A Hydrogen Bond Influences the 5-ht1a/d4 Selectivity of Way-100635 Analogues: an in Silico Approach
نویسندگان
چکیده
WAY-100635 is widely used in vitro and in vivo as an antagonist of 5-HT 1A receptors [1]. In terms of pharmacological tools and pharmacological investigations, the ideal reference molecule would be highly selective for its target over other related and non-related targets. However WAY-100635 displays affinity for and activity at D 4 dopamine receptors, and that "off-target" activity confounds its use in pharmacological studies, particularly when both receptors are present [2]. In this context, we carried out various chemical modifications of the WAY-100635 structure in order to improve its 5-HT 1A versus D 4 selectivity. An important increase of selectivity was obtained when the basic side chain of WAY-100635 was replaced by a 4-phenylpiperazine or a 4-phenyl-1,2,3,6-tetrahydropyridine moiety [3]. In contrast, the introduction of nitrogen atoms in the acyl group decreased the selectivity by reducing the affinity for 5-HT 1A receptors, on the one hand, and enhancing the affinity for D 4 receptors on the other hand [3].
منابع مشابه
Design, Synthesis and in Vitro Evaluation of Bridgehead Fluoromethyl Analogues of N-{2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl}-N- (pyridin-2-yl)cyclohexanecarboxamide (WAY-100635) for the 5-HT1A Receptor
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