PREVENTION OF ORGANOPHOSPHATE-INDUCED TOXICITY IN MICE

bis-Quaternary amines, which are acetal analogues of hemicholinium-3, were synthesized and several compounds were potent chemicals to antago nize toxicity induced by the organophosphate, paraoxon, Structural req uirements were specific and included two oxygen atoms (bis-acetal subs titution) within 6 or 7 atom heterocyclic rings, oxygen atoms spaced 2 -carbon atoms from the quaternary nitrogen, and carbonyl substitutions adjacent to the spacing moieties, either bicyclohexyl or biphenyl, Bi ological testing showed a positive potency correlation between the che micals when data from the following tests were compared: antagonism in mice of paraoxon-induced motor impairment using the incline screen an d toxicity, and ability to induce contractions of guinea-pig isolated ilea, The compounds were compared with the often used protective antag onist of organophosphate-induced toxicity, pyridostigmine. One compoun d, MFS-3, was seven times more efficacious and possessed a much higher therapeutic index. Possible mechanisms of action for these chemicals are discussed.