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

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) gamma-aminobutyric acid (GABA) receptors. In contrast, low-level antagonist activities ofmeta-diamides have been demonstrated against the human GABA type A receptor (GABA(A)R) alpha 1 beta 2 gamma 2S, mammalian GABA(A)R alpha 1 beta 3 gamma 2S, and the human glycine receptor (GlyR) alpha 1 beta. Glycine residue 336 in the membrane-spanning region M3 of theDrosophilaRDL GABA receptor is essential for its high sensitivity tometa-diamide7, [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 GABA(A)R beta 3 homomers using membrane potential assay. Picrotoxin and fipronil blocked spontaneously opened human GABA(A)Rs beta 3 and beta 3-M286G in a concentration-dependent manner. In contrast,meta-diamide7did not block spontaneously opened GABA(A)R beta 3 homomers, althoughmeta-diamide7blocked spontaneously opened GABA(A)R beta 3-M286G homomers. In addition, inhibitory potency ofmeta-diamide7for GABA-induced membrane potential change in cells expressing GABA(A)R alpha 1 beta 3-M286G was much higher than that in cells expressing GABA(A)R alpha 1 beta 3. In the same way, the equivalent mutation (A288G) in GlyR alpha 1 increased the inhibitory potency ofmeta-diamide7for GlyRs alpha 1 and alpha 1 beta. CONCLUSION Studies substituting an equivalent mutation (M288G) in spontaneously opening human GABA(A)R beta 3 homomers and human GABA(A)Rs alpha 1 beta 3 heteromers suggest that M286 in human GABA(A)R beta 3 is important for the low sensitivity tometa-diamide7. In this study, we summarize the mechanisms underlying the selectivity ofmeta-diamides between insect RDL and human GABA and glycine receptors.

Automated summary

The research demonstrates the differential antagonist activities of meta-diamides on insect and human receptors by studying the effects of equivalent mutations in human GABA receptors. This study reveals the underlying mechanisms of selectivity of meta-diamides between insect RDL and human GABA and glycine receptors.