The favorable selective toxicity of neonicotinoid insecticides (represented here by imidacloprid, thiacloprid, and a nitromethylene analogue) for insects versus mammals is not shared by three of their N-unsubstituted imine derivatives or by nicotine or epibatidine. The same selectivity pattern is evident at the receptor level, i.e., the insect nicotinic acetylcholine receptor (nAChR) versus mammalian nAChR subtypes (alpha1, alpha3, alpha4, and alpha7) assayed independently. The insect-selective compounds are not protonated with a nitroimine, cyanoimine, or nitromethylene group and the mammalian-selective compounds are ionized at physiological pH. We propose that the negatively charged tip of the nitro or cyano group (not a partial positive charge at imidazolidine N-1 as suggested earlier) interacts with a putative cationic subsite of the insect nAChR. This contrasts with the mammalian nAChRs where the iminium cation (+C-NH2 <--> C =+NH2) of the neonicotinoid imine derivatives or ammonium nitrogen of nicotine or epibatidine interacts with the anionic subsite.