Insect γ‑Aminobutyric Acid Receptors and Isoxazoline Insecticides: Toxicological Profiles Relative to the Binding Sites of [³H]Fluralaner, [³H]-4′-Ethynyl-4‑<i>n</i>‑propylbicycloorthobenzoate, and [³H]Avermectin

Isoxazoline insecticides, such as fluralaner (formerly A1443), are noncompetitive γ-aminobutyric acid (GABA) receptor (GABA-R) antagonists with selective toxicity for insects versus mammals. The isoxazoline target in house fly (Musca domestica) brain has subnanomolar affinity for [³H]­fluralaner and a unique pattern of sensitivity to isoxazolines and avermectin B_1a (AVE) but not to fipronil and α-endosulfan. Inhibitor specificity profiles for 15 isoxazolines examined with Musca GABA-R and [³H]­fluralaner, [³H]-4′-ethynyl-4-<i>n</i>-propylbicycloorthobenzoate ([³H]­EBOB), and [³H]­AVE binding follow the same structure–activity trends although without high correlation. The 3 most potent of the 15 isoxazolines tested in Musca [³H]­fluralaner, [³H]­EBOB, and [³H]­AVE binding assays and in honeybee (Apis mellifera) brain [³H]­fluralaner assays are generally those most toxic to Musca and four agricultural pests. Fluralaner does not inhibit [³H]­EBOB binding to the human GABA-R recombinant β₃ homopentamer, which is highly sensitive to all of the commercial GABAergic insecticides. The unique isoxazoline binding site may resurrect the GABA-R as a major insecticide target