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Int. J. Mol. Sci. 2013, 14(8), 16076-16086; doi:10.3390/ijms140816076

Acetylcholinesterase Reactivators (HI-6, Obidoxime, Trimedoxime, K027, K075, K127, K203, K282): Structural Evaluation of Human Serum Albumin Binding and Absorption Kinetics

1
Faculty of Military Health Sciences, University of Defence, Trebesska 1575, Hradec Kralove 500 01, Czech Republic
2
Biomedical Research Centre, University Hospital, Sokolska 581, Hradec Kralove 500 05, Czech Republic
3
Department of Chemistry, Faculty of Science, University of Hradec Kralove, Rokitanskeho 62, Hradec Kralove 500 03, Czech Republic
*
Author to whom correspondence should be addressed.
Received: 27 June 2013 / Revised: 23 July 2013 / Accepted: 25 July 2013 / Published: 2 August 2013
(This article belongs to the Section Biochemistry, Molecular Biology and Biophysics)
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Abstract

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. View Full-Text
Keywords: acetylcholinesterase; oximes; human serum albumin; pharmacokinetics; reactivator; antidote; nerve agent acetylcholinesterase; oximes; human serum albumin; pharmacokinetics; reactivator; antidote; nerve agent
This is an open access article distributed under the Creative Commons Attribution License (CC BY 3.0).

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MDPI and ACS Style

Zemek, F.; Zdarova, J.K.; Sepsova, V.; Kuca, K. Acetylcholinesterase Reactivators (HI-6, Obidoxime, Trimedoxime, K027, K075, K127, K203, K282): Structural Evaluation of Human Serum Albumin Binding and Absorption Kinetics. Int. J. Mol. Sci. 2013, 14, 16076-16086.

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