Although site-directed methyl pyridinium aldoximes have been available for six decades as OP antidotes, a full understanding of their mechanism of action either as antidotes at tissue target sites or in assisting scavenging of the toxic parent organophosphate is only emerging from recent structural data and mechanistic considerations.  Antidote efficacy in operational terms requires access to sites in the central nervous system, rapid bioavailability from dosing by practical means and a sufficient intrinsic reaction efficiency as a nucleophile at the OP-conjugated active center of acetylcholinesterase (AChE).  Zwitterionic oximes have the potential for circumventing limitations of not entering the central nervous system or crossing the chorion membrane in aquatic species, owing to the multiple charged and uncharged species in rapid equilibrium.  Within the active center gorge of AChE, we observe reactivation kinetics whose pH dependence departs from general base catalysis by the nucleophilic oximate anion.  Moreover, the deep and tortuous AChE gorge with the conjugated OP confers a unique and impacted  environment differing from that of general base catalysis by small molecules in solution.  In fact, the structure of the conjugated OP is a major determinant of the rate of reactivation owing to steric limitations of the attacking nucleophile.  Oximes appear to be preferred nucleophiles as antidotes and in assisting scavenging agents, because of their  capacity to exhibit "proton tunneling" within the active center gorge.  We also note that click-chemistry cycloaddition reactions forming triazoles, while readily occurring from azide and alkyne precursors bound to the AChE template in solution do not readily form <i>in crystallo, </i>perhaps reflecting the importance of transient electric field changes and dipole formation in the active center.  These considerations may play an important role in the design of optimal reactivating antidotes and scavengers for OP toxicity.<br/>

Reactivation and tissue disposition mechanisms affecting the efficacy of oximes in averting toxicity from organophosphate (OP) exposure

251st National Meeting (2016)

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