Phenoxytacrine derivatives: Low-toxicity neuroprotectants exerting affinity to ifenprodil-binding site and cholinesterase inhibition
Jazyk angličtina Země Francie Médium print-electronic
Typ dokumentu časopisecké články
PubMed
38218127
DOI
10.1016/j.ejmech.2024.116130
PII: S0223-5234(24)00010-2
Knihovny.cz E-zdroje
- Klíčová slova
- Acetylcholinesterase, Alzheimer's disease, Electrophysiology, Glutamate receptor, In vivo, Neuroprotection, Tacrine,
- MeSH
- acetylcholinesterasa metabolismus MeSH
- Alzheimerova nemoc * farmakoterapie MeSH
- cholinesterasové inhibitory chemie MeSH
- cholinesterasy MeSH
- lékové postižení jater * MeSH
- lidé MeSH
- neuroprotektivní látky * farmakologie terapeutické užití MeSH
- piperidiny * MeSH
- receptory N-methyl-D-aspartátu MeSH
- takrin chemie MeSH
- vazebná místa MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- acetylcholinesterasa MeSH
- cholinesterasové inhibitory MeSH
- cholinesterasy MeSH
- ifenprodil MeSH Prohlížeč
- neuroprotektivní látky * MeSH
- piperidiny * MeSH
- receptory N-methyl-D-aspartátu MeSH
- takrin MeSH
Tacrine (THA), a long withdrawn drug, is still a popular scaffold used in medicinal chemistry, mainly for its good reactivity and multi-targeted effect. However, THA-associated hepatotoxicity is still an issue and must be considered in drug discovery based on the THA scaffold. Following our previously identified hit compound 7-phenoxytacrine (7-PhO-THA), we systematically explored the chemical space with 30 novel derivatives, with a focus on low hepatotoxicity, anticholinesterase action, and antagonism at the GluN1/GluN2B subtype of the NMDA receptor. Applying the down-selection process based on in vitro and in vivo pharmacokinetic data, two candidates, I-52 and II-52, selective GluN1/GluN2B inhibitors thanks to the interaction with the ifenprodil-binding site, have entered in vivo pharmacodynamic studies. Finally, compound I-52, showing only minor affinity to AChE, was identified as a lead candidate with favorable behavioral and neuroprotective effects using open-field and prepulse inhibition tests, along with scopolamine-based behavioral and NMDA-induced hippocampal lesion models. Our data show that compound I-52 exhibits low toxicity often associated with NMDA receptor ligands, and low hepatotoxicity, often related to THA-based compounds.
Department of Neuro Pathology University of Oslo and Oslo University Hospital Oslo Norway
National Institute of Mental Health Topolova 748 250 67 Klecany Czech Republic
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