GABAA受体萜类抑制剂构效关系研究

采用DISCOtech方法建立了大鼠和家蝇GABAA受体萜类抑制剂的药效团模型, 根据药效团模型叠加规则建立了大鼠和家蝇GABAA受体萜类抑制剂CoMFA模型, 模型的交叉验证相关系数分别为0.713和0.738. 构效关系研究显示， 家蝇和大鼠受体抑制剂结合部位之间存在一个主要差别: 与受体作用的抑制剂的负电荷基团取代有利于保持其对哺乳动物的高抑制活性, 而保持对昆虫的高抑制活性是不需要的, 从而为寻找先导化合物和设计高选择性杀虫剂提供了理论指导.

Structure-activity Relationships of Inhibitor of Terpenoids in GABAA Receptor

A variety of terpenoids of plant origin such as anisatin, picrotoxinin and picrodendrins were shown to be non competitive antagonists of GABAA receptors. The results show the selectivity toward the insect receptor and thus represent new leads toward selective insecticides. Two pharmacophore models of rat and housefly′s GABAA receptors for terpenoids inhibitors were studied by DISCOtech methodology. Two pharmacophore models were verified by the study of the three dimensional quantitative structure and activity relationships, which gave two predictive CoMFA models with q2rat=0.713 and q2fly=0.738. According to these results, it was found that negatively charged particle of inhibitor contributed strongly to binding at the rat receptor but showed almost no contribution to the housefly receptor. So these findings will lay a foundation of finding leading compounds and give some guidance on synthesizing insecticides with selectivity activity.