The nicotinic acetylcholine receptors (nAChRs) are targets for human and veterinary medicines as well as insecticides. Subtypeselectivity 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 NO 2 group of imidacloprid and 2) neonicotinoid-unique stacking and CHbonds 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.

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Effects of imidacloprid, clothianidin, thiacloprid and related compounds on the acetylcholine (ACh)-induced response of the recombinant, expressed chicken a4b 2 nicotinic acetylcholine receptor (nAChR) were investigated using voltage-clamp electrophysiology. Imidacloprid and clothianidin enhanced the amplitude of the response to ACh of a4b 2 nAChR. In complete contrast, thiacloprid attenuated the amplitude of the response to ACh of a4b 2 nAChR. Replacing the nitro group of imidacloprid by a cyano group abolished the potentiating action, whereas exchanging the cyano group of thiacloprid for a nitro group conferred the ability to potentiate the ACh response. All three neonicotinoids shifted the ACh concentration-response curve without influencing the peak current amplitude of the ACh response.

P-glycoprotein (P-gp) is a member of the ATP-binding cassette transporter family. It actively transports a wide variety of compounds out of cells and functions as an energy-dependent efflux pump to protect humans from xenobiotics. P-gp also plays an important role in multidrug resistance in the treatment of cancers. However, the mechanism of P-gp substrate recognition is complicated and still poorly understood. In this study, we screened diverse chemicals, especially agrochemicals by measuring the ATPase activity of human P-gp and found that several classes of chemicals including dibenzoylhydrazine (DBH) insecticides could be substrates of P-gp. ATPase activity was quantitatively analyzed using a 3D quantitative structure-activity relationship, comparative molecular field analysis (CoMFA), and the favorable and unfavorable properties of ligands for ATPase activity were clarified. We also performed a docking simulation of a DBH-type compound with P-gp to predict the binding mode, which was supported by the CoMFA results.

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