title: Insect γ-aminobutyric acid receptors and isoxazoline insecticides: toxicological profiles relative to the binding sites of [³H]fluralaner, [³H]-4'-ethynyl-4-n-propylbicycloorthobenzoate, and [³H]avermectin.
abstract: 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-n-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.
authors.affiliation: Environmental Chemistry and Toxicology Laboratory, Department of Environmental Science, Policy, and Management, University of California , Berkeley, California 94720-3112, United States.
authors.forename: Chunqing
authors.initials: C
authors.lastname: Zhao
authors.forename: John E
authors.initials: JE
authors.lastname: Casida
mesh_terms: D000737:Androstenols / Q000737:chemistry / Q000633:toxicity; D000818:Animals; D001665:Binding Sites; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000737:chemistry / Q000633:toxicity*; D018756:GABA Antagonists / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D006793:Houseflies / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D019476:Insect Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007306:Insecticides / Q000737:chemistry / Q000633:toxicity*; D018079:Receptors, GABA / Q000378:metabolism
chemical_list: D000737:Androstenols; D019086:Bridged Bicyclo Compounds, Heterocyclic; D018756:GABA Antagonists; D019476:Insect Proteins; D007306:Insecticides; D018079:Receptors, GABA; C091518:1-(4-ethynylphenyl)-4-propyl-2,6,7-trioxabicyclo(2.2.2)octane; C017039:azastene