Studies of molecular pharmacophore/receptor models for GABAA/benzodiazepine receptor subtypes: binding affinities of substituted beta-carbolines at recombinant alpha x beta 3 gamma 2 subtypes and quantitative structure-activity relationship studies via a comparative molecular field analysis.

Drug design and discovery Pub Date : 1999-07-01
Q Huang, E D Cox, T Gan, C Ma, D W Bennett, R M McKernan, J M Cook
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Abstract

Binding affinities of a series of 44 beta-carbolines with various substituents at the 3-, 4-, 6- and 7-positions are reported at 5 distinct recombinant GABAA/benzodiazepine receptor (BzR) subtypes [alpha x beta 3 gamma 2 (x = 1-3, 5, 6)]. Many of these ligands displayed better selectivity for the alpha 1 containing GABAA isoform. The most selective BCCT 2 and SPH 195 (17) displayed potent affinity (Ki = 0.72 and 7.2 nM for the alpha 1 beta 3 gamma 2 receptor subtype, respectively) and an overall selectivity of 20 and 23 fold, respectively, for the alpha 1 beta 3 gamma 2 receptor subtype. These are the most selective ligands in vitro for the alpha 1 containing GABAA/Bz receptor isoform reported to date to our knowledge. QSAR studies of these ligands for each receptor subtype have been carried out via a Comparative Molecular Field Analysis (CoMFA) and an included volume analysis. Geometries and charge distributions of these ligands have been optimized using ab initio methods (J. Med. Chem., 1992, 35, 4001-4010). Active conformations of flexible 3-alkoxylated beta-carbolines have been examined via a CoMFA approach. QSAR studies via CoMFA support the previous hypothesis that beta-carbolines with different intrinsic activities may follow an alternative alignment rule when they bind into the pharmacophore/receptor site of the BzR. Examination of binding affinities of beta-carbolines by this modeling strategy has established some of the differences, in particular, topologic differences between the lipophilic pockets in the alpha 1 beta 3 gamma 2, alpha 2 beta 3 gamma 2, alpha 3 beta 3 gamma 2, alpha 5 beta 3 gamma 2 and alpha 6 beta 3 gamma 2 subtypes as well as some of the similarities among the pharmacophore/receptor models of these five distinct GABAA/Bz receptor subtypes.

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GABAA/苯二氮卓受体亚型的分子药效团/受体模型研究:通过比较分子场分析取代β -碳卡啉在重组α x β 3 γ 2亚型上的结合亲和力和定量构效关系研究。
据报道,在5种不同的重组GABAA/苯二氮卓受体(BzR)亚型[α x β 3 γ 2 (x = 1- 3,5,6)]中,44种β -羰基与不同取代基在3-、4-、6-和7-位置上的结合亲和性。许多这些配体对含有GABAA的α 1异构体表现出更好的选择性。选择性最高的bcct2和SPH 195(17)对α 1 β 3 γ 2受体亚型表现出强大的亲和力(Ki分别为0.72和7.2 nM),对α 1 β 3 γ 2受体亚型的总体选择性分别为20倍和23倍。这些是迄今为止据我们所知报道的含有GABAA/Bz受体异构体的α 1体外选择性最强的配体。通过比较分子场分析(CoMFA)和包括体积分析,对每种受体亚型的这些配体进行了QSAR研究。这些配体的几何形状和电荷分布已经用从头算方法优化(J. Med. Chem.)。科学通报,1992,35,4001-4010)。柔性3-烷氧基化β -碳胺的活性构象已通过CoMFA方法进行了检查。通过CoMFA进行的QSAR研究支持了先前的假设,即具有不同内在活性的β -碳卡啉在结合到BzR的药效团/受体位点时可能遵循另一种排列规则。检查绑定亲和力藤本植物的建模策略建立了一些差异,特别是网络拓扑之间的差异的亲脂性的口袋α1β3γ2,α2β3γ2,α3βγ2、α5β3γ2和α6β3γ2亚型之间的相似之处以及一些药效基因/这五个不同的对GABAA受体模型/ Bz受体亚型。
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