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异恶唑并-[3,4-d]-哒嗪-7-(6H)-酮及其相应的4,5-二取代-3-(2H)-哒嗪酮类似物作为α1-肾上腺素能受体选择性拮抗剂的新底物：合成、建模及结合研究

Isoxazolo-[3,4-d]-pyridazin-7-(6H)-ones and their corresponding 4,5-disubstituted-3-(2H)-pyridazinone analogues as new substrates for alpha1-adrenoceptor selective antagonists: synthesis, modeling, and binding studies.

作者信息

Montesano F, Barlocco D, Dal Piaz V, Leonardi A, Poggesi E, Fanelli F, De Benedetti P G

机构信息

Ist. Chimica Farmaceutica e Tossicologica, Milano, Italy.

出版信息

Bioorg Med Chem. 1998 Jul;6(7):925-35. doi: 10.1016/s0968-0896(98)00056-x.

DOI:10.1016/s0968-0896(98)00056-x
PMID:9730228
Abstract

A series of phenylpiperazinylalkyl moieties were attached to monocyclic or bicyclic substituted pyridazinones and the new compounds tested for their affinity towards alpha1-adrenoceptor and its alpha1a, alpha1b and alpha1d subtypes, as well as serotonin 5-HT1A receptor. Several analogues (5, 6, 9, and 10) showed remarkable potency and selectivity towards alpha1a, and alpha1d with respect to alpha1b subtype. None of the test compounds exhibited significant affinity for 5-HT1A receptor. Finally, on the basis of the alpha1-AR subtypes 3D models recently proposed, we have elaborated theoretical interaction models for the new compounds. The theoretical study allowed us to predict the affinity of the new compounds as well as to infer the structural/dynamics determinants of their interaction with the three alpha1-AR subtypes.

摘要

一系列苯哌嗪基烷基部分连接到单环或双环取代哒嗪酮上，并对这些新化合物针对α1-肾上腺素能受体及其α1a、α1b和α1d亚型以及5-羟色胺5-HT1A受体的亲和力进行了测试。几种类似物（5、6、9和10）对α1a和α1d相对于α1b亚型表现出显著的效力和选择性。测试化合物中没有一种对5-HT1A受体表现出显著亲和力。最后，基于最近提出的α1-AR亚型三维模型，我们为新化合物构建了理论相互作用模型。理论研究使我们能够预测新化合物的亲和力，并推断其与三种α1-AR亚型相互作用的结构/动力学决定因素。

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