title: A common mechanism for resistance to oxime reactivation of acetylcholinesterase inhibited by organophosphorus compounds.
abstract: Administration of oxime therapy is currently the standard approach used to reverse the acute toxicity of organophosphorus (OP) compounds, which is usually attributed to OP inhibition of acetylcholinesterase (AChE). Rate constants for reactivation of OP-inhibited AChE by even the best oximes, such as HI-6 and obidoxime, can vary >100-fold between OP-AChE conjugates that are easily reactivated and those that are difficult to reactivate. To gain a better understanding of this oxime specificity problem for future design of improved reactivators, we conducted a QSAR analysis for oxime reactivation of AChE inhibited by OP agents and their analogues. Our objective was to identify common mechanism(s) among OP-AChE conjugates of phosphates, phosphonates and phosphoramidates that result in resistance to oxime reactivation. Our evaluation of oxime reactivation of AChE inhibited by a sarin analogue, O-methyl isopropylphosphonofluoridate, or a cyclosarin analogue, O-methyl cyclohexylphosphonofluoridate, indicated that AChE inhibited by these analogues was at least 70-fold more difficult to reactivate than AChE inhibited by sarin or cyclosarin. In addition, AChE inhibited by an analogue of tabun (i.e., O-ethyl isopropylphosphonofluoridate) was nearly as resistant to reactivation as tabun-inhibited AChE. QSAR analysis of oxime reactivation of AChE inhibited by these OP compounds and others suggested that the presence of both a large substituent (i.e., ≥ the size of dimethylamine) and an alkoxy substituent in the structure of OP compounds is the common feature that results in resistance to oxime reactivation of OP-AChE conjugates whether the OP is a phosphate, phosphonate or phosphoramidate.
authors.affiliation: US Army Medical Research Institute of Chemical Defense, Pharmacology Branch, 3100 Ricketts Point Road, Aberdeen Proving Ground, MD 21010-5400, United States. donald.maxwell@us.army.mil
authors.forename: Donald M
authors.initials: DM
authors.lastname: Maxwell
authors.forename: Karen M
authors.initials: KM
authors.lastname: Brecht
authors.forename: Richard E
authors.initials: RE
authors.lastname: Sweeney
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism*; D002800:Cholinesterase Inhibitors / Q000737:chemistry / Q000633:toxicity*; D002801:Cholinesterase Reactivators / Q000494:pharmacology*; D058851:GPI-Linked Proteins / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D009768:Obidoxime Chloride / Q000737:chemistry / Q000494:pharmacology; D009943:Organophosphorus Compounds / Q000737:chemistry / Q000633:toxicity*; D010091:Oximes / Q000737:chemistry / Q000494:pharmacology*; D011726:Pyridinium Compounds / Q000737:chemistry / Q000494:pharmacology; D021281:Quantitative Structure-Activity Relationship; D011994:Recombinant Proteins / Q000378:metabolism; D012524:Sarin / Q000031:analogs & derivatives / Q000737:chemistry / Q000633:toxicity
chemical_list: D002800:Cholinesterase Inhibitors; D002801:Cholinesterase Reactivators; D058851:GPI-Linked Proteins; D009943:Organophosphorus Compounds; D010091:Oximes; D011726:Pyridinium Compounds; D011994:Recombinant Proteins; D009768:Obidoxime Chloride; D012524:Sarin; C548244:ACHE protein, human; D000110:Acetylcholinesterase; C022870:asoxime chloride