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

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• 作者：Yoshihisa Ozoe ; Miho Asahi ; Fumiyo Ozoe ; Kunimitsu Nakahira ; Takeshi Mita
• 关键词：GABA ; Glutamate ; Ligand-gated ion channel ; Parasiticide ; Receptor
• 刊名：Biochemical and Biophysical Research Communications
• 出版年：2010
• 出版时间：1 January 2010
• 年：2010
• 卷：391
• 期：1
• 页码：744-749
• 全文大小：489 K

文摘

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 γ-aminobutyric acid (GABA) receptor channel blocker [³H]4′-ethynyl-4-n-propylbicycloorthobenzoate (EBOB) to housefly-head membranes, with an IC₅₀ value of 455 pM. In contrast, the IC₅₀ value in rat-brain membranes is >10 μM. 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 IC₅₀ 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.