Receptor structure-guided neonicotinoid design.

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.