Antidotes acetylcholinesterase reactivators

Hrabinova, M., Musilek, K., Jun, D., Kuca, K. (2006). New group xylene linker containing acetylcholinesterase reactivators as antidotes against nerve agent cyclosarin. J. Enzyme Inhib. Med. Chem. 21 515-19. 

Kuca, K., Jun, D., Kim, T.H., Cabal, J., Jung, Y.S. (2006). In vitro evaluation of new acetylcholinesterase reactivators as causal antidotes against tabun and cyclosarin. Bull. Korean Chem. Soc. 27 395-8. 

Kuca, K. et al. Strategy for the development of new acetylcholinesterase reactivators—antidotes used for treatment of nerve agent poisonings, Biomed. Pap. Med. Fac. Univ. Palacky Olomouc Czech Repub., 149, 429, 2005. 

Dekleva, A., D. Sket, J. Sketelji, and M. Brzin. 1989. Attenuation of soman- induced lesions of skeletal muscle by acetylcholinesterase reactivating and nonreactivating antidotes. Acta Neu-ropathol. 79(2) 183 -89 cited in Chem. Abstr. CA 112(1) 93434p. 

Bajgar, J., 2010. Optimal choice of acetylcholinesterase reactivators for antidotal treatment of nerve agent intoxication. Acta Medica (Hradec Kr ove) 53,... 

The first suggestion of a practical form of antidotal therapy came in 1949 from Hestrin, who found that acetylcholinesterase (AChE) catalyzed the formation of acetohydroxamlc acid when incubated with sodium acetate and hydroxylamine. Critical in vitro studies in the next decade led to the development of a practical approach to therapy. The crucial concept in these studies was the recognition that the compound formed when AChE reacted with a phosphorus ester was a covalent phosphoryl-enzyme Intermediate similar to that formed in the hydrolysis of acetylcholine. 3 Wilson and colleagues, beginning in 1951, demonstrated that AChE inhibited by alkyl phosphate esters (tetraethyl pyrophosphate, TEPP) could be reactivated by water, but that free enzyme formed much more rapidly in the presence of hydroxylamine. 0 21 Similar results... 

Hobbiger, F.W., Vojvodic, V. (1966). The reactivating and antidotal actions of N,N -trimethylenbis (pyridinium-4-aldoxime) (TMB-4) and N,N -oxydimethylenbis (pyridinium-4-aldoxime) (toxogonin), with particular reference to their effect on phos-phorylated acetylcholinesterase in the brain. Biochem. Pharmacol. 15 1677-90. 

Worek, F., Reiter, G., Eyer, P., Szinicz, L. (2002). Reactivation kinetics of acetylcholinesterase from different species inhibited by highly toxic organophosphates. Arch. Toxicol. 76 523-9. Yang, G.Y., Yoon, J.H., Seong, C.M., Park, N.S., Jung, Y.S. (2003). Synthesis of bis-pyridinium oxime antidotes using... 

L35. Loomis, T. A., Welsh, M. J., Jr., and Miller, G. T., A comparative study of some pyridinium oximes as reactivators of phosphorylated acetylcholinesterase and as antidotes in sarin poisoning. Toxicol. Appl. Pharmacol. 5, 588-598 (1963). 

Glickman, A. H., Wing, K. D.. and Casida, J. E, (1984). Profenofos insecticide bioaciivaiion in reiatiwi to antidote action and the. slcreo,spcciriciiy of acetylcholinesterase inhibition, reactivation, and aging. Toxicol. Appl. Pharmacol. 73, 16-22. 

Khan MAS, Lo R, Bandyopadhyay TT, Ganguly BB (2011) Probing the reactivation process of sarin-inhibited acetylcholinesterase with a-nucleophiles hydroxylamine anion is predicted to be a better antidote with DFT calculations. J Mol Graph Model 29(8) 1039-1046. doi 10.1016/j.jmgm.2011.04.009... 

Antidotes. Because the acute toxicity to man of many of the phosphorus insecticides is high, first-aid remedies are kept on hand. The most useful of these is an injection of atropine (which acts primarily on muscarinic sites) followed by an oxime specific for nicotinic sites. These oximes reactivate phosphorylated acetylcholinesterase in patients (Holmes and Robins, 1955) just as with the isolated enzyme (Wilson and Meislich, 1953). This reaction involves a competition, between the hydroxyl-groups of serine and of the hydroxylamine, for the phsphoryl-group. The covalent bond with the serine is broken, and simultaneously a new covalent bond formed with the hydroxylamine (see Scheme 12.1). One of the best reactivators is pralidoxime 12.27) (2-PAM), which is the anti form of pyridine-2-aldoxime methochloride. Widely differing doses of antidote are required, depending on the strength of the phosphate-enzyme bond, which varies with the nature of the insecticide. 

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