Analysis of Three-dimensional Structure of Antagonist-Binding Site of GABA Receptors

为了获得γ-氨基丁酸受体非竞争性拮抗剂结合部位的三维结构信息，合成了分子探针，并检测了它们与该部位的结合能力和构效关系。探针1的分析表明，植物来源的萜类化合物是GABA拮抗剂。其中一些化合物对大鼠和家蝇受体都显示出结合活性，而另一些化合物对家蝇受体表现出选择性。我们的三维结合位点模型，由四个亚位点组成，证明成功地解释了孔雀花素活性和选择性的表现。探针2分析表明，bicyclophosphorothionatesBicyclophosphorothionates，含有适当的3-和4-取代基，对家蝇GABA受体具有选择性，这表明大鼠和家蝇GABA受体的结构存在差异。这些化合物的三维定量构效关系分析确定了家蝇受体中可能的B和C亚基区域。探针3、无环酯和醚的分析这一组中的大多数化合物显示出对大鼠GABA受体的拮抗活性，而对家蝇受体的拮抗活性很低。这些化合物被认为与四个亚基中的三个相互作用，因此与另一个亚基(即B)的相互作用对拮抗剂表现出选择性可能是重要的。

To obtain information on the three-dimensional structure of noncompetitive antagonist-binding site of the γ-aminobutyric acid (GABA) receptor, molecular probes were synthesized and examined for their abilities to bind to the site and structure-activity relationships.1. Analysis with probe 1, picrodendrinsPicrodendrins, plant-derived terpenoids, act as GABA antagonists. Some of the compounds showed binding activity toward both rat and housefly receptors, while other compounds exhibited selectivity for housefly receptors. Our three-dimensional binding site model, consisting of four subsites, proved to successfully explain the manifestation of picrodendrins' activity and selectivity.2. Analysis with probe 2, bicyclophosphorothionatesBicyclophosphorothionates, bearing appropriate 3- and 4-substituents, exhibited selectivity for housefly GABA receptors, suggesting structural differences between rat and housefly GABA receptors. Three-dimensional quantitative structure-activity relationship analysis of these compounds led to defining the region of putative subsites B and C in housefly receptors.3. Analysis with probe 3, acyclic esters and ethersMost compounds of this group displayed antagonist activity for rat GABA receptors, while they had only low potency for housefly receptors. These compounds are supposed to interact with three of four subsites, and so an interaction with the other subsite (i.e., B) could be of importance for antagonists to exhibit selectivity.