A hypothesis to account for the selective and diverse actions of neonicotinoid insecticides at their molecular targets, nicotinic acetylcholine receptors: catch and release in hydrogen bond networks

Abstract

The low mammalian toxicity of neonicotinoid insecticides has been shown to be attributable, at least in part, to their selective actions on insect nicotinic acetylcholine receptors (nAChRs). There are multiple nAChRs in insects and a wealth of neonicotinoid chemicals. Studies to date have discribed a wide range of effects on nAChRs, notably partial agonist, super agonist and antagonist actions. Both the diversity of the neonicotinoid actions and their selectivity for insect over vertebrate nAChRs are the result of physicochemical and steric interactions at their molecular targets (nAChRs). In such interactions, the formation and breakage of hydrogen bond (HB) networks plays a key role. Therefore the loss or gain of even a single HB resulting from either structural changes in neonicotinoids, or the amino acid sequence of a particular nAChR subunit, could result in a drastic modification of neonicotinoid actions. In addition to the amino acid residues, the backbone carbonyl of nAChRs may also be involved in the formation of HB networks with neonicotinoids.

A Role for Leu118 of Loop E in Agonist Binding to the α7 Nicotinic Acetylcholine Receptor

“…Several studies have shown that electrostatic forces are important for imidacloprid interaction with nAChRs Ihara et al, 2007). Here we show that substitutions of Leu118 in loop E by acidic or basic residues strikingly influence the responses of ␣7 to ACh.…”

Systemic action of novel neonicotinoid insecticide IPP‐10 and its effect on the feeding behaviour of Rhopalosiphum padi on wheat

“…The results of topical application indicated that IPP‐10 had profound contact activity against R. padi , and the compound could therefore be used to control sucking insects by foliar application. It has been reported that imidacloprid shows good activity against aphids by foliar application, so the mechanism of contact activity of IPP‐10 might be similar to that of imidacloprid, as both insecticides are neonicotinoids 10–13. However, the mode of action of IPP‐10 had not yet been clearly identified.…”

Binding of imidacloprid, thiamethoxam and N‐desmethylthiamethoxam to nicotinic receptors of Myzus persicae: pharmacological profiling using neonicotinoids, natural agonists and antagonists

“…Most importantly, the ligand binding site should be understood as a flexible pocket that enables structural changes of receptor peptide sequences lining the binding pocket, and eventually also of the ligand, thus achieving energetically favourable tight binding. A hypothesis in line with this view has been presented, 41 and experimental approaches to analyse ligand-receptor interactions in model systems have been taken. 42,43 Weak competitors have been frequently misunderstood as having low or even no affinity to the receptor type under study, while their intrinsic affinity to a different (perhaps even neighbouring) site on the same receptor may be high.…”