Differential mechanisms of action of the novel<i>γ</i>-aminobutyric acid receptor antagonist ectoparasiticides fluralaner (A1443) and fipronil

Asahi, Miho; Kobayashi, Masaki; Matsui, Hiroto; Nakahira, Kunimitsu

doi:10.1002/ps.3768

Cited by 69 publications

(55 citation statements)

References 17 publications

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“…aegypti adults (1.3 ng/mg at 24 h). Additionally, Asahi et al [24] showed that fluralaner had similar potent toxicity on fipronil-resistant and susceptible strains of Laodelphax striatellus Fallén, whereas fipronil showed a resistance ratio of about 1700. These findings are in agreement with results of both feeding and glass contact assays on dieldrin-resistant and susceptible strains of D. melanogaster reported here, where fluralaner showed similar activity at all recorded time points.…”

Section: Discussionmentioning

confidence: 99%

“…In two-electrode voltage clamp (TEVC) recordings of oocytes expressing M. domestica RDL receptors, fluralaner had similar IC 50 values of 2.8 nM on rdl -type receptors with A299S mutation and 5.3 nM on wild-type receptors [10]. Fluralaner also had an IC 50 value of 12 nM on fipronil-resistant RDL receptors from a plant-feeding mite, Tetranychus urticae Koch, in TEVC experiments, whereas 30 µM of fipronil only blocked 27% of GABA-induced current [24]. In the present study, fluralaner was tested on native D. melanogaster GABA receptors, in situ, instead of heterologously expressed RDL receptors.…”

Section: Discussionmentioning

confidence: 99%

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Mosquitocidal Activity and Mode of Action of the Isoxazoline Fluralaner

Jiang

Tsikolia

Bernier

et al. 2017

IJERPH

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Mosquitoes, such as Aedes aegypti and Anopheles gambiae, are important vectors of human diseases. Fluralaner, a recently introduced parasiticide, was evaluated as a mosquitocide in this study. On Ae. aegypti and An. gambiae fourth-instar larvae, fluralaner had 24-h LC50 (lethal concentration for 50% mortality) values of 1.8 ppb and 0.4 ppb, respectively. Following topical application to adult Ae. aegypti, fluralaner toxicity reached a plateau in about 3 days, with 1- and 3-day LD50 (lethal dose for 50% mortality) values of 1.3 ng/mg and 0.26 ng/mg, suggesting a slowly developing toxicity. Fipronil outperformed fluralaner by up to 100-fold in adult topical, glass contact, and feeding assays on Ae. aegypti. These data show that fluralaner does not have exceptional toxicity to mosquitoes in typical exposure paradigms. In electrophysiological recordings on Drosophila melanogaster larval central nervous system, the effectiveness of fluralaner for restoring nerve firing after gamma-aminobutyric acid (GABA) treatment, a measure of GABA antagonism, was similar in susceptible Oregon-R and cyclodiene-resistant rdl-1675 strains, with EC50 (half maximal effective concentration) values of 0.34 µM and 0.29 µM. Although this finding suggests low cross resistance in the presence of rdl, the moderate potency, low contact activity, and slow action of fluralaner argue against its use as an adult mosquitocide for vector control.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Mosquitocidal Activity and Mode of Action of the Isoxazoline Fluralaner

Jiang

Tsikolia

Bernier

et al. 2017

IJERPH

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“…Several types of evidence establish that isoxazolines [57][58][59][60][61][62][63][64][65][66] and meta-diamides (including mDA-7 [24,67] and BPB-1 [68]) are NCAs but at a different high affinity site(s) than those for compounds acting at the NCA-IA, NCA-IB and AVE targets ( …”

Section: Nca Actionmentioning

confidence: 99%

“…A 2012 compilation considering the chronology and numbers for introduction of the current insecticides gave the GABA-R targeting compounds as only 1.7% of the total with half of them introduced by 1955 [81]. Newly introduced GABAergic insecticides are flu and afoxolaner used for flea and tick control on cats and dogs [58,[62][63][64][65]. There are also important crop pests highly sensitive to NCA-IIs [24,60,82] indicating possible expanded use on optimization.…”

Section: Prospectsmentioning

confidence: 99%

Novel GABA receptor pesticide targets

Casida

Durkin

2015

Pesticide Biochemistry and Physiology

118

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The γ-aminobutyric acid (GABA) receptor has four distinct but overlapping and coupled targets of pesticide action importantly associated with little or no cross-resistance. The target sites are differentiated by binding assays with specific radioligands, resistant strains, site-directed mutagenesis and molecular modeling. Three of the targets are for non-competitive antagonists (NCAs) or channel blockers of widely varied chemotypes. The target of the first generation (20th century) NCAs differs between the larger or elongated compounds (NCA-IA) including many important insecticides of the past (cyclodienes and polychlorocycloalkanes) or present (fiproles) and the smaller or compact compounds (NCA-IB) highly toxic to mammals and known as cage convulsants, rodenticides or chemical threat agents. The target of greatest current interest is designated NCA-II for the second generation (21st century) of NCAs consisting for now of isoxazolines and meta-diamides. This new and uniquely different NCA-II site apparently differs enough between insects and mammals to confer selective toxicity. The fourth target is the avermectin site (AVE) for allosteric modulators of the chloride channel. NCA pesticides vary in molecular surface area and solvent accessible volume relative to avermectin with NCA-IBs at 20-22%, NCA-IAs at 40-45% and NCA-IIs at 57-60%. The same type of relationship relative to ligand-docked length is 27-43% for NCA-IBs, 63-71% for NCA-IAs and 85-105% for NCA-IIs. The four targets are compared by molecular modeling for the Drosophila melanogaster GABA-R. The principal sites of interaction are proposed to be: pore V1' and A2' for NCA-IB compounds; pore A2', L6' and T9' for NCA-IA compounds; pore T9' to S15' in proximity to M1/M3 subunit interface (or alternatively an interstitial site) for NCA-II compounds; and M1/M3, M2 interfaces for AVE. Understanding the relationships of these four binding sites is important in resistance management and in the discovery and use of safe and effective pest control agents.

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“…Pyrethroids like deltamethrin (DEL) kill insects by acting on sodium channels [6], and neonicotinoids like acetamiprid (ACE) act as agonists of the nicotinic acetylcholine receptors [7,8], whereas organophosphates like chlorpyrifos (CHL) inhibit the action of the acetylcholinesterase, resulting in increased acetylcholine concentrations at the synapses [9,10]. More recent compounds like the phenylpyrazol fipronil (FIP) act as agonists of the insect RDL GABA receptors [11,12]. In all cases, insecticides are neurotoxic because they disrupt neurotransmission and alter insect behavior or survival [13].…”

Section: Introductionmentioning

confidence: 99%

The Differential Effect of Low-Dose Mixtures of Four Pesticides on the Pea Aphid Acyrthosiphon pisum

Taillebois

Thany

2016

Insects

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The modes of action of most insecticides are known, but little information exists regarding the toxicological interactions involving insecticide mixtures at low doses. The effects of mixtures of four insecticides were investigated using LC10 values (concentration leading to 10% mortality), acetamiprid (ACE, 0.235 µg/mL), chlorpyriphos (CHL, 107.0 µg/mL), deltamethrin (DEL, 5.831 µg/mL), and fipronil (FIP, 3.775 µg/mL) on the larvae of the pea aphid, Acyrthosiphon pisum. After 24 h exposure, 6 of the 11 tested combinations, DEL/FIP, ACE/DEL, CHL/FIP, ACE/DEL/FIP, ACE/CHL/FIP, and ACE/DEL/CHL/FIP, were toxic through an additive effect. Four combinations, ACE/FIP, DEL/CHL, ACE/CHL, and ACE/DEL/CHL had a synergistic effect, whereas only one DEL/CHL/FIP showed an antagonistic effect. The toxic effect of these mixtures was confirmed after 48 h of exposure, revealing an enhanced toxicity of CHL, DEL, and FIP in combination with ACE. We suggest that an insect pest management strategy should be evaluated in the future using different combinations of insecticides.

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Differential mechanisms of action of the novelγ-aminobutyric acid receptor antagonist ectoparasiticides fluralaner (A1443) and fipronil

Abstract: The findings indicate that rdl-type fipronil-resistant pests do not show cross-resistance to fluralaner owing to the differential actions of fluralaner and fipronil on the GABAR.

Cited by 69 publications

References 17 publications

Mosquitocidal Activity and Mode of Action of the Isoxazoline Fluralaner

Mosquitocidal Activity and Mode of Action of the Isoxazoline Fluralaner

Novel GABA receptor pesticide targets

The Differential Effect of Low-Dose Mixtures of Four Pesticides on the Pea Aphid Acyrthosiphon pisum

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