Fluxametamide: A novel isoxazoline insecticide that acts via distinctive antagonism of insect ligand-gated chloride channels.

Fluxametamide is a novel wide-spectrum insecticide that was discovered and synthesized by Nissan Chemical Industries, Ltd. To identify the mode of action of fluxametamide, we first performed [H]4'-ethynyl-4-n-propylbicycloorthobenzoate (EBOB) binding assays. Fluxametamide potently inhibited the specific binding of [H]EBOB to housefly-head membranes, suggesting that fluxametamide affects insect γ-aminobutyric acid (GABA)-gated chloride channels (GABACls).

A Single Amino Acid Substitution in the Third Transmembrane Region Has Opposite Impacts on the Selectivity of the Parasiticides Fluralaner and Ivermectin for Ligand-Gated Chloride Channels.

Fluralaner (Bravecto) is a recently marketed isoxazoline ectoparasiticide. This compound potently inhibits GABA-gated chloride channels (GABACls) and less potently glutamate-gated chloride channels (GluCls) in insects. The mechanism underlying this selectivity is unknown.

Differential mechanisms of action of the novel γ-aminobutyric acid receptor antagonist ectoparasiticides fluralaner (A1443) and fipronil.

Background: Fluralaner (A1443) is an isoxazoline ectoparasiticide that is a novel antagonist of γ-aminobutyric acid (GABA) receptors (GABARs), with a potency comparable to that of fipronil, a phenylpyrazole ectoparasiticide. To clarify the biological effectiveness of fluralaner against fipronil-resistant pests, differences in the actions of fluralaner and fipronil on GABARs that possess resistance to dieldrin (rdl)-type mutations were evaluated.

Results: Fipronil had neither pest control nor GABAR-antagonistic activities against two-spotted spider mites (Tetranychus urticae) that had two different rdl-type amino acids (A(301) → H and T(350) → A: Drosophila melanogaster GABAR numbering) and against small brown planthoppers (Laodelphax striatellus) that had a novel rdl-type (A(283) → N) mutation in GABARs.

The antiparasitic isoxazoline A1443 is a potent blocker of insect ligand-gated chloride channels.

A structurally unique isoxazoline class compound, A1443, exhibits antiparasitic activity against cat fleas and dog ticks comparable to that of the commercial ectoparasiticide fipronil. This isoxazoline compound inhibits specific binding of the gamma-aminobutyric acid (GABA) receptor channel blocker [(3)H]4'-ethynyl-4-n-propylbicycloorthobenzoate (EBOB) to housefly-head membranes, with an IC(50) value of 455pM. In contrast, the IC(50) value in rat-brain membranes is>10muM.