Prevention of organophosphate-induced toxicity in mice

Abstract

bis-Quaternary amines, which are acetal analogues of hemicholinium-3, were synthesized and several compounds were potent chemicals to antagonize toxicity induced by the organophosphate, paraoxon. Structural requirements were specific and included two oxygen atoms (bis-acetal substitution) 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. Biological testing showed a positive potency correlation between the chemicals when data from the following tests were compared antagonism in mice of paraoxon-induced motor impairment using the incline screen and toxicity, and ability to induce contractions of guinea-pig isolated ilea. The compounds were compared with the often used protective antagonist of organophosphate-induced toxicity, pyridostigmine. One compound, MFS-3, was seven times more efficacious and possessed a much higher therapeutic index. Possible mechanisms of action for these chemicals are discussed.