Reactivation of phosphorylated acetocholinesterases by pyridinium aldoximes and related compounds

Abstract

The reactivation of diethyl and diisopropyl phosphorylacetocholinesterases by aldoximes of pyridinium and bispyridinium and related compounds was investigated. The anticholinesterase activity of these oximes and the hydrolysis of tetraethyl pyrophosphate and diisopropyl phosphorofluoridate by them were also studied. All experiments were carried out at pH 7.45 and 37[degree]. The most potent reactivators among the oximes studied were 4-monoximes and 44[image]-dioximes of NN[image]-polymethylenebis(pyridinium bromide), which were greatly superior as reactivators to 2-hydroxy-iminomethyl-N-methylpyridinium iodide (pyridine 2-aldoxime methiodide). Reactivation of human diethyl phosphorylacetocholinesterase by oximes of NN[image]-polymethylenebis-(pyridinium bromide) was faster in the presence of acetylcholine than without it. The hypothesis is put forward that an oxime phosphonate might be formed during reactivation and interfere with reactivation in the absence of acetylcholine. There is no correlation between anticholinesterase activity and effectiveness as reactivator. The ratios (potency as reactivator: reactivity with organophosphates), obtained with different oximes, support the interpretation that attachment to the phosphorylated enzyme during reactivation enhances activity. Possible sites of attachment are discussed.