Toxicity and mode of action of benzhydrolpiperidines and related compounds in insects

The benzyhydrolpiperidines are a new chemical class of insecticide with potent effects on lepidopteran larvae, but little activity against flies or cockroaches. These materials have a slow action in diet assays, causing progressive mortality over a 10 day period. Signs of intoxication also develop slowly after topical application to Helicoverpa virescens larvae, and include ataxia, paralysis, and curling, with tremors and convulsions occurring when the insects are disturbed. The central nervous system shows depressed nerve activity in prostrate larvae, unlike the hyperexcitation caused by DDT. Similarly, nerve discharge in stretch receptor preparations of tobacco budworm larvae is blocked by benzyhydrolpiperidines, whereas motor nerve activity is apparently unaffected. In cricket synaptosomes, benzyhydrolpiperidines block veratridine-evoked release of labeled acetylcholine, likely by an action on sodium channels, with several compounds having IC50 values in the nanomolar range. Highest potency was observed for N-oxide compounds, although they required prolonged incubation to observe ail effect. Metabolism studies of C-14-labeled N-oxide observed no conversion consistent with bioactivation to the corresponding piperidine, confirming that the N-oxides possessed intrinsic activity. Overall, the potency for blocking veratridine-evoked release in cricket synaptosomes displayed some correlation with LC50 values for dietary exposure to tobacco budworm larvae, although the most active compound was not toxic to crickets. Thus, a slowly developing sodium channel blockade appears to underlie the mode of action of these compounds, but the effect is only toxicologically significant in susceptible species. (C) 2002 Elsevier Science (USA). All rights reserved.