engleski

New centrally acting oxime reactivators of cholinesterases phosphorylated by tabun

New oxime reactivators containing imidazole and hydroxyimino-acetamide functional groups have a sufficient fraction of non-ionized species at physiological pH values to cross the blood-brain barrier allowing the non-ionized and ionized species to equilibrate at extra-cellular pH values in the CNS. We evaluated reactivation capacities of 20 of the more reactive oximes from a large library for reactivation of tabun conjugates of human acetylcholinesterase (hAChE), its mutant Y337A/F338A and human butyrylcholinesterase (hBChE). The reactivation potencies of tested oximes differ for reactivation of these phosphorylated enzymes. The three best reactivators of hAChE and of its mutant Y337A/F338A, reaching 60-70 % of maximal reactivation, were imidazole-containing aldoximes, while two best reactivators of hBChE (up to 30 % of maximal reactivation) were hydroximino-acetamide derivatives. However, the tabun-hBChE conjugate was noticeably more resistant to reactivation in comparison to the hAChE conjugate. Reactivation kinetics of the lead imidazole-containing hAChE reactivator, when analyzed in terms of apparent affinity (1/Kox) and maximum reactivation rate constant (k2), shows superiority and potential for further structure refinement. Our findings provide evidence that oxime access to conjugated phosphorus atom within the narrow confines of the enzyme gorge, while maintaining the phosphyl oxygen in the oxyanion hole, is an important criterion for efficient reactivation. (Supported by USPHS Grant UO-1-NS58046).

cholinesterases; oxime; imidazole; tabun; reactivation

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