Molecular determinants of recognition and activation at the cerebellar benzodiazepine receptor site.
Molecular determinants of recognition and activation at the cerebellar benzodiazepine receptor site.
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小脑苯二氮卓受体位点识别和激活的分子决定因素。
DOI：
10.1016/s0968-0896(00)82053-2
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发表时间：
1994
影响因子：
3.5
通讯作者：
Loew,GH
中科院分区：
文献类型：
--
作者：
Schove,LT;Perez,JJ;Loew,GH
进行半经验量子力学和分子力学计算，以识别和表征调节小脑 GABAA/苯二氮卓 (BDZ) 受体的配体识别和激活的空间和电子特性。为了这一假设的发展，选择了属于结构不同的化学家族的 13 种化合物进行研究。在选定的化合物中，有九种与该受体有明显的亲和力结合，四种不结合，其中一些化合物是已知的激动剂、拮抗剂和反向激动剂，通过调节小脑中 GABA（γ-氨基丁酸）增强的氯离子通量来测量。从配体之间的共性推断出的识别的立体电子要求是存在三个氢键中心中的至少两个，以及处于特定空间关系的亲脂性芳环。结果表明，其中一些配体所证明的对小脑或 I 型亚型的选择性可能无法满足与其他受体结合的要求，因为缺乏质子接受中心之一或这些配体具有较大的表面积和体积。从激动剂、拮抗剂和反激动剂性质的比较中推断出，激活的要求是相对于识别成分而言，存在以特定几何排列的电子接受芳香环。通过使用所开发的“3D 药效团”来预测未用于其开发的 11 种其他化合物的行为，探讨了其有效性。
Semiempirical quantum mechanical and molecular mechanics calculations were carried out to identify and characterize the steric and electronic properties that modulate ligand recognition and activation of the cerebellar GABAA/benzodiazepine (BDZ) receptor. For this hypothesis development, thirteen compounds belonging to structurally diverse chemical families were selected for study. Among the compounds selected were nine that bind and four that do not bind with appreciable affinity to this receptor and some that are known agonists, antagonists and inverse agonists, as measured by their modulation of GABA (γ-aminobutyric acid) enhanced chloride ion flux in cerebellum. The stereoelectronic requirements for recognition deduced from commonalities among the ligands are the presence of at least two of three hydrogen bonding centers, and a lipophilic aromatic ring, in a specific spatial relationship. The results suggest that the selectivity for the cerebellar or Type I subtype, demonstrated by some of these ligands, could be failure to meet the requirements for binding at other receptors because of the absence of one of the proton accepting centers or the larger surface area and volume of these ligands. The requirement for activation, deduced from comparisons of agonist, antagonist, and inverse agonist properties is the presence of an electron accepting aromatic ring in a specific geometric arrangement with respect to the components of recognition. The validity of the ‘3D-Pharmacophore’ developed was probed by using it for predictions of the behavior of 11 additional compounds not used for its development.
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影响因子：
6.1
作者：
R. Fryer;C. Cook;N. W. Gilman;A. Walser
通讯作者：
A. Walser
影响因子：
3.6
作者：
C. Cometta-Morini;P. Maguire;G. Loew
通讯作者：
C. Cometta-Morini;P. Maguire;G. Loew
吡唑并吡啶类非苯二氮卓类抗焦虑药的临床前研究：ICI 190,622
DOI：
--
发表时间：
1988
期刊：
Pharmacology, Biochemistry and Behavior
影响因子：
--
作者：
J. Patel;B. Meiners;A. Salama;J. Malick;D. U'prichard;R. Giles;M. E. Goldberg;T. M. Bare
通讯作者：
T. M. Bare
了解 GABAA 受体：化学门控离子通道。
影响因子：
4.1
作者：
F A Stephenson
通讯作者：
F A Stephenson
大鼠脊髓中 GABAA 受体和苯二氮卓类识别位点亚型的功能耦合。
影响因子：
5
作者：
M. Corda;O. Giorgi;B. Longoni;E. Ongini;G. Pesce;R. Cruciani;G. Biggio
通讯作者：
G. Biggio