title: Reactivation kinetics of a homologous series of bispyridinium bis-oximes with nerve agent-inhibited human acetylcholinesterase.
abstract: The reactivation of organophosphorus compound (OP)-inhibited acetylcholinesterase (AChE) by oximes is inadequate in case of different OP nerve agents. This fact led to the synthesis of numerous novel oximes by different research groups in order to identify more effective reactivators. In the present study, we investigated the reactivation kinetics of a homologous series of bispyridinium bis-oximes bearing a (E)-but-2-ene linker with tabun-, sarin-, and cyclosarin-inhibited human AChE. In part, marked differences in affinity and reactivity of the investigated oximes toward OP-inhibited human AChE were recorded. These properties depended on the position of the oxime groups and the inhibitor. None of the tested oximes was equally effective against all used OPs. In addition, the data indicate that a (E)-but-2-ene linker decreased in most cases the reactivating potency in comparison to oximes bearing an oxybismethylene linker, e.g., obidoxime and HI-6. The results of this study give further insight into structural requirements for oxime reactivators, underline the necessity to investigate the kinetic interactions of oximes and AChE with structurally different OP inhibitors, and point to the difficulty to develop an oxime reactivator which is efficient against a broad spectrum of OPs.
authors.affiliation: Bundeswehr Institute of Pharmacology and Toxicology, Munich, Germany. franzworek@bundeswehr.org
authors.forename: Franz
authors.initials: F
authors.lastname: Worek
authors.forename: Jens
authors.initials: J
authors.lastname: von der Wellen
authors.forename: Kamil
authors.initials: K
authors.lastname: Musilek
authors.forename: Kamil
authors.initials: K
authors.lastname: Kuca
authors.forename: Horst
authors.initials: H
authors.lastname: Thiermann
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism; D000475:Alkenes / Q000737:chemistry; D002800:Cholinesterase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D002801:Cholinesterase Reactivators / Q000737:chemistry / Q000494:pharmacology*; D004910:Erythrocyte Membrane / Q000187:drug effects / Q000201:enzymology; D058851:GPI-Linked Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D015394:Molecular Structure; D010755:Organophosphates / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D009943:Organophosphorus Compounds / Q000037:antagonists & inhibitors / Q000494:pharmacology; D010091:Oximes / Q000737:chemistry / Q000494:pharmacology*; D011726:Pyridinium Compounds / Q000737:chemistry / Q000494:pharmacology*; D012524:Sarin / Q000037:antagonists & inhibitors / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000475:Alkenes; D002800:Cholinesterase Inhibitors; D002801:Cholinesterase Reactivators; D058851:GPI-Linked Proteins; C518856:K075 compound; D010755:Organophosphates; D009943:Organophosphorus Compounds; D010091:Oximes; D011726:Pyridinium Compounds; D012524:Sarin; C548244:ACHE protein, human; D000110:Acetylcholinesterase; C021639:2-butene; C009374:tabun; C053914:cyclohexyl methylphosphonofluoridate