engleski

Refinement of structural leads for centrally acting oxime reactivators of phosphylated cholinesterases

We present a systematic structural optimization of uncharged, but ionizable, N-substituted 2-hydroxyiminoacetamido alkylamine reactivators of phosphylated human acetylcholinesterase (hAChE) intended to catalyze the hydrolysis of organophosphate (OP) inhibited hAChE in the CNS. Starting with the initial lead oxime RS41A, identified in our earlier study, and extending to the azepine analogue RS194B, reactivation rates for OP-hAChE conjugates formed by sarin, cyclosarin, VX, paraoxon and tabun are enhanced several fold in vitro. To analyze mechanism of intrinsic reactivation of the OP-AChE conjugate and penetration of the blood-brain barrier, the pH dependence of the imine and amine ionizing groups of the compounds and their nucleophilic potential were examined by UV/VIS spectroscopy, 1H NMR and oximolysis rates for acetylthiocholine and phosphoester hydrolysis. Oximolysis rates were compared in solution and on AChE and analyzed in terms of the reactive ionization states for reactivation of the OP conjugated AChE. In addition, toxicity and pharmacokinetic studies in mice show significantly improved CNS penetration and retention for RS194B when compared with RS41A. The enhanced intrinsic reactivity against the OP-AChE target combined with favorable pharmacokinetic properties resulted in great improvement of antidotal properties of RS194B compared to RS41A, and the standard peripherally active oxime, 2PAM. Improvement was particularly noticeable when pretreatment of mice with RS194B before OP exposure was combined with RS194B reactivation therapy following the OP insult.

oxime reactivation ; organophosphate intoxication ; CNS AChE reactivation ; hydroxyiminoacetamides ; oxime therapy in mice ; acetylcholinesterase

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