Structure-activity correlations for interactions of bicyclophosphorus esters and some polychlorocycloalkane and pyrethroid insecticides with the brain-specific t-butylbicyclophosphorothionate receptor.

Abstract

[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.

Influences on blockade by t‐butylbicyclo‐phosphoro‐thionate of GABAA receptor spontaneous gating, agonist activation and desensitization

“…Maximal inhibition of GABA‐evoked currents occurred in the presence of 10 μ m TBPS and 100 μ m picrotoxin. Our findings agree with the findings of others who have demonstrated a higher potency of TBPS compared to picrotoxin as an inhibitor of GABA A Rs (Casida & Lawrence, 1985; Maksay et al 2003).…”

An assessment of the developmental, reproductive, and neurotoxicity of endosulfan

“…However, the results from two laboratories, published in the early 1980s, showed that cyclodiene insecticides, such as endosulfan, were potent antagonists at the GABA A chloride channel. Lawrence and Casida (1984) and Casida and Lawrence (1985) demonstrated this mechanism in several assay systems, with different radioligands. Casida showed a correlation between [ 35 S]TBPS receptor binding inhibition potency and toxicity, in rodents, for a series of cyclodienes, including endosulfan.…”

Mechanisms of Toxic Action and Structure-Activity Relationships for Organochlorine and Synthetic Pyrethroid Insecticides

“…With the function of the GABA-ergic inhibitory neurons impaired, hyperexcitation results. Several chlorinated insecticides have been shown to bind at the picrotoxinin site at which t-butylbicyclophosphorothionate (TBPS) also binds (20)(21)(22). Currently the inhibition of Cl-uptake by brain vesicles (16,23) and the competitive binding for the TBPS site (24) are two valuable assays for comparing neurotoxic potencies among chlorinated cyclodienes, cyclohexanes, and bornanes.…”