NEONICOTINOID INSECTICIDE TOXICOLOGY: Mechanisms of Selective Action

Abstract

The neonicotinoids, the newest major class of insecticides, have outstanding potency and systemic action for crop protection against piercing-sucking pests, and they are highly effective for flea control on cats and dogs. Their common names are acetamiprid, clothianidin, dinotefuran, imidacloprid, nitenpyram, thiacloprid, and thiamethoxam. They generally have low toxicity to mammals (acute and chronic), birds, and fish. Biotransformations involve some activation reactions but largely detoxification mechanisms. In contrast to nicotine, epibatidine, and other ammonium or iminium nicotinoids, which are mostly protonated at physiological pH, the neonicotinoids are not protonated and have an electronegative nitro or cyano pharmacophore. Agonist recognition by the nicotinic receptor involves cation-pi interaction for nicotinoids in mammals and possibly a cationic subsite for interaction with the nitro or cyano substituent of neonicotinoids in insects. The low affinity of neonicotinoids for vertebrate relative to insect nicotinic receptors is a major factor in their favorable toxicological profile.

Structure-guided drug design: Conferring selectivity among neuronal nicotinic receptor and acetylcholine-binding protein subtypes

“…Nicotinoids and Neonicotinoids-These compounds present an interesting series owing to their selectivity for the insect receptor and their commercial applications as insecticides [4,5]. Radiolabeling experiments show that these ligands bind to the agonist site and with the pyridine ring system positioned similar to that in epibatidine or nicotine [4,5].…”

“…Radiolabeling experiments show that these ligands bind to the agonist site and with the pyridine ring system positioned similar to that in epibatidine or nicotine [4,5]. The unique characteristics of the neonicotinoids stem from substitution of the cationic nitrogen of the tertiary or quaternary agonists that stimulate the mammalian receptor.…”

“…The unique characteristics of the neonicotinoids stem from substitution of the cationic nitrogen of the tertiary or quaternary agonists that stimulate the mammalian receptor. The substitution renders the neonicotinoid nitrogen position neutral to anionic [4,5].…”

“…Moreover, if we extend our considerations beyond the mammalian species, we see even greater structural diversity, and the determinants governing ligand recognition between insect and mammalian nicotinic receptors are the basis for the selective toxicity of the neonicotinoids enjoying current use as insecticides [4,5] Of the nine subunits in neuronal nicotinic receptors in mammals, designated as α2 through α10 and containing a vicinal disulfide on the C loop of their principal binding face, α2, α3, α4 and α6 associate with the complementary β2, β3 and β4 subunits to form pentameric molecules. The α5 subunit behaves similarly to a β subunit in not having its principal face creating a binding site.…”

“…Since the nicotinic receptor in skeletal muscle forms the signal transducer for neuromuscular transmission controlling motor activity, and in the CNS, nicotinic receptors primarily mediate release of neurotransmitters from their presynaptic sites, a variety of toxins from marine snails, terrestrial plants, coral as stationary animals, and reptiles have evolved to block or modulate nicotinic receptor function. Several of these compounds, in contrast to acetylcholine, carbamylcholine, nicotine and epibatidine, show considerable selectivity towards receptor subtype [1][2][3][4][5]. Therefore these compounds can be considered as lead templates for developing selective ligands.…”