title: Strategy for the development of new acetylcholinesterase reactivators - antidotes used for treatment of nerve agent poisonings.
abstract: 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).
authors.affiliation: Department of Toxicology, Trebesská 1575, Hradec Králové, Czech Republic. kucakam@pmfhk.cz
authors.forename: Kamil
authors.initials: K
authors.lastname: Kuca
authors.forename: Jirí
authors.initials: J
authors.lastname: Cabal
authors.forename: Daniel
authors.initials: D
authors.lastname: Jun
authors.forename: Jirí
authors.initials: J
authors.lastname: Kassa
authors.forename: Lucie
authors.initials: L
authors.lastname: Bartosová
authors.forename: Gabriela
authors.initials: G
authors.lastname: Kunesová
authors.forename: Vlastimil
authors.initials: V
authors.lastname: Dohnal
mesh_terms: D002619:Chemical Warfare Agents / Q000138:chemical synthesis*; D002801:Cholinesterase Reactivators / Q000138:chemical synthesis*; D015195:Drug Design; D016571:Neural Networks, Computer
chemical_list: D002619:Chemical Warfare Agents; D002801:Cholinesterase Reactivators