Interaction of Bispyridinium Oximes and Drugs Related to the Treatment of Organophosphorus Poisoning with the Mammalian Cholinergic Receptors

摘要

The organophosphorus (OP) compounds soman, VX, and phospholine iodide were found to be weak antagonists of mammalian nicotinic acetylcholine receptor (nAChR) in BC3H-1 clonal muscle cells. The K sub ant values obtained for these OP compounds are between 0.1 and 1 micromoles. These values are higher than the corresponding concentration of OPs found in blood during acute poisoning. Thiocholine iodide, a hydrolytic product of phospholine, displays a remarkable agonistic activity with nAChR. The K sub act value, 80 micromoles, the competitive inhibition by d-tubocurarine and a reversible conversion of the nAChR to the desensitized state induced by thiocholine suggest that thiocholine activates the receptor channel via the agonist/antagonist site. The time course for the tissue distribution of various antidotes against OP poisoning was studied in mice, using tritium-labelled drugs. Aprophen displayed slower kinetics of absorption in most organs as compared to atropine. The slower absorption of aprophen may provide a pharmacodynamic basis for its use as a pretreatment for OP poisoning. High levels of aprophen and atropine were found in the lungs. Part of the radioactivity found in liver and in other tissues, following aprophen administration, may be accounted for by the presence of active metabolites.