Onozaki Yasumichi, Horikoshi Ryo, Ohno Ikuya, Kitsuda Shigeki, Durkin Kathleen A, Suzuki Tomonori, Asahara Chiaki, Hiroki Natsuko, Komabashiri Rena, Shimizu Rikako, Furutani Shogo, Ihara Makoto, Matsuda Kazuhiko, Mitomi Masaaki, Kagabu Shinzo, Uomoto Katsuhito, Tomizawa Motohiro
Agricultural and Veterinary Research Laboratories, Agricultural and Veterinary Division, Meiji Seika Pharma Co., Ltd. , Yokohama, Kanagawa 222-8567, Japan.
College of Chemistry, University of California , Berkeley, California 94720-1460, United States.
J Agric Food Chem. 2017 Sep 13;65(36):7865-7873. doi: 10.1021/acs.jafc.7b02924. Epub 2017 Aug 28.
A novel chemotype insecticide flupyrimin (FLP) [N-[(E)-1-(6-chloro-3-pyridinylmethyl)pyridin-2(1H)-ylidene]-2,2,2-trifluoroacetamide], discovered by Meiji Seika Pharma, has unique biological properties, including outstanding potency to imidacloprid (IMI)-resistant rice pests together with superior safety toward pollinators. Intriguingly, FLP acts as a nicotinic antagonist in American cockroach neurons, and [H]FLP binds to the multiple high-affinity binding components in house fly nicotinic acetylcholine (ACh) receptor (nAChR) preparation. One of the [H]FLP receptors is identical to the IMI receptor, and the alternative is IMI-insensitive subtype. Furthermore, FLP is favorably safe to rats as predicted by the very low affinity to the rat α4β2 nAChR. Structure-activity relationships of FLP analogues in terms of receptor potency, featuring the pyridinylidene and trifluoroacetyl pharmacophores, were examined, thereby establishing the FLP molecular recognition at the Aplysia californica ACh-binding protein, a suitable structural surrogate of the insect nAChR. These FLP pharmacophores account for the excellent receptor affinity, accordingly revealing differences in its binding mechanism from IMI.
一种新型化学型杀虫剂氟吡嘧菌胺（FLP）[N-[(E)-1-(6-氯-3-吡啶基甲基)吡啶-2(1H)-亚基]-2,2,2-三氟乙酰胺]，由明治制果药业发现，具有独特的生物学特性，包括对吡虫啉（IMI）抗性水稻害虫具有卓越的药效，同时对传粉者具有更高的安全性。有趣的是，FLP在美国蟑螂神经元中作为烟碱拮抗剂起作用，并且[H]FLP与家蝇烟碱乙酰胆碱（ACh）受体（nAChR）制剂中的多个高亲和力结合成分结合。[H]FLP的一种受体与IMI受体相同，另一种是对IMI不敏感的亚型。此外，正如对大鼠α4β2 nAChR的极低亲和力所预测的那样，FLP对大鼠具有良好的安全性。研究了以吡啶亚基和三氟乙酰药效团为特征的FLP类似物在受体效力方面的构效关系，从而在加州海兔ACh结合蛋白（昆虫nAChR的合适结构替代物）上建立了FLP分子识别。这些FLP药效团解释了其优异的受体亲和力，从而揭示了其与IMI结合机制的差异。
