title: Receptor structure-guided neonicotinoid design.
abstract: Neonicotinoid agonists with a nitroimino pharmacophore are used worldwide for crop protection and animal health care. Chemical and structural biology investigations on the nicotinic acetylcholine receptor structure in the neonicotinoid-bound state revealed a unique niche beyond the nitro oxygen tip toward the loop D subsite. The nitroimino pharmacophore can be replaced to suitably fit the newly recognized cavity by acylimino [═NC(O)R] and phenoxycarbonylmino [═NC(O)OPh] variants. The ═NC(O)R analogues, where R is a hydrogen acceptor pyridine, pyrazine, or trifluoromethyl, showed high receptor potency, suggesting that the extended pharmacophore undergoes hydrogen bonding with the loop D Arg basic residue. The ═NC(O)OPh analogues had appreciably higher affinity with an electron-donating substituent on the phenyl ring than with an electron-withdrawing group, predicting that the benzene plane and loop D Trp indole form a face-to-edge aromatic interaction. These studies illustrate strategic ligand design combining the chemorational approach with the three-dimensional receptor structure.
authors.affiliation: Faculty of Education, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan. mtomizaw@gifu-u.ac.jp
authors.forename: Motohiro
authors.initials: M
authors.lastname: Tomizawa
authors.forename: Shinzo
authors.initials: S
authors.lastname: Kagabu
authors.forename: John E
authors.initials: JE
authors.lastname: Casida
mesh_terms: D000691:Anabasine / Q000737:chemistry*; D000818:Animals; D001665:Binding Sites; D015195:Drug Design; D057927:Hydrophobic and Hydrophilic Interactions; D007093:Imidazoles / Q000737:chemistry / Q000378:metabolism; D007306:Insecticides / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D000073943:Neonicotinoids; D009574:Nitro Compounds / Q000737:chemistry / Q000378:metabolism; D011725:Pyridines / Q000737:chemistry / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013843:Thiazines / Q000737:chemistry / Q000378:metabolism
chemical_list: D007093:Imidazoles; D007306:Insecticides; D000073943:Neonicotinoids; D009574:Nitro Compounds; D011725:Pyridines; D011978:Receptors, Nicotinic; D013843:Thiazines; C082359:imidacloprid; C417209:thiacloprid; D000691:Anabasine