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Diverse Actions and Target-Site Selectivity of Neonicotinoids: Structural Insights

Department of Applied Biological Chemistry, Faculty of Agriculture, Kinki University, Nara, Japan (K.M.); Graduate School of Agriculture, Kyoto University, Kyoto, Japan (S.K., M.A.); and MRC Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, Le Gros Clark Building, University of Oxford, Oxford, United Kingdom (D.B.S.)

The nicotinic acetylcholine receptors (nAChRs) are targets for human and veterinary medicines as well as insecticides. Subtype-selectivity among the diverse nAChR family members is important for medicines targeting particular disorders, and pest-insect selectivity is essential for the development of safer, environmentally acceptable insecticides. Neonicotinoid insecticides selectively targeting insect nAChRs have important applications in crop protection and animal health. Members of this class exhibit strikingly diverse actions on their nAChR targets. Here we review the chemistry and diverse actions of neonicotinoids on insect and mammalian nAChRs. Electrophysiological studies on native nAChRs and on wild-type and mutagenized recombinant nAChRs have shown that basic residues particular to loop D of insect nAChRs are likely to interact electrostatically with the nitro group of neonicotinoids. In 2008, the crystal structures were published showing neonicotinoids docking into the acetylcholine binding site of molluscan acetylcholine binding proteins with homology to the ligand binding domain (LBD) of nAChRs. The crystal structures showed that 1) glutamine in loop D, corresponding to the basic residues of insect nAChRs, hydrogen bonds with the NO₂ group of imidacloprid and 2) neonicotinoid-unique stacking and CH- bonds at the LBD. A neonicotinoid-resistant strain obtained by laboratory-screening has been found to result from target site mutations, and possible reasons for this are also suggested by the crystal structures. The prospects of designing neonicotinoids that are safe not only for mammals but also for beneficial insects such as honey bees (Apis mellifera) are discussed in terms of interactions with non- nAChR subunits.

Received for publication January 30, 2009.

Accepted for publication March 25, 2009.

Address correspondence to: Dr. Kazuhiko Matsuda, Department of Applied Biological Chemistry, School of Agriculture, Kinki University, 3327-204 Nakamachi, Nara 631-8505, Japan. E-mail: kmatsuda{at}nara.kindai.ac.jp