The novel isoxazoline ectoparasiticide lotilaner (Credelio™): a non-competitive antagonist specific to invertebrates γ-aminobutyric acid-gated chloride channels (GABACls)

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.Electronic supplementary materialThe online version of this article (10.1186/s13071-017-2470-4) contains supplementary material, which is available to authorized users.

Distinct molecular targets for macrocyclic lactone and isoxazoline insecticides in the human louse: new prospects for the treatment of pediculosis

“…Arthropod RDL channels are major targets for several old insecticidal classes including dieldrin itself and fipronil [32] and they were recently shown to be the primary target for isoxazolines [39][40][41][42][43]. Therefore, we hypothesized that they could act on RDL from Pediculus humanus humanus.…”

“…Interestingly, new synthetic molecules from the isoxazoline chemical class were recently proven to be effective ectoparasiticides against fleas and ticks [38]. The isoxazoline insecticides include fluralaner, afoxolaner, sarolaner and lotilaner [39][40][41][42]. They were shown to act as potent non-competitive antagonists of GABACls from D. melanogaster as well as the cat flea Ctenocephalides felis and the livestock tick Rhipicephalus microplus by molecular experiments and voltage-clamp electrophysiology.…”

Tick paralysis in dogs and cats in Australia: treatment and prevention deliverables from 100 years of research

“…The isoxazolines are potent inhibitors of neurotransmission within insects and ticks and their development resulted from the successful application of genetic technologies utilising intensive and novel in vitro screening methods . Isoxazolines currently available in Australia (Table ) include fluralaner, afoxolaner, sarolaner, and lotilaner . Cats have historically had few options for prevention of tick paralysis but recently a spot‐on formulation of fluralaner (Bravecto®), developed specifically for cats, demonstrated 100% efficacy at 72 h for at least 84 days .…”

Neue Arzneimittel für Kleintiere 2018

“…Additionally, one drug with a new pharmaceutical form and one drug with a higher content of the active ingredient have been launched on the market for small animals. [22]. Durch die Hemmung des prä-und postsynaptischen Chloridionenaustausches durch die Zellmembranen kommt es zu einer irreversiblen, progressiven und spastischen Lähmung, was zum Tod von Insekten und Spinnentieren führt [10] [22].…”

“…[22]. Durch die Hemmung des prä-und postsynaptischen Chloridionenaustausches durch die Zellmembranen kommt es zu einer irreversiblen, progressiven und spastischen Lähmung, was zum Tod von Insekten und Spinnentieren führt [10] [22]. Da es sich bei Lotilaner wie bei allen Isoxazolinen um ein sog.…”