title: Structural requirements for effective oximes--evaluation of kinetic in vitro data with phosphylated human AChE and structurally different oximes.
abstract: Treatment of poisoning by various organophosphorus (OP) nerve agents with established acetylcholinesterase (AChE) reactivators (oximes) is insufficient. In consequence, extensive research programs have been undertaken in various countries in the past decades to identify more effective oximes. The efficacy of new compounds has been investigated with different in vitro and in vivo models which hamper the comparison of results from different laboratories. The crucial mechanism of action of oximes is the reactivation of phosphylated AChE. The kinetic properties of these compounds can be quantified in vitro with isolated AChE from different origin. It was tempting to evaluate the reactivation kinetics of a series of oximes with various OP inhibitors performed under identical experimental conditions in order to get insight into structural requirements for adequate affinity and reactivity towards inhibited AChE. The determination of reactivation rate constants with bispyridinium oximes having different linkers, bearing oxime group(s) at different positions and having in part additional substituents revealed that (a) the reactivating potency was dependent on the position of the oxime groups and of additional substituents, (b) small modifications of the oxime structure had an in part marked effect on the kinetic properties and (c) no single oxime had an adequate reactivating potency with AChE inhibited by structurally different OP. These and previous studies underline the necessity to investigate in detail the kinetic properties of novel oximes and that the identification of a single oxime being effective against a broad range of structurally different OP will remain a major challenge.
authors: Bundeswehr Institute of Pharmacology and Toxicology, Munich, Germany. franzworek@bundeswehr.org
authors: Franz
authors: F
authors: Worek
authors: Timo
authors: T
authors: Wille
authors: Marianne
authors: M
authors: Koller
authors: Horst
authors: H
authors: Thiermann
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry / Q000378:metabolism*; D002619:Chemical Warfare Agents / Q000633:toxicity; D002800:Cholinesterase Inhibitors / Q000633:toxicity; D002801:Cholinesterase Reactivators / Q000737:chemistry* / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D058851:GPI-Linked Proteins / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D010755:Organophosphates / Q000633:toxicity; D009943:Organophosphorus Compounds / Q000633:toxicity; D010091:Oximes / Q000737:chemistry* / Q000494:pharmacology*; D010766:Phosphorylation; D012524:Sarin / Q000633:toxicity; D013329:Structure-Activity Relationship
chemical_list: D002619:Chemical Warfare Agents; D002800:Cholinesterase Inhibitors; D002801:Cholinesterase Reactivators; D058851:GPI-Linked Proteins; D010755:Organophosphates; D009943:Organophosphorus Compounds; D010091:Oximes; D012524:Sarin; C548244:ACHE protein, human; D000110:Acetylcholinesterase; C009374:tabun; C053914:cyclohexyl methylphosphonofluoridate