Reactivation kinetics of a series of related bispyridinium oximes with organophosphate-inhibited human acetylcholinesterase--Structure-activity relationships.
Despite extensive research in the last six decades, oximes are the only available drugs which enable a causal treatment of poisoning by organophosphorus compounds (OP). However, numerous in vitro and in vivo studies demonstrated a limited ability of these oximes to reactivate acetylcholinesterase (AChE) inhibited by different OP pesticides and nerve agents. New oximes were mostly tested for their therapeutic efficacy by using different animal models and for their reactivating potency with AChE from different species. Due to the use of different experimental protocols a comparison of data from the various studies is hardly possible. Now, we found it tempting to determine the reactivation kinetics of a series of bispyridinium oximes bearing one or two oxime groups at different positions and having an oxybismethylene or a trimethylene linker under identical conditions with human AChE inhibited by structurally different OP. The data indicate that the position of the oxime group(s) is decisive for the reactivating potency and that different positions of the oxime groups are important for different OP inhibitors while the nature of the linker, oxybismethylene or trimethylene, is obviously of minor importance. Hence, these and previous data emphasize the necessity for thorough kinetic investigations of OP-oxime-AChE interactions and underline the difficulty to develop a broad spectrum oxime reactivator which is efficient against structurally different OP inhibitors.
Bundeswehr Institute of Pharmacology and Toxicology, Neuherbergstrasse 11, 80937 Munich, Germany. franzworek@bundeswehr.org
Franz
F
Worek
Timo
T
Wille
Marianne
M
Koller
Horst
H
Thiermann
D000110:Acetylcholinesterase / Q000187:drug effects*; D002800:Cholinesterase Inhibitors / Q000633:toxicity*; D002801:Cholinesterase Reactivators / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D010755:Organophosphates / Q000633:toxicity; D009943:Organophosphorus Compounds / Q000633:toxicity*; D010091:Oximes / Q000737:chemistry / Q000494:pharmacology*; D010261:Paraoxon / Q000633:toxicity; D013329:Structure-Activity Relationship
D002800:Cholinesterase Inhibitors; D002801:Cholinesterase Reactivators; D010755:Organophosphates; D009943:Organophosphorus Compounds; D010091:Oximes; D000110:Acetylcholinesterase; D010261:Paraoxon; C009374:tabun; C053914:cyclohexyl methylphosphonofluoridate