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SUMMARY Three potential reactivators of nerve agents-inhibited acetylcholinesterase: 2-[(hydroxyimino)phenylmethyl]-1-methylpyridinium iodide 3a, 2-[(hydroxyimino)pyridin-2-ylmethyl]-1-methylpyridinium iodide 3b and 2-[(1-hydroxyimino) ethyl]-1-methylpyridinium iodide 3c were synthesized. Their reactivation potency was examined using a standard in vitro reactivation test. A rat brain homogenate was used as the source of acetylcholinesterase. Their reactivation potency was compared with a currently used acetylcholinesterase reactivator - 2-PAM (pralidoxime) 4. All tested reactivators were less effective acetylcholinesterase reactivators compared to 2-PAM. In this study, we also tested the reactivation potency of the oxime 2-PAM against inhibition of acetylcholinesterase by sarin, cyclosarin, VX and tabun. Satisfactory results are shown only for the reactivation sarin- and VX-inhibited acetylcholinesterase. KEY WORDS VX; reactivation; acetylcholinesterase; oximes; sarin; tabun; cyclosarin REFERENCES Bajgar J.: The influence of inhibitors and other factors on cholinesterases. Sb. Věd. Prací LFUK (Hradec Kralove) 34:3-77, 1994. Bielavsky J., J. Kassa, I. Elsnerova, L. Dejmek: Cholinesterase reactivators derived from pyridine-2-carbaldoxime. Coll. Czech. Chem. Commun. 63:199-204, 1997. Cabal J.: A comparison of the features of the esters of dialkylamidofluorophosphate acids with other fluorophosphates (In Czech). Voj. Zdrav. Listy 5/6:215-221, 1992. Cabal J. and J. Bajgar: Tabun - reappearance 50 years later (In Czech). Chem. Listy 93:27-31, 1999. Daroszewski J., B. Serafin, G. Borkowska, S. Rump: Potential acetylcholinesterase reactivators, pyridine and a-oxooxime derivatives. Pharmazie 41:699-702, 1986. Ginsburg S. and I.B. Wilson: Oxime of pyridine series. J. Am. Chem. Soc. 79:481-483, 1957. Hampl F., J. Mazac, F. Liska, J. Srogl, L. Kabrt, M. Suchanek: Quarternary heteroarenium aldoximes as catalysts for cleveage of phosphate esters. Collect Czech. Chem. Commun. 60:883-893, 1995. Kassa J. and J. Bajgar: Comparison of the efficacy of HI-6 and obidoxime against cyclohexyl methylphosphonofluoridate (GF) in rats. Hum. Exp. Toxicol. 14:923-928, 1995. Kassa J.and J. Cabal: A comparison of the efficacy of acetylcholinesterase reactivators against cyclohexyl methylphosphonofluoridate (GF agent) by in vitro and in vivo methods. Pharmacol. Toxicol. 84:41-45, 1999a. Kassa J. and J. Cabal: A comparison of the efficacy of a new asymmetric bispyridinium oxime BI-6 with presently used oximes and H oximes against sarin by in vitro and in vivo methods. Human Exp. Toxicol. 18:560-565, 1999b. Kassa J.: Review of oximes in the antidotal treatment of poisoning by organophosphorus nerve agents. J. Toxicol. Clin. Toxicol. 40:803-816, 2002. Kuca K. and J. Cabal: Reactivation of cyclosarin - inhibited acetylcholinesterase (In Czech). Chem. Listy 11:951, 2002. Kuca K., J. Bielavsky, J. Cabal, M. Bielavska: Synthesis of a potential reactivator of acetylcholinesterase 1-(4-hydroxyiminomethylpyridinium)-3-(carbamoylpyridinium)-propane dibromide. Tetrahedron Lett. 44:3123-3125, 2003a. Kuca K. and J. Kassa: A Comparison of the ability of a new bispyridinium oxime -1-(4-hydroxyiminomethylpyridinium)-4-(4-carbamoyl-pyridinium)butane dibromide and currently used oximes to reactivate nerve agent-inhibited rat brain acetylcholinesterase by in vitro ethods. J. Enz. Inhibition (In Press), 2003b. Maekawa K.: The sarin poisoning incident in Tokyo subway. Oral presentation, The fift International Symposium on Protection Against CBWA, Stockholm, June 11-16, 1995. Marrs T.C.: Organophosphate poisoning. Pharmacol. Therap. 58:51-66, 1993. Patocka J., J. Bielavsky, F. Ornst: Reactivating effect of alpha, omega-bis-(4-pyridinealdoxime)-2-trans-butene dibromide on isopropylmethylphosphonylatedacetylcholinesterase. FEBS Lett. 10:182-184, 1970. Petrova I. and J. Bielavsky: An overview of syntheses of cholinesterase reactivators from 1980 to 1992 (In Czech). Voj. Zdrav. Listy 70:63-73, 2001. Taylor P.: Anticholinergic agents. In: The Pharmacological Basis of Therapeutics. McGraw Hill, New York 1996, pp. 161. Thiermann H., L. Szinicz, F. Eyer, F. Worek, P. Eyer, N. Felgenhauer, T. Zilker: Modern strategies in therapy of organophosphate poisoning. Toxicol. Lett. 107:233-239, 1999. Wilson I.B. and F. Sondheimer: A specific antidote against lethal alkyl phosphate intoxication. V. Antidotal properties. Arch. Biochem. Biophys. 69:468-474, 1957. Worek F., R. Widmann, O. Knopff, L. Szinicz: Reactivating potency of obidoxime, pralidoxime, HI-6 and Hlo-7 in human erythrocyte acetylcholinesterase inhibited by highly toxic organophosphorus compound. Arch. Toxicol. 72:237-243, 1998. Worek F., C. Diepold, P. Eyer: Dimethylphosphoryl-inhibited human cholinesterases: inhibition, reactivation, and aging kinetics. Arch. Toxicol. 73:7-14, 1999. |
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