title: Kinetic analysis of reactivation and aging of human acetylcholinesterase inhibited by different phosphoramidates.
abstract: The high number of fatalities due to poisoning by organophosphorus compound-based (OP) pesticides and the availability of highly toxic OP-type chemical warfare agents (nerve agents) emphasize the necessity for an effective medical treatment. Acute OP toxicity is mainly caused by inhibition of acetylcholinesterase (AChE, EC 3.1.1.7). Reactivators (oximes) of inhibited AChE are a mainstay of treatment. However, human AChE inhibited by certain OP, e.g. the phosphoramidates tabun and fenamiphos, is rather resistant towards reactivation by oximes while AChE inhibited by others, e.g. the phosphoramidate methamidophos is easily reactivated by oximes. To get more insight into a potential structure-activity relationship human AChE was inhibited by 16 different tabun analogues and the time-dependent reactivation by 1mM obidoxime, TMB-4, MMB-4, HI 6 or HLö 7, the reactivation kinetics of obidoxime and the kinetics of aging and spontaneous reactivation were investigated. A clear structure-activity relationship of aging, spontaneous and oxime-induced reactivation kinetics could be determined with AChE inhibited by N-monoalkyl tabun analogues depending on the chain length of the N-alkyl residue. N,N-dialkyl analogues bearing ethyl and n-propyl residues were completely resistant towards reactivation while N,N-di-i-propyl tabun was highly susceptible towards reactivation by oximes. AChE inhibited by phosphonoamidate analogues of tabun, bearing a N,N-dimethyl and N,N-diethyl group, could be reactivated and had comparable reactivation kinetics with obidoxime. These results in conjunction with previous data with organophosphates and organophosphonates emphasizes the necessity for kinetic studies as basis for future work on structural analysis with human AChE and for the development of effective broad-spectrum oximes.
authors: Bundeswehr Institute of Pharmacology and Toxicology, Neuherbergstrasse 11, 80937 Munich, Germany. FranzWorek@Bundeswehr.org
authors: Franz
authors: F
authors: Worek
authors: Nadine
authors: N
authors: Aurbek
authors: Marianne
authors: M
authors: Koller
authors: Christian
authors: C
authors: Becker
authors: Peter
authors: P
authors: Eyer
authors: Horst
authors: H
authors: Thiermann
mesh_terms: D000110:Acetylcholinesterase / Q000187:drug effects / Q000378:metabolism*; D000375:Aging / Q000378:metabolism*; D000577:Amides / Q000494:pharmacology*; D002801:Cholinesterase Reactivators; D006801:Humans; D007700:Kinetics; D009768:Obidoxime Chloride / Q000737:chemistry / Q000494:pharmacology; D010755:Organophosphates / Q000737:chemistry / Q000494:pharmacology; D010091:Oximes / Q000737:chemistry / Q000494:pharmacology; D010756:Phosphoric Acids / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D002801:Cholinesterase Reactivators; D010755:Organophosphates; D010091:Oximes; D010756:Phosphoric Acids; D009768:Obidoxime Chloride; C011067:phosphoramidic acid; D000110:Acetylcholinesterase; C009374:tabun