Reactivation Potency of the Acetylcholinesterase Reactivator Obidoxime Is Limited

Kuča, Kamil; Musílek, Kamil; Pohanka, Miroslav; Dohnal, Vlastimil; Patočka, Jiří

doi:10.5507/bp.2009.044

Cited by 3 publications

(3 citation statements)

References 37 publications

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“…Our results show that all five compounds can counteract VX and GB poisoning but fail against A-234. None of them reached at least 10% reactivation of inhibited AChE, which is the recommended reactivation potency affecting the prognosis of an intoxicated organism (Kuca et al 2009 ). The following kinetic study confirmed the results of the reactivation screening for HI-6 and methoxime.…”

Section: Discussionmentioning

confidence: 99%

“…To assess the protective ratio, we selected three oximes based on availability in the Czech Republic. Obidoxime is the only oxime approved for treating OP poisonings in the civilian sector (Kuca et al 2009 ), while the Czech army is equipped with HI-6 and methoxime (Bajgar 2012 ). The results confirmed that atropine and diazepam are effective drugs regardless of the nerve agent nature.…”

Section: Discussionmentioning

confidence: 99%

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A-series agent A-234: initial in vitro and in vivo characterization

Hrabinova,

Pejchal,

Hepnarova

et al. 2024

Arch Toxicol

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A-series agent A-234 belongs to a new generation of nerve agents. The poisoning of a former Russian spy Sergei Skripal and his daughter in Salisbury, England, in March 2018 led to the inclusion of A-234 and other A-series agents into the Chemical Weapons Convention. Even though five years have already passed, there is still very little information on its chemical properties, biological activities, and treatment options with established antidotes. In this article, we first assessed A-234 stability in neutral pH for subsequent experiments. Then, we determined its inhibitory potential towards human recombinant acetylcholinesterase (HssAChE; EC 3.1.1.7) and butyrylcholinesterase (HssBChE; EC 3.1.1.8), the ability of HI-6, obidoxime, pralidoxime, methoxime, and trimedoxime to reactivate inhibited cholinesterases (ChEs), its toxicity in rats and therapeutic effects of different antidotal approaches. Finally, we utilized molecular dynamics to explain our findings. The results of spontaneous A-234 hydrolysis showed a slow process with a reaction rate displaying a triphasic course during the first 72 h (the residual concentration 86.2%). A-234 was found to be a potent inhibitor of both human ChEs (HssAChE IC50 = 0.101 ± 0.003 µM and HssBChE IC50 = 0.036 ± 0.002 µM), whereas the five marketed oximes have negligible reactivation ability toward A-234-inhibited HssAChE and HssBChE. The acute toxicity of A-234 is comparable to that of VX and in the context of therapy, atropine and diazepam effectively mitigate A-234 lethality. Even though oxime administration may induce minor improvements, selected oximes (HI-6 and methoxime) do not reactivate ChEs in vivo. Molecular dynamics implies that all marketed oximes are weak nucleophiles, which may explain the failure to reactivate the A-234 phosphorus-serine oxygen bond characterized by low partial charge, in particular, HI-6 and trimedoxime oxime oxygen may not be able to effectively approach the A-234 phosphorus, while pralidoxime displayed low interaction energy. This study is the first to provide essential experimental preclinical data on the A-234 compound.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

A-series agent A-234: initial in vitro and in vivo characterization

Hrabinova,

Pejchal,

Hepnarova

et al. 2024

Arch Toxicol

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“…Obidoxime (LuH-6, Toxogonin) discovered by Lüttringhaus and Hagedorn ( 1964 ) is a chemical antidote against nerve agent poisoning (tabun, sarin, VX) in civilians, as well as against some insecticides including paraoxon (Inns & Leadbeater, 1983 ; Kim et al , 2006 ; Petroianu et al , 2007b ; Kuca et al , 2009 ). Paraoxon is an organophosphorus compound with high human toxicity and its acute effects include nausea, diarrhea, excessive salivation, pupillary constriction, bronchoconstriction, muscle twitching, convulsions, coma, respiratory failure (Gosselin et al , 1984 ).…”

Section: Discussionmentioning

confidence: 99%

Pd(II) complexes of acetylcholinesterase reactivator obidoxime

Nedzhib

Stoykova

Atanasov

et al. 2014

Interdisciplinary Toxicology

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The ability of the acetylcholinesterase reactivator obidoxime (H2L2+) to bind palladium(II) cations was evaluated spectrophotometrically at different reaction conditions (pH, reaction time, metal-to-ligand molar ratio). The results showed that immediately after mixing the reagents, pH 7.4, complex species of composition [PdHL]3+ existed predominantly with a value of conditional stability constant lgβ‘=6.52. The reaction was completed within 24 hours affording the formation of species [Pd2L]4+ with significantly increased stability (lgβ‘=9.34). The spectral data suggest that obidoxime coordinates metal(II) ions through the oximate functional groups. The in vitro reactivation assay of paraoxon-inhibited rat brain acetylcholinesterase revealed that the new complex species were much less active than the non-coordinated obidoxime. The lack of reactivation ability could be explained by the considerable stability of complexes in solution as well as by the deprotonation of oxime groups essential for recovery of the enzymatic activity.

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SAR study to find optimal cholinesterase reactivator against organophosphorous nerve agents and pesticides

et al. 2016

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Irreversible inhibition of acetylcholinesterase (AChE) by organophosphates leads to many failures in living organism and ultimately in death. Organophosphorus compounds developed as nerve agents such as tabun, sarin, soman, VX and others belong to the most toxic chemical warfare agents and are one of the biggest threats to the modern civilization. Moreover, misuse of nerve agents together with organophosphorus pesticides (e.g. malathion, paraoxon, chlorpyrifos, etc.) which are annually implicated in millions of intoxications and hundreds of thousand deaths reminds us of insufficient protection against these compounds. Basic treatments for these intoxications are based on immediate administration of atropine and acetylcholinesterase reactivators which are currently represented by mono- or bis-pyridinium aldoximes. However, these antidotes are not sufficient to ensure 100 % treatment efficacy even they are administered immediately after intoxication, and in general, they possess several drawbacks. Herein, we have reviewed new efforts leading to the development of novel reactivators and proposition of new promising strategies to design novel and effective antidotes. Structure-activity relationships and biological activities of recently proposed acetylcholinesterase reactivators are discussed and summarized. Among further modifications of known oximes, the main attention has been paid to dual binding site ligands of AChE as the current mainstream strategy. We have also discussed new chemical entities as potential replacement of oxime functional group.

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Reactivation Potency of the Acetylcholinesterase Reactivator Obidoxime Is Limited

Cited by 3 publications

References 37 publications

A-series agent A-234: initial in vitro and in vivo characterization

A-series agent A-234: initial in vitro and in vivo characterization

Pd(II) complexes of acetylcholinesterase reactivator obidoxime

SAR study to find optimal cholinesterase reactivator against organophosphorous nerve agents and pesticides

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