Mechanisms underlying the selectivity of meta‐diamides between insect resistance to dieldrin (RDL) and human γ‐aminobutyric acid (GABA) and glycine receptors

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 (GABAAR) α1β2γ2S, mammalian GABAAR 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 GABAAR β3 homomers using membrane potential assay. Picrotoxin and fipronil blocked spontaneously opened human GABAARs β3 and β3‐M286G in a concentration‐dependent manner. In contrast, meta‐diamide 7 did not block spontaneously opened GABAAR β3 homomers, although meta‐diamide 7 blocked spontaneously opened GABAAR β3‐M286G homomers. In addition, inhibitory potency of meta‐diamide 7 for GABA‐induced membrane potential change in cells expressing GABAAR α1β3‐M286G was much higher than that in cells expressing GABAAR 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 GABAAR β3 homomers and human GABAARs α1β3 heteromers suggest that M286 in human GABAAR 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

Application of computational methods in the analysis of pesticide target-site and resistance mechanisms

“…Although meta-diamides inhibited the DM-RDL receptor with a high potency, low-level inhibitory activities of meta-diamides have been demonstrated against the human GABA type A re- ceptor (GABA A R) α1β2γ2S and β3, mammalian GABA A R α1β3γ2S, and human glycine receptor (GlyR) α1 and α1β. 13,14) The G336 in the DM-RDL subunit is essential for the high inhibitory activity of meta-diamide 7. 6) The alanine residue 288 in human GlyR α1 and methionine residue 286 (M286) in human GABA A R β3 are the equivalent positions of G336 in DM-RDL.…”

“…4). 14) A homology model of human GABA A R β3 homomers in a closed state was made using human GABA A R α1β3γ2 (PDB entry code 6HUK) as a template. As shown in Fig.…”

“…Based on the docking studies of meta-diamide 7 to human GABA A R β3 homomers using the CDOCKER module of BIOVIA Discovery Studio 2019, the interaction energies of meta-diamide 7 in top-scoring poses were −42.0 kcal mol −1 for the M286G mutant and −27.4 kcal mol −1 for the wild type, indicating that it was more favorable for metadiamide 7 to bind to the M286G mutant than to the wild type. 14) Meta-diamide 7 was attached to the surface of the wild-type receptor and was not allowed to interact with the intersubunit pocket, whereas most of its parts were inserted into the pocket of the M286G mutant receptor (Fig. 5).…”

“…The amino acids of human GABA A Rs at positions equivalent to the G336 of DM-RDL are not glycine residues, except for GABA A R π, whose amino acids around the intersubunit pocket had a low similarity with those of insect GABA receptors. 14) Thus, meta-diamides are expected to be highly specific for insect GABA receptors.…”

Understanding the biological action of insecticides is the key to their continuous improvement

“…Nakao and Banba of Mitsui Chemicals contributed two research articles, illuminating important mechanisms and structural features of the insect GABA receptor, the target of the recently introduced meta‐diamide class of insecticides 16,17 . Using the RDL mutation models of the GABA receptor, they quantify the activity on insect receptors and similar human receptors, and demonstrate the specificity of these compounds toward insects.…”