Understanding receptor selectivity and ligand stereochemistry of insecticides and therapeutic agents for nicotinic acetylcholine receptor subtypes

Abstract

Neonicotinoids are insecticides selective for nicotinic acetylcholine receptors (nAChRs) in agricultural pests having a far lower affinity for vertebrate receptors. Additional understanding for the basis of receptor selectivity with the nAChRs is crucial for ascertaining whether insecticides are responsible for the bee “colony collapse disorder” or other toxicities in insect populations. Moreover receptor selectivity is integral to improved efficacy of new nicotinic therapeutic agents. The acetylcholine binding protein (AChBP), through mutagenesis modifications, can serve as a template for design of new therapeutic agents and insecticides. Its chief advantage stems from its solubility, making complexes amenable to crystallography and physical studies. Ligand dissociation constants were determined for steriosomers with radio‐ligand binding assays, using [3H]‐Epibatidine competing for purified Aplysia or Lymnaea AChBP sites. We have obtained evidence that stereochemistry in alkaloid, nicotinoid, and neonicotinoid ligands results in substantial differences of binding affinity to specific AChBPs. These data will be compared with crystallographic data to ascertain determinants essential for agonist and antagonist selectivity.Support from (R37‐GM18360, F32 NS043063, R01 ES08424, GM07752‐29)