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.
Brown
G B
GB
Neuropsychiatry Research Program, University of Alabama, Birmingham 35294.
Gaupp
J E
JE
Olsen
R W
RW
D000494:Allosteric Regulation; D000818:Animals; D001496:Batrachotoxins / Q000378:metabolism; D003634:DDT / Q000494:pharmacology; D066298:In Vitro Techniques; D007306:Insecticides / Q000494:pharmacology; D007473:Ion Channels / Q000187:drug effects*; D011722:Pyrethrins / Q000494:pharmacology*; D051381:Rats; D011950:Receptors, Cholinergic / Q000187:drug effects*; D012964:Sodium / Q000378:metabolism*; D015222:Sodium Channels; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D001496:Batrachotoxins; D007306:Insecticides; D007473:Ion Channels; D011722:Pyrethrins; D011950:Receptors, Cholinergic; D015222:Sodium Channels; C041417:batrachotoxin receptor; D012964:Sodium; D003634:DDT