title: The antiparasitic isoxazoline A1443 is a potent blocker of insect ligand-gated chloride channels.
abstract: 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. To study the mode of action of this isoxazoline, we utilized MdGBCl and MdGluCl cDNAs, which encode the subunits of housefly GABA- and glutamate-gated chloride channels, respectively. Two-electrode voltage clamp electrophysiology was used to confirm that A1443 blocks GABA- and glutamate-induced chloride currents in Xenopus oocytes expressing MdGBCl or MdGluCl channels, with IC(50) values of 5.32 and 79.9 nM, respectively. Blockade by A1443 was observed in A2'S-MdGBCl and S2'A-MdGluCl mutant channels at levels similar to those of the respective wild-types, and houseflies expressing A2'S-MdGBCl channels were as susceptible to A1443 as standard houseflies. These findings indicate that A1443 is a novel and specific blocker of insect ligand-gated chloride channels.
authors: Department of Life Science and Biotechnology, Shimane University, Matsue, Shimane 690-8504, Japan. ozoe-y@life.shimane-u.ac.jp
authors: Yoshihisa
authors: Y
authors: Ozoe
authors: Miho
authors: M
authors: Asahi
authors: Fumiyo
authors: F
authors: Ozoe
authors: Kunimitsu
authors: K
authors: Nakahira
authors: Takeshi
authors: T
authors: Mita
mesh_terms: D000818:Animals; D000977:Antiparasitic Agents / Q000494:pharmacology*; D001921:Brain / Q000378:metabolism; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology; D002415:Cats; D018118:Chloride Channels / Q000037:antagonists & inhibitors*; D004285:Dogs; D018755:GABA Agonists / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology; D006793:Houseflies / Q000187:drug effects*; D015640:Ion Channel Gating / Q000187:drug effects*; D008024:Ligands; D009154:Mutation; D051381:Rats; D018079:Receptors, GABA / Q000187:drug effects / Q000235:genetics; D017470:Receptors, Glutamate / Q000187:drug effects / Q000235:genetics; D005423:Siphonaptera / Q000187:drug effects*; D013987:Ticks / Q000187:drug effects*; D014970:Xanthines / Q000494:pharmacology*; D014981:Xenopus
chemical_list: D000977:Antiparasitic Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D018118:Chloride Channels; D018755:GABA Agonists; D018756:GABA Antagonists; D008024:Ligands; D018079:Receptors, GABA; D017470:Receptors, Glutamate; D014970:Xanthines; C091518:1-(4-ethynylphenyl)-4-propyl-2,6,7-trioxabicyclo(2.2.2)octane; C053414:BW A1433U