Passive diffusion of acetylcholinesterase oxime reactivators through the blood–brain barrier: Influence of molecular structure

Karasová, Jana Žďárová; Pohanka, Miroslav; Musílek, Kamil; Zemek, Filip; Kuča, Kamil

doi:10.1016/j.tiv.2010.05.009

Cited by 36 publications

(21 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Furthermore, future oxime development should focus on improving distribution across the organism to overcome maybe the main hindrance in improving therapy. Current antidotal research mostly revolves around passive diffusion linked to lipophilicity (46,47). This perspective requires changing the oxime's structure to obtain more desirable properties, but such changes greatly affect the oxime's potency to reactivate inhibited cholinesterases.…”

Section: Figure 1 Rat Plasma and Tissue Concentrations Of K048 After mentioning

confidence: 99%

Translation of in vitro to in vivo pyridinium oxime potential in tabun poisoning / Translacija učinkovitosti piridinijevih oksima kod trovanja tabunom iz in vitro sustava u in vivo primjenu

Katalinić

Hrvat

Karasová

et al. 2015

Archives of Industrial Hygiene and Toxicology

View full text Add to dashboard Cite

Even if organophosphorus (OP) nerve agents were banned entirely, their presence would remain a problem as weapons of terror (like in Syria). Oxime antidotes currently used in medical practice still fall short of their therapeutic purpose, as they fail to fully restore the activity of cholinesterases, the main target for OPs. As orphan drugs, these antidotes are tested too seldom for anybody's benefit. Over the last few decades, search for improved reactivators has reached new levels, but the translation of data obtained in vitro to in vivo application is still a problem that hinders efficient therapy. In this study, we tested the strengths and weaknesses of extrapolating pyridinium oxime antidotes reactivation efficiency from in vitro to in vivo application. Our results show that this extrapolation is possible with well-determined kinetic constants, but that it also largely depends on oxime circulation time and its tissue-specific distribution. This suggests that pharmacokinetic studies should be planned at the early stages of antidote development. Special attention should also be given to improving oxime distribution throughout the organism to overcome this major constraint in improving overall OP therapy.

show abstract

Section: Figure 1 Rat Plasma and Tissue Concentrations Of K048 After mentioning

confidence: 99%

Translation of in vitro to in vivo pyridinium oxime potential in tabun poisoning / Translacija učinkovitosti piridinijevih oksima kod trovanja tabunom iz in vitro sustava u in vivo primjenu

Katalinić

Hrvat

Karasová

et al. 2015

Archives of Industrial Hygiene and Toxicology

View full text Add to dashboard Cite

show abstract

“…This simple set of rules does not provide an exhaustive study of all the descriptors that define overall compound drug-likeness, the Ro5 specifically offers a fair estimation of drug-likeness with regard to good in vivo permeability and is the most quick profiling tool for drug likeness [28]. Although the charged structure and hydrophilic nature of oxime moiety makes pyridinium oximes rather less permeable to BBB, study of molecular descriptors is essential for prediction of their acute properties [29][30][31][32]. Herein, we have reported lipophilicity and hydrogen bonding parameters of tested oximes calculated by MarvinSketch version 6.2.2, 2014 (http://www.chemaxon.com).…”

Section: Singh Et Al: Physicochemical Properties Of Xylene Linked Bimentioning

confidence: 99%

Acid Dissociation Constants and Molecular Descriptors of Some Xylene Linked Bispyridinium Oximes

Singh¹,

Soukup²,

Doležal³

et al. 2015

MMSL

View full text Add to dashboard Cite

SummaryThe present article is aimed at determination of acid dissociation constants (pK a ), lipophilicity (logP) and hydrogen bond acceptor (HBA) and donor (HBD) counts of some novel xylene-linked bispyridiniumoxime based AChE reactivators. The choice was supported by their use in the therapy of acute intoxication with organophosphorus AChE inhibitors. UV-Vis spectrophotometry has been used to measure experimental pK a values at 27°C, while software Marvin Sketch (chemaxon) has been used to estimate structure based computational pK a , logP values and hydrogen bonding parameters. The results were compared with standard oximes (HI-6 and obidoxime) under similar conditions. All the calculated pK a values lie in the range of 7.45-9.85 which is well in agreement with most of the oxime reactivators studied so far.

show abstract

“…Although a quaternary nitrogen atom is believed to be necessary for binding the inhibited enzyme anionic site [5], it limits passage of the compound through the blood-brain-barrier (BBB) where uptake is thought desirable for combating the toxic effects of NAs on the central nervous system [6,7]. The acid dissociation constant (pK a ) of the oxime group determines the concentration of oximate ion and thus the rate of reactivation.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of some fluorine-containing pyridinealdoximes of potential use for the treatment of organophosphorus nerve-agent poisoning

Timperley

Banks

Young

et al. 2011

Journal of Fluorine Chemistry

View full text Add to dashboard Cite

Passive diffusion of acetylcholinesterase oxime reactivators through the blood–brain barrier: Influence of molecular structure

Cited by 36 publications

References 30 publications

Translation of in vitro to in vivo pyridinium oxime potential in tabun poisoning / Translacija učinkovitosti piridinijevih oksima kod trovanja tabunom iz in vitro sustava u in vivo primjenu

Translation of in vitro to in vivo pyridinium oxime potential in tabun poisoning / Translacija učinkovitosti piridinijevih oksima kod trovanja tabunom iz in vitro sustava u in vivo primjenu

Acid Dissociation Constants and Molecular Descriptors of Some Xylene Linked Bispyridinium Oximes

Synthesis of some fluorine-containing pyridinealdoximes of potential use for the treatment of organophosphorus nerve-agent poisoning

Contact Info

Product

Resources

About