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7-phenoxytacrine is a dually acting drug with neuroprotective efficacy in vivo
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SYSNO ASEP 0543350 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title 7-phenoxytacrine is a dually acting drug with neuroprotective efficacy in vivo Author(s) Kaniaková, Martina (FGU-C) RID, ORCID
Korábečný, J. (CZ)
Holubová, Kristína (FGU-C) ORCID, SAI, RID
Kletečková, Lenka (FGU-C) ORCID
Chvojková, Markéta (FGU-C) RID, ORCID
Hakenová, K. (CZ)
Prchal, L. (CZ)
Novák, M. (CZ)
Doležal, R. (CZ)
Hepnarová, V. (CZ)
Svobodová, B. (CZ)
Kučera, T. (CZ)
Lichnerová, Katarina (FGU-C) ORCID
Krausová, B. (CZ)
Horák, Martin (FGU-C) RID, ORCID
Valeš, Karel (FGU-C) RID, ORCID, SAI
Soukup, O. (CZ)Article number 114460 Source Title Biochemical Pharmacology. - : Elsevier - ISSN 0006-2952
Roč. 186, Apr (2021)Number of pages 13 s. Language eng - English Country US - United States Keywords behavioral experiment ; electrophysiology ; glutamate receptor ; mutation ; ion channel ; acetylcholinesterase Subject RIV FR - Pharmacology ; Medidal Chemistry OECD category Pharmacology and pharmacy R&D Projects EF16_025/0007444 GA MZd - Ministry of Health (MZ) Method of publishing Limited access Institutional support FGU-C - RVO:67985823 UT WOS 000640416800002 EID SCOPUS 85100905242 DOI 10.1016/j.bcp.2021.114460 Annotation N-methyl-D-aspartaterecepro receptor (NMDARs) are a subclass of glutamate receptors, which play an essential role in excitatory neurotransmission, but their excessive overactivation by glutamate leads to excitotoxicity. NMDARs are hence a valid pharmacological target for the treatment of neurodegenerative disorders, however, novel drugs targeting NMDARs are often associated with specific psychotic side effects and abuse potential. Motivated by currently available treatment against neurodegenerative diseases involving the inhibitors of acetylcholinesterase (AChE) and NMDARs, administered also in combination, we developed a dually-acting compound 7-phenoxytacrine (7-PhO-THA) and evaluated its neuropsychopharmacological and drug-like properties for potential therapeutic use. Indeed, we have confirmed the dual potency of 7-PhO-THA, i.e. potent and balanced inhibition of both AChE and NMDARs. We discovered that it selectively inhibits the GluN1/GluN2B subtype of NMDARs via an ifenprodil-binding site, in addition to its voltage-dependent inhibitory effect at both GluN1/GluN2A and GluN1/GluN2B subtypes of NMDARs. Furthermore, whereas NMDA-induced lesion of the dorsal hippocampus confirmed potent anti-excitotoxic and neuroprotective efficacy, behavioral observations showed also a cholinergic component manifesting mainly in decreased hyperlocomotion. From the point of view of behavioral side effects, 7-PhO-THA managed to avoid these, notably those analogous to symptoms of schizophrenia. Thus, CNS availability and the overall behavioral profile are promising for subsequent investigation of therapeutic use. Workplace Institute of Physiology Contact Lucie Trajhanová, lucie.trajhanova@fgu.cas.cz, Tel.: 241 062 400 Year of Publishing 2022 Electronic address https://doi.org/10.1016/j.bcp.2021.114460
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