Structure-Activity Relationships for the Action of Dihydropyrazole Insecticides on Mouse Brain Sodium Channels

Assays of radiosodium uptake into mouse brain vesicles and the binding of [³H]batrachotoxinin A 20-α-benzoate (BTX-B) were used to compare the actions of six dihydropyrazole (3-aryl-1-arylcarbamoyl-2-pyrazoline) insecticides on mouse brain sodium channels. The relative potencies of the six dihydropyrazoles as inhibitors of either pumiliotoxin B-stimulated sodium uptake measured in the presence of scorpion (Leiurus quinquestriatus) venom or veratridine-stimulated sodium uptake were closely correlated with the relative potencies of these compounds as inhibitors of the binding of BTX-B to mouse brain sodium channels. A comparison of the enantiomers of the most potent dihydropyrazole, RH 3421, as inhibitors of radiosodium uptake showed that the (−) enantiomer of RH 3421 was approximately six-fold more potent than the (+) enantiomer. The potencies of these dihydropyrazoles in these assays and the stereoselectivity observed in the action of enantiomers of RH 3421 are in good agreement with available information on insecticidal activity in this group of compounds. Assays of the combined effects of RH 3421 and dibucaine as inhibitors of BTX-B binding revealed mutually competitive interactions between these compounds. This finding is consistent with the existence of a common site of action for dihydropyrazoles and local anesthetics on the sodium channel. The results of these studies provide further evidence for the toxicological relevance of the effects of dihydropyrazoles on sodium channels.