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Structure of ligand-binding site of mutated GABA receptors of insects with resistance for antagonists

拮抗剂抗性昆虫突变 GABA 受体配体结合位点结构

基本信息

批准号：
13660109
负责人：
OZOE Yoshihisa
金额：
$ 2.3万
依托单位：
Shimane University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2002
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13660109/
关键词：
GABA receptor antagonist insecticide resistance insect EBOB neurotransmitter 構造変異結合部位殺虫剤抵抗性

项目摘要

OCR houseflies with an A299S mutation in the binding site of noncompetitive GABA antagonists displayed 1 or 2 orders lower resistance to the insecticide fipronil and EBOB than to the insecticide dieldrin (several thousand-fold resistance). Scatchard analysis showed that OCR receptors had 4-fold lower affinity for [^3H]EBOB and 1.3-fold less binding sites than receptors of susceptible WHO files. Dieldrin was 45-fold less potent in inhibiting [^3H]EBOB binding in OCR receptors than in WHO receptors, while fipronil and EBOB were 2-and 6-fold less potent in OCR receptors than in WHO receptors, respectively. 3, 4, 5,-substituted 1-(2,6-dichioro-4-trifluoromethylphenyl)pyrazoles, fipronil analogues, exhibited different structure-activity relationships in OCR receptors from those in WHO receptors. Although most of the analogues had remarkably low affinities for OCR receptors, several analogues with an electron-withdrawing group in the 4-position of the pyrazole ring showed relatively high affinity. However, the affinities were several hundred-fold lower than the affinities for WHO receptors; IC_<50s> were in the micromolar order. An analogue with a bromine atom in the 4-position had >1600-fold lower affinity for OCR receptors than that for WHO receptors. Although the introduction of an amino group into the 5-position led to a decrease in affinity for OCR receptors in one case, three compounds with an amino group in the 5-position, compounds structurally closely related to fipronil, showed only <4-fold decrease in affinity for OCR receptors, compared to that for WHO receptors. The results indicate that only limited compounds with special structures seem to fit into the GABA antagonist-binding site of dieldrin-resistant houseflies. Factor(s) apart from decrease in affinity might be involved in the mechanism underlying the resistance of OCR files for noncompetitive GABA antagonists.

非竞争性GABA拮抗剂结合位点A299 S突变的OCR家蝇对杀虫剂氟虫腈和EBOB的抗性比杀虫剂狄氏剂低1或2个数量级（数千倍抗性）。Scatchard分析表明，OCR受体对[^3H]EBOB的亲和力比敏感的WHO文件中的受体低4倍，结合位点少1.3倍。狄氏剂抑制OCR受体中[^3H]EBOB结合的效力是WHO受体的45倍，而氟虫腈和EBOB在OCR受体中的效力分别是WHO受体的2倍和6倍。氟虫腈类似物3，4，5-取代的1-（2，6-二氯-4-三氟甲基苯基）吡唑类化合物在OCR受体和WHO受体中表现出不同的构效关系。虽然大多数类似物对OCR受体的亲和力非常低，但在吡唑环的4-位具有吸电子基团的几种类似物显示出相对较高的亲和力。然而，亲和力比对WHO受体的亲和力低几百倍; IC_<50s>为微摩尔量级。在4位具有溴原子的类似物对OCR受体的亲和力比对WHO受体的亲和力低>1600倍。尽管在一种情况下将氨基引入5位导致对OCR受体的亲和力降低，但与WHO受体相比，在5位具有氨基的三种化合物（结构上与氟虫腈密切相关的化合物）对OCR受体的亲和力仅降低<4倍。结果表明，只有有限的具有特殊结构的化合物似乎适合GABA拮抗剂结合位点的狄氏醇抗性家蝇。除亲和力降低外，其他因素可能参与OCR文件对非竞争性GABA拮抗剂耐药的机制。