A structure-activity analysis of the variation in oxime efficacy against nerve agents.
A structure-activity analysis was used to evaluate the variation in oxime efficacy of 2-PAM, obidoxime, HI-6 and ICD585 against nerve agents. In vivo oxime protection and in vitro oxime reactivation were used as indicators of oxime efficacy against VX, sarin, VR and cyclosarin. Analysis of in vivo oxime protection was conducted with oxime protective ratios (PR) from guinea pigs receiving oxime and atropine therapy after sc administration of nerve agent. Analysis of in vitro reactivation was conducted with second-order rate contants (k(r2)) for oxime reactivation of agent-inhibited acetylcholinesterase (AChE) from guinea pig erythrocytes. In vivo oxime PR and in vitro k(r2) decreased as the volume of the alkylmethylphosphonate moiety of nerve agents increased from VX to cyclosarin. This effect was greater with 2-PAM and obidoxime (>14-fold decrease in PR) than with HI-6 and ICD585 (<3.7-fold decrease in PR). The decrease in oxime PR and k(r2) as the volume of the agent moiety conjugated to AChE increased was consistent with a steric hindrance mechanism. Linear regression of log (PR-1) against log (k(r2)[oxime dose]) produced two offset parallel regression lines that delineated a significant difference between the coupling of oxime reactivation and oxime protection for HI-6 and ICD585 compared to 2-PAM and obidoxime. HI-6 and ICD585 appeared to be 6.8-fold more effective than 2-PAM and obidoxime at coupling oxime reactivation to oxime protection, which suggested that the isonicotinamide group that is common to both of these oximes, but absent from 2-PAM and obidoxime, is important for oxime efficacy.
US Army Medical Research Institute of Chemical Defense, Research Division, Pharmacology Branch, 3100 Ricketts Point Road, Aberdeen Proving Ground, MD 21010-5400, USA. donald.maxwell@amedd.army.mil
Donald M
DM
Maxwell
Irwin
I
Koplovitz
Franz
F
Worek
Richard E
RE
Sweeney
D000110:Acetylcholinesterase / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001285:Atropine / Q000494:pharmacology; D002619:Chemical Warfare Agents / Q000633:toxicity; D002800:Cholinesterase Inhibitors / Q000633:toxicity*; D002801:Cholinesterase Reactivators / Q000737:chemistry / Q000494:pharmacology*; D004912:Erythrocytes / Q000201:enzymology; D006168:Guinea Pigs; D016014:Linear Models; D008297:Male; D009768:Obidoxime Chloride / Q000494:pharmacology; D009943:Organophosphorus Compounds / Q000633:toxicity*; D009946:Organothiophosphorus Compounds / Q000633:toxicity; D010091:Oximes / Q000737:chemistry / Q000494:pharmacology*; D011220:Pralidoxime Compounds / Q000494:pharmacology; D011726:Pyridinium Compounds / Q000494:pharmacology; D012524:Sarin / Q000633:toxicity; D013329:Structure-Activity Relationship
D000110:Acetylcholinesterase; D001285:Atropine; D002619:Chemical Warfare Agents; D002800:Cholinesterase Inhibitors; D002801:Cholinesterase Reactivators; D009768:Obidoxime Chloride; D009943:Organophosphorus Compounds; D009946:Organothiophosphorus Compounds; D010091:Oximes; D011220:Pralidoxime Compounds; D011726:Pyridinium Compounds; D012524:Sarin; C531547:1-((4-(aminocarbonyl)pyridinio)trimethylene)-2-((hydroxyimino)methyl)pyridinium; C009680:VX-agent; C022870:asoxime chloride; C451779:S-(N,N-diethylaminoethyl) isobutyl methylphosphothiolate; C028797:pralidoxime; C053914:cyclohexyl methylphosphonofluoridate