Bioactivation and mode of action of the oxadiazine indoxacarb in insects

DPX-MP062 (indoxacarb) is a novel oxadiazine insecticide which has good fie ld activity against a number of pest Lepidoptera, as well as certain Homopt era and Coleoptera. Indoxacarb (discovered and developed by E.I. DuPont and Co.) is a 75%S:25%R mixture of enantiomers at the chiral bicyclic carbon; DPX-JW062 is the corresponding racemic compound: Several species of lepidop teran larvae can rapidly metabolize C-14-JW062 to C-14-DCJW (for N-decarbom ethoxyllated JW062) after ingestion, and more slowly after topical treatmen t; this conversion is correlated with the appearance of neurotoxic symptoms . Several sucking insects are also capable of absorbing and bioactivating i ndoxacarb after either dermal or oral administration, but do so much more s lowly than the Lepidoptera. DCJW is a highly potent, voltage-dependent bloc ker of Na+-dependent compound action potentials when tested in a Manduca se xta larval abdominal motoneuron preparation; DPX-JW062 was much less potent in this regard. When larvae were poisoned in vivo, onset of paralysis and block of central nervous system action potentials was more rapid with DCJW than with DPX-JW062; onset of neurotoxic symptoms leads to a rapid and irre versible halt in feeding. The S-enantiomer of DCJW is active both in the mo toneuron preparation in vitro and in lepidopteran larvae in vivo; however S -DPX-JW062 is active in vivo only, while the R-enantiomers of DCJW and DPX- MP062 are inactive in both. Thus, activation of the parent oxadiazines to t he S-enantiomers of the N-decarbomethoxyllated metabolites, which are power ful sodium channel blockers, is the toxic mechanism of action in Lepidopter a and apparently for other pest insects as well; however, the rate of bioac tivation is a critical factor in determining the speed and ultimate toxicit y of this compound in different insect species. Indoxacarb's inherent activ ity against Lepidoptera is comparable to the most potent insecticides ever commercialized. (C) 2000 Elsevier Science Ltd. All rights reserved.