In vitro and in silico Evaluation of Non-Quaternary Reactivators of AChE as Antidotes of Organophosphorus Poisoning - a New Hope or a Blind Alley?
Jazyk angličtina Země Nizozemsko Médium print
Typ dokumentu časopisecké články
PubMed
29332594
DOI
10.2174/1573406414666180112105657
PII: MC-EPUB-87865
Knihovny.cz E-zdroje
- Klíčová slova
- Anxiety, acetylcholinesterase, neurotransmission, non-quaternary oximes, organophosphate, oxime reactivators, quaternary oximes,
- MeSH
- antidota chemická syntéza farmakologie toxicita MeSH
- butyrylcholinesterasa metabolismus MeSH
- cholinesterasové inhibitory chemická syntéza farmakologie toxicita MeSH
- hematoencefalická bariéra účinky léků MeSH
- krysa rodu Rattus MeSH
- myši MeSH
- organofosfáty toxicita MeSH
- otrava organofosfáty farmakoterapie MeSH
- oximy chemická syntéza farmakologie toxicita MeSH
- paraoxon toxicita MeSH
- počítačová simulace MeSH
- reaktivátory cholinesterázy chemická syntéza farmakologie toxicita MeSH
- sarin toxicita MeSH
- zvířata MeSH
- Check Tag
- krysa rodu Rattus MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- antidota MeSH
- butyrylcholinesterasa MeSH
- cholinesterasové inhibitory MeSH
- organofosfáty MeSH
- oximy MeSH
- paraoxon MeSH
- reaktivátory cholinesterázy MeSH
- sarin MeSH
- tabun MeSH Prohlížeč
BACKGROUND: In the last decade, the concept of uncharged reactivators potentially able to penetrate the CNS has been introduced as an alternative to the classic charged oxime reactivators. However, this concept brings with it several associated drawbacks such as higher lipophilicity, difficulty in administration, lower affinity to cholinesterases, and higher toxicity risk. OBJECTIVE: In this study, we compare data obtained for a set of five classic charged reactivators and a set of three recently published uncharged oximes supplemented by two novel ones. METHODS: This time, we used only in silico prediction and in vitro approaches. RESULTS: Our data showed that tested uncharged oximes have low affinity for cholinesterases, do not possess high reactivation potency, and certainly represent a greater toxicity risk due to higher lipophilicity. We assume that balanced physicochemical properties will be required for the successful treatment of OP poisoning. Nevertheless, the compound meeting such criteria and pinpointed in silico (K1280) failed in this particular case. CONCLUSION: From the presented data, it seems that the concept of uncharged reactivators will have to be modified, at least to improve the bioavailability and to satisfy requirements for in vivo administration.
Citace poskytuje Crossref.org
Strategies for enhanced bioavailability of oxime reactivators in the central nervous system
