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Molecular Pharmacology

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OtherMINIREVIEW

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

Kazuhiko Matsuda, Satoshi Kanaoka, Miki Akamatsu and David B. Sattelle
Molecular Pharmacology July 2009, 76 (1) 1-10; DOI: https://doi.org/10.1124/mol.109.055186
Kazuhiko Matsuda
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Satoshi Kanaoka
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Miki Akamatsu
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David B. Sattelle
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Abstract

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-π 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-α nAChR subunits.

Footnotes

  • This work was supported by the “Academic Frontier” Project for Private Universities from the Ministry of Education, Culture, Sports, Science and Technology [Grant 04F011]; a Grant-in-Aid for Scientific Research (B) from the Japan Society for the Promotion of Science [Grant 21380039]; the Integrated Research Project for Plant, Insect and Animal using Genome Technology from the Ministry of Agriculture, Forestry and Fisheries of Japan [Grant 1302]; and by The Medical Research Council of the United Kingdom.

  • ABBREVIATIONS: nAChR, nicotinic acetylcholine receptor; Ac, Aplysia californica; ACh, acetylcholine; AChBP, acetylcholine binding protein; LBD, ligand binding domain; Ls, Lymnaea stagnalis; TM, transmembrane region; EP, electrostatic potential; PDB, Protein Data Bank.

    • Accepted March 25, 2009.
    • Received January 30, 2009.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 76 (1)
Molecular Pharmacology
Vol. 76, Issue 1
1 Jul 2009
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OtherMINIREVIEW

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

Kazuhiko Matsuda, Satoshi Kanaoka, Miki Akamatsu and David B. Sattelle
Molecular Pharmacology July 1, 2009, 76 (1) 1-10; DOI: https://doi.org/10.1124/mol.109.055186

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OtherMINIREVIEW

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

Kazuhiko Matsuda, Satoshi Kanaoka, Miki Akamatsu and David B. Sattelle
Molecular Pharmacology July 1, 2009, 76 (1) 1-10; DOI: https://doi.org/10.1124/mol.109.055186
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  • Article
    • Abstract
    • Neonicotinoids and Nicotinic Ligands Defined by Computational Chemistry
    • Differential Binding of Nicotine and Neonicotinoids
    • Structural Factors and the Diverse Actions of Neonicotinoids
    • Target-Based Neonicotinoid Resistance: A Structural Interpretation
    • Prospects for Design of Species-Specific Insecticides
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