Minor structural changes in nicotinoid insecticides confer differential subtype selectivity for mammalian nicotinic acetylcholine receptors

Abstract

1. The major nitroimine insecticide imidacloprid (IMI) and the nicotinic analgesics epibatidine and ABT-594 contain the 6-chloro-3-pyridinyl moiety important for high activity and/or selectivity. ABT-594 has considerable nicotinic acetylcholine receptor (AChR) subtype specificity which might carry over to the chloropyridinyl insecticides. This study considers nine IMI analogues for selectivity in binding to immune-isolated α1, α3 and α7 containing nicotinic AChRs and to purported α4β2 nicotinic AChRs. 2. α1- and α3-Containing nicotinic AChRs (both immune-isolated by mAb 35, from Torpedo and human neuroblastoma SH-SY5Y cells, respectively) are between two and four times more sensitive to DN-IMI than to (-)-nicotine. 3. With immune-isolated α3 nicotinic AChRs, the tetrahydropyrimidine analogues of IMI with imine or nitromethylene substituents are 3-4 fold less active than (-)-nicotine. The structure-activity profile with α3 nicotinic AChRs from binding assays is faithfully reproduced in agonist potency as induction of 86rubidium ion efflux in intact cells. 4. α7-Containing nicotinic AChRs of SH-SY5Y cells (immune-isolated by mAb 306) and rat brain membranes show maximum sensitivity to the tetrahydropyrimidine analogue of IMI with the nitromethylene substituent. 5. The purported α4β2 nicotinic AChRs [mouse and rat brain] are similar in sensitivity to DN-IMI, the tetrahydropyrimidine nitromethylene and nicotine. 6. The commercial insecticides (IMI, acetamiprid and nitenpyram) have low to moderate potency at the α3 and purported α4β2 nicotinic AChRs and are essentially inactive at α1 and α7 nicotinic AChRs. 7. In conclusion, the toxicity of the analogues and metabolites of nicotinoid insecticides in mammals may involve action at multiple receptor subtypes with selectivity conferred by minor structural changes.