Strategy for the development of new acetylcholinesterase reactivators - antidotes used for treatment of nerve agent poisonings.
The mechanism of intoxication with organophosphorus compounds, including highly toxic nerve agents, is based on the formation of irreversibly inhibited acetylcholinesterase (AChE; EC 3.1.1.7) that could be followed by a generalized cholinergic crisis. Nerve agent poisoning is conventionally treated using a combination of a cholinolytic drug (atropine mostly) to counteract the accumulation of acetylcholine at muscarinic receptors and AChE reactivators (pralidoxime or obidoxime) to reactivate inhibited AChE. At the Department of Toxicology, the strategy of the development of new more potent AChE reactivators consists of several steps: description of the nerve agent intoxication mechanism on the molecular basis (molecular design), prediction of the biological active structure of AChE reactivators (artificial neural networks), their synthesis, in vitro evaluation of their potencies (potentiometric titration and Ellman's method), in vivo studies (therapeutic index, LD(50) of newly synthesized reactivators, reactivation in different tissues, neuroprotective efficacy).
Kuca
Kamil
K
Department of Toxicology, Trebesská 1575, Hradec Králové, Czech Republic. kucakam@pmfhk.cz
Cabal
Jirí
J
Jun
Daniel
D
Kassa
Jirí
J
Bartosová
Lucie
L
Kunesová
Gabriela
G
Dohnal
Vlastimil
V
D002619:Chemical Warfare Agents / Q000138:chemical synthesis*; D002801:Cholinesterase Reactivators / Q000138:chemical synthesis*; D015195:Drug Design; D016571:Neural Networks, Computer
D002619:Chemical Warfare Agents; D002801:Cholinesterase Reactivators