Structure-affinity studies for a novel series of homochiral naphtho and tetrahydronaphtho analogues of α1 antagonist WB-4101
Structure-affinity studies for a novel series of homochiral naphtho and tetrahydronaphtho analogues of α1 antagonist WB-4101
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DOI：
10.1016/j.bmc.2004.06.040
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发表时间：
2004-09-15
影响因子：
3.5
通讯作者：
Valoti, E
中科院分区：
文献类型：
--
作者：
Bolchi, C;Catalano, P;Valoti, E
设计并合成了WB-4101（1）的萘二氧杂环己烷、四氢萘二氧杂环己烷和萘氧基类似物的许多对映体对，以改善母体化合物的选择性，希望有利于α（1a）-AR相对于其他两种α（1）亚型和5-HT 1A受体的选择性。在对α（1a）-AR、α（1b）-AR、α（1d）-AR和5-HT 1A受体的结合试验中测试了新化合物2-8以及1的两种对映体。其中两种，即萘并-和四氢萘并二氧杂环己烷衍生物（S）-2和（S）-3，显示出比（S）-1低但显著更特异的α（1a）亲和力，而2-甲氧基-1-萘氧基类似物6的两种对映异构体保持了（S）-1的大部分非常高的α（1a）亲和性及其α（1a）对α（1b）的选择性，略微增加了α（1a）/α（1d）和α（1a）/5 HT（1A）亲和力比。根据已知的α（1）、亚型药效团和文献诱变研究所得WB-4101的α（1a）-AR结合模式评价SAR数据，这些研究揭示了与这些模型的一些有趣的一致性。(C)2004 Elsevier Ltd.保留所有权利。
A number of enantiomeric pairs of naphthodioxane, tetrahydronaphthodioxane and naphthoxy analogues of WB-4101 (1) were designed and synthesized in order to improve the selectivity profile of the parent compound, hopefully in favour of the alpha(1a)-AR with respect to the other two alpha(1), subtypes and the 5-HT1A receptor. The new compounds 2-8 and, in addition, the two enantiomers of 1 were tested in binding assays on the alpha(1a)-AR, alpha(1b)-AR, alpha(1d)-AR, and the 5-HT1A receptor. Two of them, namely the naphtho- and tetrahydronaphthodioxane derivatives (S)-2 and (S)-3, showed lower, but significantly more specific alpha(1a), affinity than (S)-1, while the two enantiomers of the 2-methoxy-1-naphthoxy analogue 6 maintained most of the very high alpha(1a) affinity of (S)-1 and its alpha(1a) versus alpha(1b) selectivity slightly increasing the alpha(1a)/alpha(1d) and alpha(1a)/5HT(1A) affinity ratios. The SAR data were evaluated in the light of known alpha(1), subtype pharmacophores and of the alpha(1a)-AR binding mode of WB-4101 resultant from literature mutagenesis studies disclosing some interesting consonances with these models. (C) 2004 Elsevier Ltd. All rights reserved.