Pyridinium Oximes as Cholinesterase Reactivators. Structure-Activity Relationship and Efficacy in the Treatment of Poisoning with Organophosphorus Compounds

Abstract

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, HI-6) and diazepam has been 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 have found their application 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. In this article, we review data on structure-activity relationship of pyridinium oximes and discuss their pharmacological and toxicological significance.

A Comparison of the Neuroprotective Efficacy of Individual Oximes (Hi-6, Trimedoxime, K203) and Their Mixtures (Hi-6 + Trimedoxime, Hi-6 + K203) in Cyclosarin-Poisoned Rats

“…Even the oxime HI-6 that is considered to be the best reactivator of cyclosarin-inhibited AChE (6,9,10,20,21) is not satisfactorily effective oxime for the elimination of cyclosarin-induced neurotoxic signs and symptoms due to low penetration through BBB and low reactivating efficacy in the CNS (6,22). On the other hand, it is known that the oximes may also attentuate nerve agent-induced brain insult via different mechanisms other than AChE reactivation (35).…”

“…Nevertheless, our results demonstrate that the combination of the oxime HI-6 with trimedoxime or K203 did not bring any beneficial effect for the potency of single oximes (HI-6, trimedoxime, K203) to reduce acute neurotoxic effects of cyclosarin. The absence of an increase in the neuroprotective efficacy of chosen oxime mixtures compared to tested single oximes could be explained by a limited penetration of oximes through BBB (22) and limited reactivation of nerve agent-inhibited AChE in the brain (6,9).…”

“…The neuroprotective efficacy of the chosen mixtures of oximes in combination with atropine was evaluated against cyclosarin (GF; cyclohexyl methylphosphonofluoridate) because its acute neurotoxicity is difficult to antagonize due to low potency of all commonly used oximes to reactivate cyclosarin-inhibited brain AChE (6,27) The main aim of this study was to compare the neuroprotective efficacy of three individual oximes (trimedoxime, HI-6, K203) with two mixtures of oximes containing the oxime HI-6 and trimedoxime or the oxime K203 in combination with an anticholinergic drug atropine in cyclosarin-poisoned rats. The cyclosarin-induced neurotoxic signs were determined using a functional observational battery, a non-invasive and relatively sensitive type of neurological examination for a wide range of neurobiological functions including measurements of sensory, motor and autonomic nervous functions.…”

HLö-7 - A REVIEW OF ACETYLCHOLINESTERASE REACTIVATOR AGAINST ORGANOPHOSPHOROUS INTOXICATION

“…soman 2-4 minutes; sarin 5-12 hours; tabun 46 hours; VX 48 hours) which is important for better antidote treatment. [16][17][18][19] The similarity between murine AChE (mAChE) and hAChE helped to describe in detail the mechanism of OPs binding. 20 The OPs binding is directed by its covalent bond with the catalytic serine (Ser203 on hAChE).…”

Dose Dependent Prophylactic Efficacy of 6-Chlorotacrine in Soman-Poisoned Mice

“…Generally, anticholinergics (mainly atropine) are used for relieving muscarinic signs and symptoms whereas AChE reactivators (generally nucleophilic compounds with high affinity for phosphorus), called oximes, are used to repair the biochemical lesion by dephosphonylation of AChE and restoring its activity. Although the antidotes against nerve agents and organophosphorus insecticides have been developed based on the knowledge of above-mentioned basic mechanism of acute toxicity of organophosphorus compounds, their efficacy is limited (3)(4).…”