Acetylcholinesterase (AChE) reactivators (oximes) are compounds predominantly targeting the active site of the enzyme. Toxic effects of organophosphates nerve agents (OPNAs) are primarily related to their covalent binding to AChE and butyrylcholinesterase (BChE), critical detoxification enzymes in the blood and in the central nervous system (CNS). After exposure to OPNAs, accumulation of acetylcholine (ACh) overstimulates receptors and blocks neuromuscular junction transmission resulting in CNS toxicity. Current efforts at treatments for OPNA exposure are focused on non-quaternary reactivators, monoisonitrosoacetone oximes (MINA), and diacylmonoxime reactivators (DAM). However, so far only quaternary oximes have been approved for use in cases of OPNA intoxication. Five acetylcholinesterase reactivator candidates (K027, K075, K127, K203, K282) are presented here, together with pharmacokinetic data (plasma concentration, human serum albumin binding potency). Pharmacokinetic curves based on intramuscular application of the tested compounds are given, with binding information and an evaluation of structural relationships. Human Serum Albumin (HSA) binding studies have not yet been performed on any acetylcholinesterase reactivators, and correlations between structure, concentration curves and binding are vital for further development. HSA bindings of the tested compounds were 1% (HI-6), 7% (obidoxime), 6% (trimedoxime), and 5%, 10%, 4%, 15%, and 12% for K027, K075, K127, K203, and K282, respectively.

Faculty of Military Health Sciences University of Defence Trebesska 1575 Hradec Kralove 500 01 Czech Republic

Zobrazit více v PubMed

Singh S.S. Preclinical pharmacokinetics: An approach towards safer and efficacious drugs. Curr. Drug Metab. 2006;7:165–182. PubMed

Lipinski C.A., Lombardo F., Dominy S.W., Feeney P.J. Experimental and computational approaches to estimate solubility and permeability in drug discovery. Adv. Drug Deliv. Rev. 1997;23:3–25. PubMed

Walters W.P. Going further than Lipinski’s rule in drug design. Expert Opin. Drug Discov. 2012;7:99–107. PubMed

Sudlow G., Birkett D.J., Wade D.N. The characterization of two specific drug binding sites on human serum albumin. Mol. Pharmacol. 1975;11:824–832. PubMed

Hage D.S., Austin J. High-performance affinity chromatography and immobilized serum albumin as probes for drug and hormone binding. J. Chromatogr. B Biomed. Sci. Appl. 2000;739:39–54. PubMed

Kim H.S., Wainer I.W. Rapid analysis of the interactions between drugs and human serum albumin (HSA) using high-performance affinity chromatography (HPAC) J. Chromatogr. B Biomed. Sci. Appl. 2008;870:22–26. PubMed PMC

Kragh-Hansen U. Relations between high-affinity binding sites for l-tryptophan, diazepam, salicylate and Phenol Red on human serum albumin. Biochem. J. 1983;209:135–142. PubMed PMC

Kragh-Hansen U. Relations between high-affinity binding sites of markers for binding regions on human serum albumin. Biochem. J. 1985;225:629–638. PubMed PMC

Kragh-Hansen U. Evidence for a large and flexible region of human serum albumin possessing high affinity binding sites for salicylate, warfarin, and other ligands. Mol. Pharmacol. 1988;34:160–171. PubMed

Joseph K.S., Moser A.C., Basiaga S.B.G., Schiel J.E.S., Hage D.S. Evaluation of alternatives to warfarin as probes for Sudlow site I of human serum albumin: Characterization by high-performance affinity chromatography. J. Chromatogr. A. 2009;1216:3492–3500. PubMed PMC

Petersen C.E., Ha C.E., Harohalli K., Feix J.B., Bhagavan N.V. A dynamic model for bilirubin binding to human serum albumin. J. Biol. Chem. 2000;275:20985–20995. PubMed

Ghuman J., Zunszain P.A., Peptitpas I., Bhattacharay A.A., Otagari M., Curry S. Structural basis of the drug-binding specificity of human serum albumin. J. Mol. Biol. 2005;353:38–52. PubMed

Varshney A., Ahmad B., Khan R.H. Comparative studies of unfolding and binding of ligands to human serum albumin in the presence of fatty acid: Spectroscopic approach. Int. J. Biol. Macromol. 2008;42:483–490. PubMed

Dill K.A., Shortie D. Denatured states of proteins. Ann. Rev. Biochem. 1991;60:795–825. PubMed

Petitpas I., Petersen C.E., Ha C.E., Bhattacharay A.A., Zunszain P.A., Ghuman J. Structural basis of albumin-thyroxine interactions and familial dysalbuminemic hyperthyroxinemia. Proc. Natl. Acad. Sci. USA. 2003;100:6440–6445. PubMed PMC

Petitpas I., Grune T., Bhattacharya A.A., Curry S. Crystal structures of human serum albumin complexed with monounsaturated and polyunsaturated fatty acids. J. Mol. Biol. 2001;314:955–960. PubMed

Zemek F., Korabecny J., Sepsova V., Karasova J.Z., Musilek K., Kuca K. Albumin and α1-acid glycoprotein: Old acquaintances. Expert Opin. Drug Metab. Toxicol. 2013;9:943–954. PubMed

Bajgar J. Optimal choice of acetylcholinesterase reactivators for antidotal treatment of nerve agent intoxication. Acta Medica. 2010;53:207–211. PubMed

Colovic M.B., Krstic D.Z., Lazarevic-Pasti T.D., Bondzic A.M., Vasic V.M. Acetylcholinesterase inhibitors: Pharmacology and toxicology. Curr. Neuropharmacol. 2013;11:315–335. PubMed PMC

Litchfield M.H. Estimates of acute pesticide poisoning in agricultural workers in less developed countries. Toxicol. Rev. 2005;24:271–278. PubMed

Karasova J.Z., Chladek J., Hroch M., Josef F., Hnidkova D., Kuca K. Pharmacokinetic study of two acetylcholinesterase reactivators, trimedoxime and newly synthesized oxime K027, in rat plasma. J. Appl. Toxicol. 2013;33:18–23. PubMed

Kalasz H., Szegi P., Janoki G., Balogh L., Postenyi Z., Musilek K., Petroianu G.A., Siddiq A., Tekes K. Study on medicinal chemistry of K203 in wistar rats and beagle dogs. Curr. Med. Chem. 2013;20:2137–2144. PubMed

Karasova J.Z., Novotny L., Antos K., Zivna H., Kuca K. Time-dependent changes in concentration of two clinically used acetylcholinesterase reactivators (HI-6 and obidoxime) in rat plasma determined by HPLC techniques after in vivo administration. Anal. Sci. 2010;26:63–67. PubMed

Kassa J., Misik J., Karasova J.Z. A comparison of the potency of a novel bispyridinium oxime K203 and currently available oximes (obidoxime, HI-6) to counteract the acute neurotoxicity of sarin in rats. Basic Clin. Pharmacol. Toxicol. 2012;111:333–338. PubMed

Karasova J.Z., Pohanka M., Pavlik M., Kassa J., Musilek K., Zemek F., Kuca K. Distribution study of acetylcholinesterase reactivators after application of therapeutic doses in guinea pigs. Toxicol. Lett. 2011;205:S116.

Kuca K., Musilek K., Jun D., Pohanka M., Ghosh K.K., Hrabinova M. Oxime K027: Novel low-toxic candidate for the universal reactivator of nerve agent-and pesticide-inhibited acetylcholinesterase. J. Enzyme Inhib. Med. Chem. 2010;25:509–512. PubMed

Matos K.S., da Cunha E.F.F., Goncalves A.S., Wilter A., Kuca K., Franca T.C.C., Ramalho T.C. First principles calculations of thermodynamics and kinetic parameters and molecular dynamics simulations of acetylcholinesterase reactivators: Can mouse data provide new insights into humans? J. Biomol. Struct. Dyn. 2012;30:546–558. PubMed

Worek F., Thiermann H. Reactivation of organophosphate-inhibited human acetylcholinesterase by isontrosoacetone (MINA): A kinetic analysis. Chem. Biol. Interact. 2011;194:91–96. PubMed

Skovira J.W., O’Donnell J.C., Koplovitz I., Kan R.K., McDonough J.H., Snih T.M. Reactivation of brain acetylcholinesterase by monoisonitrosoacetone increases the therapeutic efficacy against nerve agents in guinea pigs. Chem. Biol. Interact. 2010;187:318–324. PubMed

Kovarik Z., Macek N., Sit R.K., Radic Z., Fokin V.V., Baarry Sharpless K., Taylor P. Centrally acting oximes in reactivation of tabun-phosphoramidated AChE. Chem. Biol. Interact. 2013;203:77–80. PubMed PMC

Karasova J.Z., Kassa J., Jung Y.S., Musilek K., Pohanka M., Kuca K. Effect of several new and currently available oxime cholinesterase reactivators on tabun-intoxicated rats. Int. J. Mol. Sci. 2008;9:2243–2252. PubMed PMC

Kassa J., Karasova J.Z., Tesarova S., Kuca K., Musilek K. A comparison of the ability of newly-developed bispyridinium oxime K203 and currently available oximes (trimedoxime, obidoxime, HI-6) to counteract the acute neurotoxicity of soman in rats. Toxicol. Mech. Methods. 2010;20:445–451. PubMed