The inhibition of
acetylcholinesterase (AChE) by
organophosphorus compounds (OPs) causes acute toxicity or death of the intoxicated individual. One group of these compounds, the OP
nerve agents, pose an increasing threat in the world due to their possible use in the battlefield or terrorist acts. Antidotes containing
oxime compounds to reactivate the inhibited
enzyme are highly valued for treatment against OP
poisoning. One of these reactivators,
HI-6, was shown to be significantly more effective in treating
soman toxicity than other
oximes, such as
2-PAM, TMB4, and
obidoxime. However,
HI-6 was less effective in reactivating AChE inhibited by the OP
pesticide,
paraoxon. In this study, the mechanism for HI-6-induced reactivation of OP-AChE conjugates was investigated using mouse mutant
AChEs inhibited with different OPs including
organophosphate paraoxon, and several methylphosphonates. Results indicate that the
HI-6 molecule may assume two different orientations in the reactivation of AChE inhibited by
organophosphate and Sp methylphosphonates. These conclusions were further corroborated by reactivation studies using an analog of
HI-6 in which the bispyridinium moieties are linked by a methylene bridge rather than an
ether oxygen.