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首页> 外文期刊>European Journal of Medicinal Chemistry: Chimie Therapeutique >Active conformation of some arylpiperazine postsynaptic 5-HT(1A) receptor antagonists.
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Active conformation of some arylpiperazine postsynaptic 5-HT(1A) receptor antagonists.

机译：某些芳基哌嗪突触后5-HT（1A）受体拮抗剂的主动构象。

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摘要

The synthesis and pharmacological properties of novel conformationally restricted arylpiperazine (2b-4b) or 1,2,3,4-tetrahydroisoquinoline (5b and 6b) derivatives of the known, flexible 5-HT(1A) receptor ligands 2a-6a (K(i)=0.95-7 nM) with different intrinsic activities are reported. Replacement of a tetramethylene chain with a 1e,4e-disubstituted cyclohexane ring in the structure of flexible ligands resulted in insignificant diminution of the 5-HT(1A) receptor affinity in the case of 2b-4b (K(i)=15-52 nM), whereas derivatives 5b and 6b were practically inactive (K(i)>1354 nM). The results of in vivo behavioural tests showed that 2a and 3a acted as postsynaptic 5-HT(1A) receptor partial agonists. Like the flexible 4a, the new rigid compounds 2b-4b showed features of postsynaptic 5-HT(1A) receptor antagonists. Since all possible conformations of the constrained compounds belong to an extended family--as indicated by molecular modelling studies--our hypothesis that such conformations are responsible for the blockade of postsynaptic 5-HT(1A) receptors has been confirmed. Determination of regions explored by terminal amide, or imide and hydrocarbon groups of the restricted compounds as well as the results of in vitro and in vivo studies allowed us to discuss the bioactive conformations of flexible ligands.
机译：已知的柔性5-HT（1A）受体配体2a-6a（K（ i）= 0.95-7 nM）具有不同的内在活性。在2b-4b（K（i）= 15-52）的情况下，在柔性配体结构中用1e，4e-二取代的环己烷环取代四亚甲基链导致5-HT（1A）受体亲和力的降低不明显nM），而衍生物5b和6b实际上没有活性（K（i）> 1354 nM）。体内行为测试的结果表明2a和3a充当突触后5-HT（1A）受体部分激动剂。像柔性4a一样，新的刚性化合物2b-4b显示出突触后5-HT（1A）受体拮抗剂的特征。由于分子化合物研究表明，受约束化合物的所有可能构象均属于一个大家族，因此我们已经证实了这种构象导致突触后5-HT（1A）受体阻断的假设。确定末端酰胺或限制化合物的酰亚胺基和烃基所探索的区域以及体外和体内研究的结果使我们能够讨论柔性配体的生物活性构象。

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