Oxidative mechanisms for the biotransformation of 1-methyl-1,6-dihydropyridine-2-carbaldoxime to pralidoxime chloride

Khan, Farhat A.; Campbell, Amy J.; Hoyt, Benjamin W.; Herdman, Christine A.; Ku, Therese; Thangavelu, Sonia G.; Gordon, Richard K.

doi:10.1016/j.lfs.2011.09.019

Cited by 7 publications

(5 citation statements)

References 53 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A prodrug derivative of 2-PAM, pro-PAM, was reported in 1976 as the uncharged dihydropyridine derivative of 2-PAM, with the potential to be activated to 2-PAM in the brain. 19,20 However, pro-PAM was considered not efficacious enough to be worthy of appreciable further study. Sugar oximes were synthesized with the theory that they could be transported into the brain on the glucose transporter, and some efficacy was observed.…”

Section: Summary Of Research Programs Seeking a Brain-penetrating Achmentioning

confidence: 99%

“…However, the in vivo studies conducted on these compounds delivered the oximes very shortly after OP administration, so that peripheral reactivation cannot be ruled out as the major action of these compounds. A prodrug derivative of 2‐PAM, pro‐PAM, was reported in 1976 as the uncharged dihydropyridine derivative of 2‐PAM, with the potential to be activated to 2‐PAM in the brain 19,20 . However, pro‐PAM was considered not efficacious enough to be worthy of appreciable further study.…”

Section: Summary Of Research Programs Seeking a Brain‐penetrating Achmentioning

confidence: 99%

See 1 more Smart Citation

Central neuroprotection demonstrated by novel oxime countermeasures to nerve agent surrogates

Chambers

Meek

2020

Annals of the New York Academy of Sciences

View full text Add to dashboard Cite

Oximes remain a long-standing element of the therapy for nerve agents, organophosphates (OPs) that poison by inhibiting the enzyme acetylcholinesterase (AChE), resulting in hypercholinergic activity both centrally and peripherally. Oximes, such as the pyridinium oxime pralidoxime (2-PAM) in the United States, can reactivate the inhibited AChE and restore cholinergic function. However, there are several drawbacks to the current oximes; one of them, the inability of these oximes to effectively enter the brain, is the subject of study by several laboratories, including ours. Our laboratory invented a platform of substituted phenoxyalkyl pyridinium oximes that were tested against highly relevant surrogates of the nerve agents, sarin and VX. Using high sublethal dosages of the OPs, the novel oximes were observed to attenuate seizure-like behavior in rats and to reduce the levels of glial fibrillary acidic protein (an indicator of glial scarring) to control levels, in contrast to levels observed with 2-PAM or no oxime therapy. Using lethal levels of surrogates, some novel oximes protected against lethality compared with 2-PAM, shortened the time to cessation of seizure-like behavior (from 8+ to 6 h), and protected the brain neurons. Therefore, some of these novel oximes are showing exceptional promise alone or in combination with 2-PAM as therapeutics against nerve agent toxicity.

show abstract

Section: Summary Of Research Programs Seeking a Brain-penetrating Achmentioning

confidence: 99%

Section: Summary Of Research Programs Seeking a Brain‐penetrating Achmentioning

confidence: 99%

Central neuroprotection demonstrated by novel oxime countermeasures to nerve agent surrogates

Chambers

Meek

2020

Annals of the New York Academy of Sciences

View full text Add to dashboard Cite

show abstract

“…Unfortunately, ionic compounds, like the cationic oximes, normally can not permeate the hematoencephalic barrier. One example of an oxime with capacity for hematoencephalic barrier permeation is pro-2-PAM, 42 a neutral compound that is converted to 2-PAM by oxidation after permeation, 43 but possesses poor AChE reaction activity. 44 On the other hand, neutral compounds with a polar surface area (PSA) lower that 60 Å 2 and molecular mass below 450 Da have better permeation possibility.…”

Section: Introductionmentioning

confidence: 99%

The effect of neutral oximes on the reactivation of human acetylcholinesterase inhibited with paraoxon

Ribeiro¹,

Prates²,

Alves³

et al. 2012

J. Braz. Chem. Soc.

View full text Add to dashboard Cite

Importantes agentes para defesa contra armas de guerra química são reativadores da acetilcolinesterase humana (huAChE) inibida por compostos organofosforados neurotóxicos (OP), e precisam de uma permeabilidade razoável pela barreira hematoencefálica (HB). Neste trabalho, oximas neutras, que penetram HB melhor do que as oximas catiônicas atualmente utilizadas como agentes de defesa, foram testadas como reativadores da huAChE inibida com paraoxon usando o método de Ellman modificado e pralidoxima (2-PAM) como padrão positivo. A oxima neutra mais ativa foi a 2-tiofenoaldoxima, que reativou 93% da huAChE inibida, sendo 12% mais eficiente do que a 2-PAM. Os resultados mostraram que oximas neutras simples possuem potencial para atuarem como antídotos para intoxicação com OPs neurotóxicos, sugerindo maior investigação no desenvolvimento de agentes de defesa neutros.Important defense agents against chemical warfare weapons, which are reactivators of human acetylcholinesterase (huAChE) inhibited by neurotoxic organophosphorus compounds (OP), need a reasonable permeation of the hematoencephalic barrier (HB). In this work, neutral oximes, which permeate HB better than the cationic oximes currently used as defense agents, were tested as reactivators of huAChE inhibited with paraoxon using the modified Ellman test with pralidoxime (2-PAM) as positive standard. The most active neutral oxime was (thiophen-2-yl)aldoxime, which reactivated 93% of the inhibited huAChE and was 12% more effective than 2-PAM. The results showed that simple neutral oximes have potential to function as antidotes for intoxication with neurotoxic OPs, suggesting further research on the development of neutral defense agents.Keywords: neutral oximes, huAChE reactivation, paraoxon, chemical warfare, (thiophen-2-yl)aldoxime IntroductionIntoxication with neurotoxic organophosphorus compounds is a serious problem caused by some pesticides used in agriculture, such as paraoxon (1) and malathion (2) ( Figure 1) and chemical warfare agents. [1][2][3][4][5][6][7][8][9][10][11] According to the World Health Organization, there are about 220,000 intoxications with organophosphorus pesticides throughout the world every year, leading to approximately 20,000 deaths. 1,[12][13][14] The most dangerous neurotoxic compounds are the chemical warfare agents soman (3), sarin (4), tabun (5) and VX (6) ( Figure 1). Though their use is prohibited by the United Nations, these agents have been employed as weapons by terrorist groups and by countries that did not sign the Chemical Weapon Convention administered by the Organization for the Prohibition of Chemical Weapons (OPCW).The principal target for the action of neurotoxic organophosphorus compounds is the enzyme acetylcholinesterase (AChE), a serine hydrolase that controls the nerve impulses at the cholinergic receptors in the central and peripheral nervous systems. 1,15-20 As shown in Ribeiro et al. 1217 Vol. 23, No. 7, 2012 Figure 2, the function of AChE (7) is the hydrolysis of the nerve impulse transmitter acetylcholine...

show abstract

“…A significant amount of research is currently being conducted to develop novel oxime-based reactivators that more readily cross the BBB [ 40 ]. These molecules include 2-PAM prodrugs [ 41 ], novel delivery methods [ 42 , 43 ], and novel oxime molecules [ 40 , 44 ]. This work demonstrates a pipeline that can be used to evaluate brain penetrance including absolute quantification and the localization of novel oxime countermeasures with or without OPNA exposure.…”

Section: Discussionmentioning

confidence: 99%

Characterization of Humanized Mouse Model of Organophosphate Poisoning and Detection of Countermeasures via MALDI-MSI

Tressler,

Wadsworth,

Carriero

et al. 2024

IJMS

View full text Add to dashboard Cite

Organophosphoate (OP) chemicals are known to inhibit the enzyme acetylcholinesterase (AChE). Studying OP poisoning is difficult because common small animal research models have serum carboxylesterase, which contributes to animals’ resistance to OP poisoning. Historically, guinea pigs have been used for this research; however, a novel genetically modified mouse strain (KIKO) was developed with nonfunctional serum carboxylase (Es1 KO) and an altered acetylcholinesterase (AChE) gene, which expresses the amino acid sequence of the human form of the same protein (AChE KI). KIKO mice were injected with 1xLD50 of an OP nerve agent or vehicle control with or without atropine. After one to three minutes, animals were injected with 35 mg/kg of the currently fielded Reactivator countermeasure for OP poisoning. Postmortem brains were imaged on a Bruker RapifleX ToF/ToF instrument. Data confirmed the presence of increased acetylcholine in OP-exposed animals, regardless of treatment or atropine status. More interestingly, we detected a small amount of Reactivator within the brain of both exposed and unexposed animals; it is currently debated if reactivators can cross the blood–brain barrier. Further, we were able to simultaneously image acetylcholine, the primary affected neurotransmitter, as well as determine the location of both Reactivator and acetylcholine in the brain. This study, which utilized sensitive MALDI-MSI methods, characterized KIKO mice as a functional model for OP countermeasure development.

show abstract

Oxidative mechanisms for the biotransformation of 1-methyl-1,6-dihydropyridine-2-carbaldoxime to pralidoxime chloride

Cited by 7 publications

References 53 publications

Central neuroprotection demonstrated by novel oxime countermeasures to nerve agent surrogates

Central neuroprotection demonstrated by novel oxime countermeasures to nerve agent surrogates

The effect of neutral oximes on the reactivation of human acetylcholinesterase inhibited with paraoxon

Characterization of Humanized Mouse Model of Organophosphate Poisoning and Detection of Countermeasures via MALDI-MSI

Contact Info

Product

Resources

About