Pralidoxime-like reactivator with increased lipophilicity - Molecular modeling and in vitro study
Language English Country Ireland Media print-electronic
Document type Journal Article
PubMed
37788753
DOI
10.1016/j.cbi.2023.110734
PII: S0009-2797(23)00401-5
Knihovny.cz E-resources
- Keywords
- 2-PAM, Antidote, Nerve agent, Pesticide, Reactivator,
- MeSH
- Acetylcholinesterase metabolism MeSH
- Antidotes pharmacology MeSH
- Cholinesterase Inhibitors pharmacology metabolism MeSH
- Humans MeSH
- Organophosphate Poisoning * MeSH
- Oximes pharmacology chemistry MeSH
- Pralidoxime Compounds pharmacology MeSH
- Cholinesterase Reactivators * chemistry MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- Acetylcholinesterase MeSH
- Antidotes MeSH
- Cholinesterase Inhibitors MeSH
- Oximes MeSH
- pralidoxime MeSH Browser
- Pralidoxime Compounds MeSH
- Cholinesterase Reactivators * MeSH
Acetylcholinesterase (AChE, EC 3.1.1.7) reactivators (2-PAM, trimedoxime, obidoxime, asoxime) have become an integral part of antidotal treatment in cases of nerve agent and organophosphorus (OP) pesticide poisonings. They are often referred to as specific antidotes due to their ability to restore AChE function when it has been covalently inhibited by an OP compound. Currently available commercial reactivators exhibit limited ability to penetrate the blood-brain barrier, where reactivation of inhibited AChE is crucial. Consequently, there have been numerous efforts to discover more brain-penetrating AChE reactivators. In this study, we examined a derivative of 2-PAM designed to possess increased lipophilicity. This enhanced lipophilicity was achieved through the incorporation of a benzyl group into its molecular structure. Initially, a molecular modeling study was conducted, followed by a comparison of its reactivation efficacy with that of 2-PAM against 10 different AChE inhibitors in vitro. Unfortunately, this relatively significant structural modification of 2-PAM resulted in a decrease in its reactivation potency. Consequently, this derivative cannot be considered as a broad-spectrum AChE reactivator.
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