title: Kinetic analysis of interactions of different sarin and tabun analogues with human acetylcholinesterase and oximes: is there a structure-activity relationship?
abstract: The repeated misuse of highly toxic organophosphorus compound (OP) based chemical warfare agents in military conflicts and terrorist attacks poses a continuous threat to the military and civilian sector. The toxic symptomatology of OP poisoning is mainly caused by inhibition of acetylcholinesterase (AChE, E.C. 3.1.1.7) resulting in generalized cholinergic crisis due to accumulation of the neurotransmitter acetylcholine (ACh) in synaptic clefts. Beside atropine as competitive antagonist of ACh at muscarinic ACh receptors oximes as reactivators of OP-inhibited AChE are a mainstay of standard antidotal treatment. However, human AChE inhibited by certain OP is rather resistant to oxime-induced reactivation. The development of more effective oxime-based reactivators may fill the gaps. To get more insight into a potential structure-activity relationship between human AChE, OPs and oximes in vitro studies were conducted to investigate interactions of different tabun and sarin analogues with human AChE and the oximes obidoxime and HI 6 by determination of various kinetic constants. Rate constants for the inhibition of human AChE by OPs, spontaneous dealkylation and reactivation as well as reactivation by obidoxime and HI 6 of OP-inhibited human AChE were determined. The recorded kinetic data did not allow a general statement concerning a structure-activity relationship between human AChE, OP and oximes.
authors.affiliation: Bundeswehr Institute of Pharmacology and Toxicology, Munich, Germany.
authors.forename: Nadine
authors.initials: N
authors.lastname: Aurbek
authors.forename: Nadja M
authors.initials: NM
authors.lastname: Herkert
authors.forename: Marianne
authors.initials: M
authors.lastname: Koller
authors.forename: Horst
authors.initials: H
authors.lastname: Thiermann
authors.forename: Franz
authors.initials: F
authors.lastname: Worek
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism*; D002800:Cholinesterase Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D002801:Cholinesterase Reactivators / Q000737:chemistry / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects*; D006801:Humans; D007700:Kinetics; D009768:Obidoxime Chloride / Q000737:chemistry / Q000494:pharmacology; D010755:Organophosphates / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D010091:Oximes / Q000737:chemistry / Q000494:pharmacology*; D011485:Protein Binding; D011726:Pyridinium Compounds / Q000737:chemistry / Q000494:pharmacology; D012524:Sarin / Q000031:analogs & derivatives / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D002800:Cholinesterase Inhibitors; D002801:Cholinesterase Reactivators; D010755:Organophosphates; D010091:Oximes; D011726:Pyridinium Compounds; D009768:Obidoxime Chloride; D012524:Sarin; D000110:Acetylcholinesterase; C022870:asoxime chloride; C009374:tabun