Structure-activity correlations for interactions of bicyclophosphorus esters and some polychlorocycloalkane and pyrethroid insecticides with the brain-specific t-butylbicyclophosphorothionate receptor.
[35S]t-Butylbicyclophosphorothionate or [35S]TBPS is an improved radioligand for the picrotoxinin binding site in rat brain synaptic membranes. The toxic isomers of the hexachlorocyclohexanes, polychlorobornanes, and chlorinated cyclodienes displace [35S]TBPS with a stereospecificity and potency generally correlated with their mammalian toxicity. In a few cases this correlation is improved by correction for metabolic activation or detoxification on using a coupled brain receptor/liver microsomal oxidase system. The alpha-cyano-3-phenoxybenzyl pyrethroids, although less potent, inhibit [35S]TBPS binding in a stereospecific manner correlated with their toxicity. Scatchard analyses indicate that these three classes of polychlorocycloalkane insecticides act at the TBPS binding site within the gamma-aminobutyric acid (GABA) receptor-ionophore complex whereas the alpha-cyano pyrethroids interact with a closely associated site. These insecticides and TBPS analogs may serve as useful probes further to elucidate the topography of the TBPS binding site and its relationship to the chloride channel.
Casida
J E
JE
Lawrence
L J
LJ
D000818:Animals; D001667:Binding, Competitive; D001921:Brain / Q000187:drug effects*; D001643:Bridged Bicyclo Compounds / Q000378:metabolism*; D019086:Bridged Bicyclo Compounds, Heterocyclic; D001952:Bridged-Ring Compounds / Q000378:metabolism*; D002712:Chlorides / Q000378:metabolism; D001556:Hexachlorocyclohexane / Q000633:toxicity; D066298:In Vitro Techniques; D007306:Insecticides / Q000633:toxicity*; D007473:Ion Channels / Q000187:drug effects; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D011722:Pyrethrins / Q000633:toxicity*; D051381:Rats; D011963:Receptors, GABA-A / Q000032:analysis / Q000187:drug effects*; D013329:Structure-Activity Relationship; D013462:Sulfur Radioisotopes; D013570:Synaptic Membranes / Q000032:analysis
D001643:Bridged Bicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D001952:Bridged-Ring Compounds; D002712:Chlorides; D007306:Insecticides; D007473:Ion Channels; D011722:Pyrethrins; D011963:Receptors, GABA-A; D013462:Sulfur Radioisotopes; C037480:picrotoxinin receptor; D001556:Hexachlorocyclohexane; C037476:tert-butylbicyclophosphorothionate