title: Specification of the structure of oximes able to reactivate tabun-inhibited acetylcholinesterase.
abstract: The efficacy of various oximes to reactivate acetylcholinesterase phosphorylated by tabun (O-ethyl-N,N-dimethyl phosphoramidocyanidate) was tested by in vitro and in vivo methods. The oximes commonly used for the treatment of acute poisonings with highly toxic organophosphates appeared to be almost ineffective (HI-6, pralidoxime, methoxime) or just slightly effective (obidoxime) against tabun. On the other hand, trimedoxime seemed to be a significantly more efficacious reactivator than the others in the case of tabun poisonings. In vitro, the concentration of trimedoxime corresponding to 1.0 mmol/l was able to reach 50% reactivation of tabun-inhibited brain acetylcholinesterase. Higher reactivating potency of trimedoxime in comparison with the other commonly used oximes was demonstrated by in vivo method, too. In addition, other structural analogues of trimedoxime were found to be efficacious in counteracting tabun-induced acetylcholinesterase inhibition although not as efficacious as trimedoxime itself. Some effective acetylcholinesterase reactivators were characterised by dissociation constant of enzyme-reactivator complex as well as enzyme-inhibitor-reactivator complex and by rate constant of reactivation.
authors.affiliation: Department of Toxicology, Purkyne Military Medical Academy, 500 01 Hradec Králové, Czech Republic.
authors.forename: Jirí
authors.initials: J
authors.lastname: Cabal
authors.forename: K
authors.initials: K
authors.lastname: Kuca
authors.forename: J
authors.initials: J
authors.lastname: Kassa
mesh_terms: D000109:Acetylcholine / Q000378:metabolism; D000110:Acetylcholinesterase / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D004353:Drug Evaluation, Preclinical / Q000379:methods; D007928:Lethal Dose 50; D008297:Male; D008968:Molecular Conformation; D010755:Organophosphates / Q000009:adverse effects / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010091:Oximes / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D010766:Phosphorylation; D011726:Pyridinium Compounds / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D021281:Quantitative Structure-Activity Relationship; D051381:Rats; D017208:Rats, Wistar
chemical_list: D010755:Organophosphates; D010091:Oximes; D011726:Pyridinium Compounds; D000110:Acetylcholinesterase; C022870:asoxime chloride; D000109:Acetylcholine; C009374:tabun