Agrochemicals Research Center, Mitsui Chemicals Agro, Inc., Chiba, Japan.
Pest Manag Sci. 2021 Aug;77(8):3744-3752. doi: 10.1002/ps.6116. Epub 2020 Oct 13.
Meta-diamides [3-benzamido-N-(4-(perfluoropropan-2-yl)phenyl)benzamides] show high insecticide activity by acting as antagonists to the insect resistance to dieldrin (RDL) γ-aminobutyric acid (GABA) receptors. In contrast, low-level antagonist activities of meta-diamides have been demonstrated against the human GABA type A receptor (GABA R) α1β2γ2S, mammalian GABA R α1β3γ2S, and the human glycine receptor (GlyR) α1β. Glycine residue 336 in the membrane-spanning region M3 of the Drosophila RDL GABA receptor is essential for its high sensitivity to meta-diamide 7, [3-benzamido-N-(2-bromo-4-(perfluoropropan-2-yl)-6-(trifluoromethyl)phenyl)-2-fluorobenzamide].
We examined the effects of an equivalent mutation (M288G) in spontaneously opened human GABA R β3 homomers using membrane potential assay. Picrotoxin and fipronil blocked spontaneously opened human GABA Rs β3 and β3-M286G in a concentration-dependent manner. In contrast, meta-diamide 7 did not block spontaneously opened GABA R β3 homomers, although meta-diamide 7 blocked spontaneously opened GABA R β3-M286G homomers. In addition, inhibitory potency of meta-diamide 7 for GABA-induced membrane potential change in cells expressing GABA R α1β3-M286G was much higher than that in cells expressing GABA R α1β3. In the same way, the equivalent mutation (A288G) in GlyR α1 increased the inhibitory potency of meta-diamide 7 for GlyRs α1 and α1β.
Studies substituting an equivalent mutation (M288G) in spontaneously opening human GABA R β3 homomers and human GABA Rs α1β3 heteromers suggest that M286 in human GABA R β3 is important for the low sensitivity to meta-diamide 7. In this study, we summarize the mechanisms underlying the selectivity of meta-diamides between insect RDL and human GABA and glycine receptors. © 2020 Society of Chemical Industry.
间二酰胺（3-苯甲酰胺-N-（4-（全氟丙烷-2-基）苯基）苯甲酰胺）通过作为昆虫对狄氏剂（RDL）γ-氨基丁酸（GABA）受体的抗性的拮抗剂表现出高杀虫剂活性。相比之下，间二酰胺对人类 GABA 型 A 受体（GABA R）α1β2γ2S、哺乳动物 GABA Rα1β3γ2S 和人类甘氨酸受体（GlyR）α1β的低水平拮抗剂活性已得到证实。果蝇 RDL GABA 受体跨膜区 M3 中的甘氨酸残基 336 对其对间二酰胺 7（[3-苯甲酰胺-N-（2-溴-4-（全氟丙烷-2-基）-6-（三氟甲基）苯基）-2-氟苯甲酰胺]）的高敏感性至关重要。
我们使用膜电位测定法检查了在自发开启的人类 GABA Rβ3 同型二聚体中等效突变（M288G）的影响。Picrotoxin 和氟虫腈以浓度依赖性方式阻断自发开启的人类 GABA Rβ3 和β3-M286G。相比之下，间二酰胺 7 不会阻断自发开启的 GABA Rβ3 同型二聚体，尽管间二酰胺 7 阻断了自发开启的 GABA Rβ3-M286G 同型二聚体。此外，间二酰胺 7 对表达 GABA Rα1β3-M286G 的细胞中 GABA 诱导的膜电位变化的抑制效力远高于表达 GABA Rα1β3 的细胞。同样，甘氨酸受体α1 中的等效突变（A288G）增加了间二酰胺 7 对 GlyRsα1 和α1β的抑制效力。
研究用自发开启的人类 GABA Rβ3 同型二聚体和人类 GABA Rsα1β3 异源二聚体中的等效突变（M288G）取代表明，人类 GABA Rβ3 中的 M286 对间二酰胺 7 的低敏感性很重要。在这项研究中，我们总结了间二酰胺在昆虫 RDL 和人类 GABA 和甘氨酸受体之间选择性的机制。© 2020 化学工业协会。
