Kinetic analysis of interactions of different sarin and tabun analogues with human acetylcholinesterase and oximes: is there a structure-activity relationship?

Chemico-biological Interactions
Nadine AurbekFranz Worek

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-inhibi...Continue Reading

References

Oct 26, 1999·Clinica Chimica Acta; International Journal of Clinical Chemistry·F WorekP Eyer
Jan 18, 2003·Analytical Biochemistry·Peter EyerElsa Reiner
Mar 24, 2004·Journal of Intensive Care Medicine·Sage W Wiener, Robert S Hoffman

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Citations

Jun 29, 2016·Archives of Toxicology·Franz WorekHorst Thiermann
Jul 8, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Franz WorekTimo Wille
Jun 9, 2020·Archives of Toxicology·Franz WorekTimo Wille
Jun 26, 2021·Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences·Marianne KollerTimo Wille

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