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

1999; Wiley; Volume: 127; Issue: 1 Linguagem: Inglês

10.1038/sj.bjp.0702526

1476-5381

Motohiro Tomizawa, John E. Casida,

Cholinesterase and Neurodegenerative Diseases

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 immuno‐isolated α 1 , α 3 and α 7 containing nicotinic AChRs and to purported α 4 β 2 nicotinic AChRs. α 1 ‐ and α 3 ‐Containing nicotinic AChRs (both immuno‐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. With immuno‐isolated α 3 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 α 3 nicotinic AChRs from binding assays is faithfully reproduced in agonist potency as induction of 86 rubidium ion efflux in intact cells. α 7 ‐Containing nicotinic AChRs of SH‐SY5Y cells (immuno‐isolated by mAb 306) and rat brain membranes show maximum sensitivity to the tetrahydropyrimidine analogue of IMI with the nitromethylene substituent. The purported α 4 β 2 nicotinic AChRs [mouse ( Chao & Casida, 1997 ) and rat brain] are similar in sensitivity to DN‐IMI, the tetrahydropyrimidine nitromethylene and nicotine. The commercial insecticides (IMI, acetamiprid and nitenpyram) have low to moderate potency at the α 3 and purported α 4 β 2 nicotinic AChRs and are essentially inactive at α 1 and α 7 nicotinic AChRs. 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. British Journal of Pharmacology (1999) 127 , 115–122; doi: 10.1038/sj.bjp.0702526