Mini ReviewNovel GABA receptor pesticide targets
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GABAergic pesticides
Our continuing ability to control pests that compete for food and fiber and transmit disease is dependent on the discovery of new compounds and biochemical targets that circumvent cross-resistance patterns and give a fresh start in pesticide management to maintain effective control [1]. Any novel target is therefore a valuable contribution not only to science but also to human welfare. The γ-aminobutyric acid (GABA) receptor (GABA-R) is the target for many insecticides, acaricides,
Structure and function
GABA is the principal inhibitory neurotransmitter in the insect and mammalian nervous systems [5], [6], [7], [8], [9], [10], [11]. Ionotropic GABA-Rs are ligand-gated chloride channels consisting of five heteromeric subunits in mammals (usually two α subunits. two β subunits and an additional subunit) and presumably the homopentameric RDL subunit [12] in insects arranged around a central pore. The amino acid sequences and genomics are well characterized [10], and the individual subunits can be
Structures
The first generation or 20th century GABAergic insecticides, designated here as non-competitive antagonist (NCA) Type IA (NCA-IA) (Fig. 1), consist of many major commercial compounds (Fig. 2 and Supplementary Material Fig. S1). The botanical picrotoxinin was reported in 1875 to control pest insects. The polychlorocycloalkanes (lindane and toxaphene) and cyclodienes (e.g. dieldrin and α-endosulfan) were introduced in 1945–1961 and the phenylpyrazole fipronil in 1988. A large number and variety
Structures
The last 5 years has been an exciting time in studies of the GABAergic insecticides with the announcement of two second generation or 21st century chemotypes acting as NCAs and designated here as NCA-II (Fig. 1, Fig. 3). The research in every case started from phthalic and anthranilic diamides, which are activators of insect ryanodine receptors, and ended up with insecticides of a completely different mode of action. Researchers at Nissan Chemical Industries in Japan and DuPont in the United
Allosteric modulator (AVE)
The macrocyclic lactone ave (Fig. 4) was first used as an antiparasitic drug in 1981 and as an agricultural pesticide in 1985 [69] and several analogs and derivatives (such as emamectin benzoate, lepimectin and milbemectin) are also important commercial compounds [1]. Ivermectin was the essential agent in greatly reducing the incidence of river blindness in millions of people by controlling the schistisome vector [69]. Ave is a positive allosteric modulator of several ligand-gated channels
Radioligand binding assays
Radioligand binding studies play an important role in defining GABAergic pesticide action. The best radioligand for each binding site is the pesticide itself or an arguably relevant analog, highly potent (i.e. high affinity and percent-specific binding) and available or attainable at adequate specific activity (normally 3H, 32P or 35S analyzed by liquid scintillation counting but recently 14C quantified by accelerator mass spectroscopy [50]). The radioligands considered here for the four
Prospects
The prospects for GABAergic pesticides can be projected from the rate at which new compounds have been introduced (Fig. 1) and the amounts used. More than three billion pounds of NCA-IA insecticides were used in the past seven decades. There was no target site cross-resistance of the NCA-IA compounds to DDT, organophosphate or any other major insecticide chemotypes. Use of NCA-IAs drastically declined in the late 20th century with problems of resistance, persistence and environmental
Acknowledgments
We thank Madhur Garg, Breanna Ford and Liane Kuo for outstanding contributions in literature research, discussions and manuscript preparation. KAD acknowledges NSF grant CHE-0840505 for support of the Molecular Graphics and Computation Facility.
References (82)
γ-Aminobutyrate- and glutamate-gated chloride channels as targets of insecticides
Adv. Insect Physiol
(2013)GABA receptors of insects
Adv. Insect Physiol
(1990)- et al.
GABA receptor subunit composition relative to insecticide potency and selectivity
Toxicol. Lett
(2001) - et al.
Role of human GABAA receptor β3 subunit in insecticide toxicity
Toxicol. Appl. Pharmacol
(2001) - et al.
Meta-diamide insecticides acting on distinct sites of RDL GABA receptor from those for conventional noncompetitive antagonists
Insect Biochem. Mol. Biol
(2013) - et al.
Inhibition of gamma-aminobutyric acid (GABA)-induced chloride uptake by gamma-BHC and heptachlor epoxide
Comp. Biochem. Physiol. C Comp. Pharmacol
(1982) - et al.
GABA-gated chloride channel: binding site for 4’-ethynyl-4-n-[2.3-3H2]propylbicycloorthobenzoate ([3H]EBOB) in vertebrate brain and insect head
Pestic. Biochem. Physiol
(1992) - et al.
Fipronil-based photoaffinity probe for Drosophila and human β3 GABA receptors
Bioorg. Med. Chem. Lett
(2001) - et al.
House fly brain γ-aminobutyric acid-gated chloride channel: target for multiple classes of insecticides
Pestic. Biochem. Physiol
(1991) - et al.
Action of phenylpyrazole insecticides at the GABA-gated chloride channel
Pestic. Biochem. Physiol
(1993)
Role of cerebellar granule cell-specific GABAA receptor subtype in the differential sensitivity of [3H]ethynylbicycloorthobenzoate binding to GABA mimetics
Neurosci. Lett
Drosophila GABA-gated chloride channel: modified [3H]EBOB binding site associated with Ala → Ser or Gly mutants of Rdl subunit
Life Sci
Structure-toxicity relationships of 2,6,7-trioxabicyclo[2.2.2]octanes and related compounds
Toxicol. Appl. Pharmacol
Structure-toxicity relationships of 1-substituted-4-alkyl-2,6,7-trioxabicyclo[2.2.2]octanes
Toxicol. Appl. Pharmacol
House fly head GABA-gated chloride channel: four putative insecticide binding sites differentiated by [3H]EBOB and [35S]TBPS
Pestic. Biochem. Physiol
House fly head GABA-gated chloride channel: toxicologically relevant binding site for avermectins coupled to site for ethynylbicycloorthobenzoate
Pestic. Biochem. Physiol
Differential antagonism of tetramethylenedisulfotetramine-induced seizures by agents acting at NMDA and GABAA receptors
Toxicol. Appl. Pharmacol
The antiparasitic isoxazoline A1443 is a potent blocker of insect ligand-gated chloride channels
Biochem. Biophys. Res. Commun
4-Azolylphenyl isoxazoline insecticides acting at the GABA gated chloride channel
Bioorg. Med. Chem. Lett
Discovery and mode of action of afoxolaner, a new isoxazoline parasiticide for dogs
Vet. Parasitol
The novel isoxazoline ectoparasiticide fluralaner: selective inhibition of arthropod γ-aminobutyric acid- and L-glutamate-gated chloride channels and insecticidal/acaricidal activity
Insect Biochem. Mol. Biol
Insecticidal 3-benzamido-N-phenylbenzamides specifically bind with high affinity to a novel allosteric site in housefly GABA receptors
Pestic. Biochem. Physiol
Anticholinesterase insecticide retrospective
Chem. Biol. Interact
IRAC MoA Classification Scheme
Insecticide action at the GABA-gated chloride channel: recognition, progress, and prospects
Arch. Insect Biochem. Physiol
Insecticide binding sites on γ-aminobutyric acid receptors of insects and mammals
Recent advances on heterocyclic insecticides acting as GABA antagonists
Non-competitive GABA antagonists: probing the mechanisms of their selectivity for insect versus mammalian receptors
Pest Manag. Sci
Insect GABA receptors: splicing, editing, and targeting by antiparasitics and insecticides
Mol. Pharmacol
γ-Aminobutyric acid receptors: a rationale for developing selective insect pest control chemicals
International Union of Pharmacology. LXX. Subtypes of γ-aminobutyric acidA receptors: classification on the basis of subunit composition, pharmacology, and function. Update
Pharmacol. Rev
Crystal structure of human GABAA receptor
Nature
RDL receptors
Biochem. Soc. Trans
A single-amino acid substitution in γ-aminobutyric acid subtype A receptor locus is associated with cyclodiene insecticide resistance in Drosophila populations
Proc. Natl. Acad. Sci. U.S.A.
Structural model for γ-aminobutyric acid receptor noncompetitive antagonist binding: widely diverse structures fit the same site
Proc. Natl. Acad. Sci. U.S.A.
X-ray structure of a prokaryotic pentameric ligand-gated ion channel
Nature
Principles of activation and permeation in an anion-selective cys-loop receptor
Nature
A hierarchical approach to all-atom protein loop prediction
Proteins Struct. Funct. Bioinformat
The SWISS-MODEL workspace: a web-based environment for protein structure homology modelling
Bioinformatics
Protein structure homology modeling using SWISS-MODEL workspace
Nat. Protoc
SWISS-MODEL: modelling protein tertiary and quaternary structure using evolutionary information
Nucleic Acids Res
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