Nonquaternary Cholinesterase Reactivators.
Abstract
We prepared a series of dialkylaminoalkyl alpha-ketothiohydroximates and evaluated them in vitro as reactivators of acetylcholinesterase (AChE) inhibited by ethyl p-nitrophenyl methylphosphonate (EPMP). The compounds conformed to the general formula 4-RH6H4C(O)C(NOH)S(CH2)nNH2.HCl where: R = MeO, n = 2, 3; and R' = CH3 or C2H5. For comparison as also examined 2-hydroxyiminomethyl-l-methylpyridinium iodide (2PAM), p-BrC6H4C(O)C(NOH)SCH2CH2CH3, and the related alpha-oximino thiohydroximate CH(NOH)C(NOH)SCH2CH2NMe.HCl. The thiohydroximates reactivate ethyl methylphosphonyl-AChE via a mechanism involving equilibrium binding of reactivator to inhibited enzyme followed by displacement of the inhibitor by reactivator. 2PAM is at least 50 times more reactive toward ethyl methylphosphonyl-AChE than any of the above nonquaternary reactivators. The differences in reactivity apparently relate to entropic factors associated with formation of the reactivator/phosphonylated enzyme complex. We also prepared a series of oxadiazoles, thiadiazoles, and triazoles with aldoxime or diethylaminoethyl thiohydroximate functional groups. These compounds were characterized with respect to structure, acidity, and activity as reactivators of ethyl methylphosphnyl-AChE. Of seven alpha-heteroaromatic aldoximes, only one, 5-hydroxyiminomethyl-3-phenyl-1,2,4-oxadiazole, exhibits an oxime acidity (pKa = 7.9) near the optimal value of pKa = 8. This compound is the best nonquaternary AChE reactivator studied to date.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jan 27, 1982
- Accession Number
- ADA157214
Entities
People
- C. D. Bedford
- C. W. Mosher
- R. A. Howd
- R. A. Kenley
Organizations
- SRI International