Nicotinic Acetylcholine Receptor Competitive Modulators, Allosteric Modulators, and Channel Blockers: Target and Selectivity Aspects

Identification and characterization of insect nicotinic acetylcholine receptor ( n AChR) subtypes may open a new era for subtype-selective insecticides with specific biological profiles and maximal safety. Crystal structures of acetylcholine binding proteins (AChBPs) show conserved architectural folds and provide a theoretical foundation for homology models for ligand binding domains of insect n AChRs. Ligand-receptor interactions of AChBP subtypes have been established by high-resolution crystal structures of AChBP-neonicotinoid complexes with selected neonicotinoids demonstrating their molecular recognition, binding mode, and binding conformations. Over the past decade, fluorine-containing insecticides targeting n AChR at the orthosteric binding site have been developed, showing improvements in insect selectivity and environmental profiles. Recently, functional expression of n AChRs conjugated with auxiliary proteins enhanced understanding of fruit fly, honeybee, and bumblebee n AChRs and their interactions with neonicotinoids. Today, identification of expression-enabling cofactors leads to studying the interaction of ligands with n AChRs. Latest examples demonstrate the n AChRs as targets for insect pest control in modern crop protection.