Pyridinium Oximes as Cholinesterase Reactivators. An Update of the Structure-Activity Relationship and Efficacy in the Treatment of Poisoning with Organophosphorus Compounds
Pp. 171-205 (35)
Milan Jokanović and Radica Stepanović Petrović
During more than five decades, pyridinium oximes have been developed as
therapeutic agents used in the medical treatment of poisoning with organophosphorus
compounds. Their mechanism of action is reactivation of acetylcholinesterase (AChE)
inhibited by organophosphorus agents. Organophosphorus compounds (OPC) are used
as pesticides and developed as warfare nerve agents such as tabun, soman, sarin, VX
and others. Exposure to even small amounts of an OPC can be fatal and death is usually
caused by respiratory failure resulting from paralysis of the diaphragm and intercostal
muscles, depression of the brain respiratory center, bronchospasm, and excessive
bronchial secretions. The mechanism of OPC poisoning involves phosphorylation of the
serine hydroxyl group at the active site of AChE leading to the inactivation of this
essential enzyme, which has an important role in neurotransmission. AChE inhibition
results in the accumulation of acetylcholine at cholinergic receptor sites, producing
continuous stimulation of cholinergic fibers throughout the central and peripheral
nervous systems. Presently, a combination of an antimuscarinic agent, e.g. atropine,
AChE reactivator such as one of the standard pyridinium oximes (pralidoxime,
trimedoxime, obidoxime, asoxime) and diazepam are used for the treatment of
organophosphate poisoning in humans.
Despite enormous efforts devoted to synthesis and development of new pyridinium
oximes as potential antidotes against poisoning with OPC, only four compounds are
used in human medicine so far. However, they differ in their activity in poisoning with
warfare nerve agents and pesticides and there is still no universal broad-spectrum oxime
capable of protecting against all known OPC. This article reviews the latest data on
structure-activity relationship of pyridinium oximes including their efficacy in treatment
of poisoning with organophosphorus compounds.
Acetylcholinesterase, asoxime, atropine, cyclosarin, diazepam, HI-6, HLö-
7, LüH-6, methoxime, MMB-4, obidoxime, organophosphorus compounds, PAM-
2, pralidoxime, pyridinium oximes, sarin, soman, tabun, TMB-4, trimedoxime, VX.
Faculty of Medicine, University of Nish, Nish, Serbia.