A structure-activity analysis of the variation in oxime efficacy against nerve agents

Journal Article · Mon Sep 01 00:00:00 EDT 2008 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/j.taap.2008.04.007· OSTI ID:21140939

Koplovitz, Irwin ^[1]; Worek, Franz ^[2]; Sweeney, Richard E ^[1]

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1. US Army Medical Research Institute of Chemical Defense, Research Division, Pharmacology Branch, 3100 Ricketts Point Road, Aberdeen Proving Ground, MD 21010-5400 (United States)
2. Bundeswehr Institute of Pharmacology and Toxicology, Neuherbergstrasse 11, Munich (Germany)

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{sub r2}) for oxime reactivation of agent-inhibited acetylcholinesterase (AChE) from guinea pig erythrocytes. In vivo oxime PR and in vitro k{sub 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{sub 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{sub r2} {center_dot} [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.

• OSTI ID: 21140939
• Journal Information: Toxicology and Applied Pharmacology, Vol. 231, Issue 2; Other Information: DOI: 10.1016/j.taap.2008.04.007; PII: S0041-008X(08)00176-2; Copyright (c) 2008 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA); ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
ATROPINE
CHLORIDES
ERYTHROCYTES
GUINEA PIGS
IN VITRO
IN VIVO
OXIMES