Abstract
Background: 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 (GABAA R) α1β2γ2S, mammalian GABAA 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]. Results: We examined the effects of an equivalent mutation (M288G) in spontaneously opened human GABAA R β3 homomers using membrane potential assay. Picrotoxin and fipronil blocked spontaneously opened human GABAA Rs β3 and β3-M286G in a concentration-dependent manner. In contrast, meta-diamide 7 did not block spontaneously opened GABAA R β3 homomers, although meta-diamide 7 blocked spontaneously opened GABAA R β3-M286G homomers. In addition, inhibitory potency of meta-diamide 7 for GABA-induced membrane potential change in cells expressing GABAA R α1β3-M286G was much higher than that in cells expressing GABAA 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. Conclusion: Studies substituting an equivalent mutation (M288G) in spontaneously opening human GABAA R β3 homomers and human GABAA Rs α1β3 heteromers suggest that M286 in human GABAA 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.
