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首页> 外文期刊>Journal of Medicinal Chemistry >Predictive models for GABAA/benzodiazepine receptor subtypes: studies of quantitative structure-activity relationships for imidazobenzodiazepines at five recombinant GABAA/benzodiazepine receptor subtypes (alphaxbeta3gamma2 (x = 1-3, 5, and 6)) via c
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Predictive models for GABAA/benzodiazepine receptor subtypes: studies of quantitative structure-activity relationships for imidazobenzodiazepines at five recombinant GABAA/benzodiazepine receptor subtypes (alphaxbeta3gamma2 (x = 1-3, 5, and 6)) via c

机译：GABAA /苯并二氮杂receptor受体亚型的预测模型：通过c通过5种重组GABAA /苯并二氮杂receptor受体亚型（alphaxbeta3gamma2（x = 1-3、5和6））对咪唑并苯并二氮杂s进行定量构效关系研究

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摘要

Affinities of a series of substituted imidazobenzodiazepines at recombinant alpha1beta3gamma2, alpha2beta3gamma2, alpha3beta3gamma2, alpha5beta3gamma2, and alpha6beta3gamma2 GABAA/benzodiazepine receptor subtypes are reported. Many of these ligands displayed high affinities (low-nanomolar to subnanomolar scale) at all five receptor subtypes. Furthermore, a number of imidazobenzodiazepines exhibited relatively good selectivity at the alpha5-containing receptor isoform. For example, ligand 27 (RY-023) demonstrated a 55-fold higher selectivity at alpha5beta3gamma2 isoforms in comparison to other receptor subtypes. The affinity ratio of alpha1 (the most prevalent subtype in the brain) to alpha5 of this series of ligands ranged from 60- to 75-fold for the most selective ligands. Studies of quantitative structure-activity relationships (QSAR) by means of comparative molecular field analysis (CoMFA) were carried out. As a result, examination of CoMFA models for all five receptor subtypes demonstrated their predictability for affinities of imidazobenzodiazepines at the five receptor subtypes. Regions of molecular fields which would favor or disfavor the binding affinity of a ligand at a specific receptor subtype were examined via CoMFA for alpha1, alpha2, alpha3, alpha5, and alpha6 subtypes. A CoMFA regression analysis was applied to predict the ratio of Ki alpha1/Ki alpha5, an index for the selectivity of a ligand at the alpha5 subtype. All of the CoMFA models offered good cross-validated correlations for the ligands in the test set as well as the ratios of Ki alpha1/Ki alpha5, which demonstrated their potential for prediction.
机译：报道了一系列取代的咪唑并苯并二氮杂at在重组α1β3γ2，α2β3γ2，α3β3γ2，α5β3γ2和α6β3γ2GABAA /苯并二氮杂receptor受体亚型的亲和力。这些配体中的许多在所有五个受体亚型上都表现出高亲和力（低纳摩尔级至亚纳摩尔级）。此外，许多咪唑并苯并二氮杂at对含α5的受体同工型表现出相对较好的选择性。例如，与其他受体亚型相比，配体27（RY-023）对alpha5beta3gamma2亚型的选择性高55倍。该系列配体的alpha1（大脑中最普遍的亚型）与alpha5的亲和力比，对于最具有选择性的配体而言，范围是60到75倍。通过比较分子场分析（CoMFA）研究了定量构效关系（QSAR）。结果，对所有五个受体亚型的CoMFA模型进行了检查，结果表明它们对咪唑并二氮杂卓在这五个受体亚型上的亲和力具有可预测性。通过CoMFA检查了α1，α2，α3，α5和α6亚型的分子场区域，该区域有利于或不利于配体对特定受体亚型的结合亲和力。应用CoMFA回归分析来预测Ki alpha1 / Ki alpha5的比率，Ki alpha1 / Ki alpha5的比率是α5亚型配体选择性的指标。所有CoMFA模型都为测试集中的配体以及Ki alpha1 / Ki alpha5的比率提供了良好的交叉验证相关性，这证明了它们的预测潜力。

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