Fluxametamide is a novel isoxazoline insecticide that was discovered and synthesized by Nissan Chemical Industries, Ltd. and it has highly insecticidal activity against various pests of Lepidoptera, Thysanoptera, Diptera, and Tetranychidae. To elucidate the mode of action of this compound, we performed the following investigation. The binding of [3H]4’-ethynyl-4-n-propylbicycloorthobenzoate to the membrane fractions of housefly heads was potently inhibited by fluxametamide, suggesting that the compound acts as an antagonist of insect GABA-gated chloride channels. Investigation of its antagonistic activity against GABA-gated chloride channels (GABACls) and glutamate-gated chloride channels (GluCls) using a two-electrode voltage clamp method showed that fluxametamide inhibits both chloride channels. Although GABACl is one of the major target sites of insecticides, the emergence of many resistant pests against existing GABACl antagonists was reported so far. In these pests, an amino acid substitution in the M2 region of GABACl subunit at the 2’-alanine position causes resistance against GABACl antagonists: resistance to dieldrin (RDL)-type pests. On the other hand, GABACls of two-spotted spider mites (Tetranychus urticae) have RDL-type amino acid sequences in the M2 region with no drug selections.Fluxametamide showed not only superior pest-control activities against both type resistance pests but also excellent antagonistic activities against these GABACls in electrophysiological experiments. These findings strongly suggest that fluxametamide has a different binding site in GABACls from existing antagonists. The isoxazoline insecticide did not affect mammalian ligand-gated chloride channels in vitro. Overall, our results indicate that fluxametamide belongs to a novel class of ligand-gated chloride channel antagonist and that it has excellent selectivity to pests over mammals.

Mode-of-action studies of a novel ligand-gated chloride channel antagonist insecticide, fluxametamide

254th National Meeting (2017)

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