Abstract
BackgroundThe isoxazolines are a novel class of parasiticides that are potent inhibitors of γ-aminobutyric acid (GABA)-gated chloride channels (GABACls) and, to a lesser extent, of inhibitory glutamate-gated chloride channels (GluCls). Lotilaner (Credelio™), a novel representative of this chemical class, is currently evaluated for its excellent ectoparasiticide properties.MethodsIn this study, we investigated the molecular mode of action and pharmacology of lotilaner. We report the successful gene identification, cDNA cloning and functional expression in Xenopus oocytes of Drosohpila melanogaster (wild type and dieldrin/fipronil-resistant forms), Lepeophtheirus salmonis (an ectoparasite copepod crustacean of salmon), Rhipicephalus microplus and Canis lupus familiaris GABACls. Automated Xenopus oocyte two-electrode voltage clamp electrophysiology was used to assess GABACls functionality and to compare ion channel inhibition by lotilaner with that of established insecticides addressing GABACls as targets.ResultsIn these assays, we demonstrated that lotilaner is a potent non-competitive antagonist of insects (fly) GABACls. No cross-resistance with dieldrin or fipronil resistance mutations was detected, suggesting that lotilaner might bind to a site at least partly different from the one bound by known GABACl blockers. Using co-application experiments, we observed that lotilaner antagonism differs significantly from the classical open channel blocker fipronil. We finally confirmed for the first time that isoxazoline compounds are not only powerful antagonists of GABACls of acari (ticks) but also of crustaceans (sea lice), while no activity on a dog GABAA receptor was observed up to a concentration of 10 μM.ConclusionsTogether, these results demonstrate that lotilaner is a non-competitive antagonist specific to invertebrate’s γ-aminobutyric acid-gated chloride channels (GABACls). They contribute to our understanding of the mode of action of this new ectoparasiticide compound.
Highlights
The isoxazolines are a novel class of parasiticides that are potent inhibitors of γ-aminobutyric acid (GABA)-gated chloride channels (GABACls) and, to a lesser extent, of inhibitory glutamate-gated chloride channels (GluCls)
Identification and cloning of GABACl subunits For the identification of the full-length GABACl subunit gene of Lepeophtheirus salmonis (Ls). salmonis (Ls-GABA1), internal primers were designed based on a published partial sequence (ABI95854.1)
In summary, our study demonstrates that the novel isoxazoline parasiticide lotilaner acts as a potent noncompetitive antagonist of GABACls from insects, Acari and crustaceans while it shows no effect on dog GABAA receptors up to a concentration of 10 μM
Summary
The isoxazolines are a novel class of parasiticides that are potent inhibitors of γ-aminobutyric acid (GABA)-gated chloride channels (GABACls) and, to a lesser extent, of inhibitory glutamate-gated chloride channels (GluCls). Neurotransmitter receptors are membrane proteins that are directly involved in transmembrane signalling in both neurons and muscle cells They are important for the function and regulation of the nervous system and as common targets of drugs, endo- and ectoparasiticides [1]. Phenylpyrazoles such as fipronil (Fig. 1) and ethiprole, and macrolides such as avermectins and milbemycins, are commercially available insecticides and parasiticides that target γ-aminobutyric acid (GABA)gated chloride channels (GABACls) and inhibitory glutamate-gated chloride channels (GluCls) in invertebrates [2].
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