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.
J E
JE
Casida
L J
LJ
Lawrence
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