Development of a 3D pharmacophore for nonspecific ligand recognition of alpha1, alpha2, alpha3, alpha5, and alpha6 containing GABA(A)/benzodiazepine receptors.
Development of a 3D pharmacophore for nonspecific ligand recognition of alpha1, alpha2, alpha3, alpha5, and alpha6 containing GABA(A)/benzodiazepine receptors.
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开发 3D 药效团，用于非特异性配体识别包含 GABA(A)/苯二氮卓受体的 α1、α2、α3、α5 和 α6。
DOI：
10.1016/s0968-0896(00)00112-7
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发表时间：
2000
影响因子：
3.5
通讯作者：
Loew,GH
中科院分区：
文献类型：
--
作者：
Filizola,M;Harris,DL;Loew,GH
利用含有GABAA/苯二氮卓类受体(BDZRs)的转基因细胞，系统地测定了α1、α2、α3、α5和α6亚型的配体与β2和γ2的亲和力。迄今研究的所有配体对这些α亚型受体都有较高的亲和力。因此，这些配体必须包含有利于每个亚型组合识别的共同立体化学性质。在本工作中，我们开发了一种通用的三维(3D)药效载体，用于识别α1、α2、α3、α5和α6受体类型，并以27种不同化合物在转基因细胞中测量的受体亲和力为数据库进行了评估。所开发的3D识别药效基团由三个质子接受基团、一个疏水基团和一个芳香环的质心组成，该芳环在19个非选择性配体中以共同的几何排列存在。对这个药效团进行了三个测试：(I)使用四个低亲和力化合物作为阴性对照，(Ii)将四个高亲和力化合物排除在药效团开发之外，作为药效团验证的化合物，(Iii)使用3D药效团搜索3D数据库。这些类型评估的每一种结果都为3D药效团提供了强有力的验证。这种三维药效团现在可以用来发现新的非选择性配体，这些配体可能在不同的行为终点具有激活选择性。此外，通过确定建议合成的候选配体是否符合这个药效团，并选择不符合的进行进一步的实验评估，它可以作为设计更具选择性的配体的指南。
Transfected cells containing GABAA/benzodiazepine receptors (BDZRs) have been utilized to systematically determine the affinity of ligands at α1, α2, α3, α5 and α6 subtypes in combination with β2and γ2. All but a few of the ligands thus far studied have relatively high affinities for each of these α subtype receptors. Thus, these ligands must contain common stereochemical properties favorable for recognition by each of the subtype combinations. In the present work, such a common three-dimensional (3D) pharmacophore for recognition of α1, α2, α3, α5 and α6 containing GABAA/BDZRs types of receptors has been developed and assessed, using as a database receptor affinities measured in transfected cells for 27 diverse compounds. The 3D-recognition pharmacophore developed consists of three proton accepting groups, a hydrophobic group, and the centroid of an aromatic ring found in a common geometric arrangement in the 19 nonselective ligands used. Three tests were made to assess this pharmacophore: (i) Four low affinity compounds were used as negative controls, (ii) Four high affinity compounds, excluded from the pharmacophore development, were used as compounds for pharmacophore validation, (iii) The 3D pharmacophore was used to search 3D databases. The results of each of these types of assessments provided robust validation of the 3D pharmacophore. This 3D pharmacophore can now be used to discover novel nonselective ligands that could be activation selective at different behavioral end points. Additionally, it may serve as a guide in the design of more selective ligands, by determining if candidate ligands proposed for synthesis conform to this pharmacophore and selecting those that do not for further experimental assessment.