School of Chemical Engineering and Pharmacy, Wuhan Institute of Technology, Wuhan, China.
Pest Manag Sci. 2010 Sep;66(9):1002-10. doi: 10.1002/ps.1973.
Bicyclophosphorothionates (2,6,7-trioxa-1-phosphabicyclo[2.2.2]octane-1-sulfides) are blockers (or non-competitive antagonists) of gamma-aminobutyric acid (GABA) receptor channels. Twenty-two bicyclophosphorothionates with different 3- and 4-substituents were synthesised, and [(3)H]4'-ethynyl-4-n-propylbicycloorthobenzoate (EBOB) binding assays were performed to evaluate their affinities for housefly and rat GABA receptors.
Introduction of an isopropyl group at the 3-position enhanced the affinity of bicyclophosphorothionates for housefly GABA receptors and reduced the affinity towards rat GABA receptors. The 4-isopentyl-3-isopropylbicyclophosphorothionate showed the highest affinity for housefly GABA receptors (IC(50) = 103 nM) among the analogues tested, while the 4-cyclohexylbicyclophosphorothionate showed the highest affinity for rat GABA receptors (IC(50) = 125 nM). Among the bicyclophosphorothionates synthesised to date, the former analogue exhibited the highest selectivity for housefly GABA receptors, with an IC(50)(rat)/IC(50)(fly) ratio of approximately 97. Three-dimensional GABA receptor models successfully explained the structure-activity relationships of the bicyclophosphorothionates.
The results indicate that minor structural modifications of blockers can change their selectivity for insect versus mammalian GABA receptors. The substituent at the 3-position of the bicyclophosphorothionates dictates selectivity for housefly versus rat GABA receptors. This information should prove useful for the design of safer insecticides and parasiticides.
双环磷硫代膦酸酯（2,6,7-三氧-1-磷杂双环[2.2.2]辛烷-1-硫代）是γ-氨基丁酸（GABA）受体通道的阻断剂（或非竞争性拮抗剂）。合成了 22 种具有不同 3-和 4-取代基的双环磷硫代膦酸酯，并进行了[（3）H]4'-乙炔基-4-正丙基双环邻苯二甲酸酯（EBOB）结合测定，以评估它们对家蝇和大鼠 GABA 受体的亲和力。
在 3-位引入异丙基增强了双环磷硫代膦酸酯对家蝇 GABA 受体的亲和力，降低了对大鼠 GABA 受体的亲和力。在所测试的类似物中，4-异戊基-3-异丙基双环磷硫代膦酸酯对家蝇 GABA 受体表现出最高的亲和力（IC50=103 nM），而 4-环己基双环磷硫代膦酸酯对大鼠 GABA 受体表现出最高的亲和力（IC50=125 nM）。在所合成的双环磷硫代膦酸酯中，前者类似物对家蝇 GABA 受体表现出最高的选择性，IC50（大鼠）/IC50（蝇）比值约为 97。GABA 受体的三维模型成功解释了双环磷硫代膦酸酯的构效关系。
结果表明，阻断剂的微小结构修饰可以改变其对昆虫与哺乳动物 GABA 受体的选择性。双环磷硫代膦酸酯 3-位取代基决定了其对家蝇与大鼠 GABA 受体的选择性。这些信息对于设计更安全的杀虫剂和杀寄生虫剂应该是有用的。
