Cordova Daniel, Benner Eric A, Clark David A, Bolgunas Stephen P, Lahm George P, Gutteridge Steven, Rhoades Daniel F, Wu Lihong, Sopa Jeffrey S, Rauh James J, Barry James D
FMC, Agricultural Solutions Discovery Biology, Stine Research Center, 1090 Elkton Road, Newark, DE 19711, USA.
FMC, Agricultural Solutions Discovery Biology, Stine Research Center, 1090 Elkton Road, Newark, DE 19711, USA.
Pestic Biochem Physiol. 2021 May;174:104798. doi: 10.1016/j.pestbp.2021.104798. Epub 2021 Feb 21.
The ryanodine receptor (RyR) is an intracellular calcium channel critical to the regulation of insect muscle contraction and the target site of diamide insecticides such as chlorantraniliprole, cyantraniliprole and flubendiamide. To-date, diamides are the only known class of synthetic molecules with high potency against insect RyRs. Target-based screening of an informer library led to discovery of a novel class of RyR activators, pyrrole-2-carboxamides. Efforts to optimize receptor activity resulted in analogs with potency comparable to that of commercial diamides when tested against RyR of the fruit fly, Drosophila melanogaster. Surprisingly, testing of pyrrole-2-carboxamides in whole-insect screens showed poor insecticidal activity, which is partially attributed to differential selectivity among insect receptors and rapid detoxification. Among various lepidopteran species field resistance to diamide insecticides has been well documented and in many cases has been attributed to a single point mutation, G4946E, of the RyR gene. As with diamide insecticides, the G4946E mutation confers greatly reduced sensitivity to pyrrole-2-carboxamides. This, coupled with findings from radioligand binding studies, indicates a shared binding domain between anthranilic diamides and pyrrole-2-carboxamides.
兰尼碱受体（RyR）是一种细胞内钙通道，对昆虫肌肉收缩的调节至关重要，也是氯虫苯甲酰胺、氰虫酰胺和氟苯虫酰胺等双酰胺类杀虫剂的作用靶标位点。迄今为止，双酰胺类是已知的唯一一类对昆虫RyR具有高效活性的合成分子。基于靶标的信息素文库筛选发现了一类新型的RyR激活剂——吡咯-2-甲酰胺。优化受体活性的研究工作产生了一些类似物，在针对果蝇黑腹果蝇的RyR进行测试时，其活性与市售双酰胺类相当。令人惊讶的是，在全虫筛选中测试吡咯-2-甲酰胺时发现其杀虫活性较差，这部分归因于昆虫受体之间的选择性差异以及快速解毒作用。在各种鳞翅目物种中，对双酰胺类杀虫剂的田间抗性已有充分记录，在许多情况下，这归因于RyR基因的单点突变G4946E。与双酰胺类杀虫剂一样，G4946E突变使对吡咯-2-甲酰胺的敏感性大大降低。这一点，再加上放射性配体结合研究的结果，表明邻氨基苯甲酰胺类和吡咯-2-甲酰胺类之间存在共同的结合域。
