, Chojnacka-Wojcik E: 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. Bioorg Med Chem. 2006 Mar 1;14(5):1391-402. Epub 2005 Nov 2. 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-HT (1A) receptors. In vitro binding experiments revealed that all the compounds were potent 5-HT (1A) receptor agents (K (i) = 1.9-74 nM). Some derivatives tested additionally showed also high affinity for alpha (1)-adrenergic receptors (K (i) = 2.9-101 nM) and for 5-HT (7) receptors. Functional in vivo examination revealed that rigid ligands with o-OCH (3) group in the aryl moiety and cyclic imide system in the opposite terminal behaved like postsynaptic 5-HT (1A) receptor antagonists. On the other hand, unsubstituted, m-Cl, or m-CF (3) 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-HT (1A) antagonists 9 and 10, and partial agonist 16, showed anxiolytic-like activity in the conflict drinking (Vogel) test in rats. |
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