title: Acetylcholinesterase reactivators (HI-6, obidoxime, trimedoxime, K027, K075, K127, K203, K282): structural evaluation of human serum albumin binding and absorption kinetics.
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.
authors.affiliation: Faculty of Military Health Sciences, University of Defence, Trebesska 1575, Hradec Kralove 500 01, Czech Republic. zemek.filip@gmail.com
authors.forename: Filip
authors.initials: F
authors.lastname: Zemek
authors.forename: Jana Karasova
authors.initials: JK
authors.lastname: Zdarova
authors.forename: Vendula
authors.initials: V
authors.lastname: Sepsova
authors.forename: Kamil
authors.initials: K
authors.lastname: Kuca
mesh_terms: D000109:Acetylcholine / Q000378:metabolism; D000110:Acetylcholinesterase / Q000378:metabolism; D000327:Adsorption; D000818:Animals; D020134:Catalytic Domain; D002490:Central Nervous System / Q000187:drug effects*; D002801:Cholinesterase Reactivators / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics; D008297:Male; D009469:Neuromuscular Junction / Q000187:drug effects* / Q000378:metabolism; D010755:Organophosphates / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D051381:Rats; D017208:Rats, Wistar; D012709:Serum Albumin / Q000378:metabolism*
chemical_list: D002801:Cholinesterase Reactivators; D010755:Organophosphates; D012709:Serum Albumin; D000110:Acetylcholinesterase; D000109:Acetylcholine
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