Pyrethroid insecticides: stereospecific allosteric interaction with the batrachotoxinin-A benzoate binding site of mammalian voltage-sensitive sodium channels.

Pyrethroid insecticides are synthetic neurotoxins patterned after the naturally occurring pyrethrins. Their mechanism of action is thought to involve effects primarily at the voltage-sensitive sodium channel of both insect and mammalian neurons, although recent studies have raised the possibility that these compounds may also act at the gamma-aminobutyric acid receptor-chloride ionophore complex. Here we show that active pyrethroids of the alpha-cyano-3-phenoxybenzyl class allosterically enhance the binding of [3H]batrachotoxinin-A 20-alpha-benzoate to voltage-sensitive sodium channels of rat brain in a dose-dependent and stereospecific manner. Comparison of the rank order of potency for enhancement of [3H]batrachotoxinin-A 20-alpha-benzoate binding and insecticidal activity in a series of toxic stereoisomers of cypermethrin, representative of the class, reveals a correlation between the two measures. These results support a sodium channel site model for pyrethroid action and suggest a useful and practical method to help evaluate the relationship between effects at the sodium channel and insecticidal potency for members of this class of compounds.