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Structure-activity relationships of dually-acting acetylcholinesterase inhibitors derived from tacrine on N-methyl-d-Aspartate receptors
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SYSNO ASEP 0542659 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title Structure-activity relationships of dually-acting acetylcholinesterase inhibitors derived from tacrine on N-methyl-d-Aspartate receptors Author(s) Gorecki, L. (CZ)
Misiachna, Anna (FGU-C)
Damborský, J. (CZ)
Doležal, R. (CZ)
Korábečný, J. (CZ)
Čejková, L. (CZ)
Hakenová, K. (CZ)
Chvojková, M. (CZ)
Zdarová Karasová, J. (CZ)
Prchal, L. (CZ)
Novák, M. (CZ)
Kolcheva, Marharyta (FGU-C)
Kortus, Štěpán (FGU-C) ORCID
Valeš, K. (CZ)
Horák, Martin (FGU-C) RID, ORCID
Soukup, O. (CZ)Article number 113434 Source Title European Journal of Medicinal Chemistry. - : Elsevier - ISSN 0223-5234
Roč. 219, 5 July (2021)Number of pages 16 s. Language eng - English Country FR - France Keywords QSAR ; acetylcholinesterase ; electrophysiology ; glutamate receptor ; ion channel ; pharmacology ; in vivo ; tacrine 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 Open access Institutional support FGU-C - RVO:67985823 UT WOS 000646945500020 EID SCOPUS 85104312152 DOI 10.1016/j.ejmech.2021.113434 Annotation Tacrine is a classic drug whose efficacy against neurodegenerative diseases is still shrouded in mystery. It seems that besides its inhibitory effect on cholinesterases, the clinical benefit is co-determined by NMDAR-antagonizing activity. Our previous data showed that the direct inhibitory effect of tacrine, as well as its 7-methoxy derivative (7-MEOTA), is ensured via a “foot-in-the-door” open-channel blockage, and that interestingly both tacrine and 7-MEOTA are slightly more potent at the GluN1/GluN2A receptors when compared with the GluN1/GluN2B receptors. Here, we report that in a series of 30 novel tacrine derivatives, designed for assessment of structure-activity relationship, blocking efficacy differs among different compounds and receptors using electrophysiology with HEK293 cells expressing the defined types of NMDARs. Selected compounds (4 and 5) potently inhibited both GluN1/GluN2A and GluN1/GluN2B receptors, other compounds (7 and 23) more effectively inhibited the GluN1/GluN2B receptors, or the GluN1/GluN2A receptors (21 and 28). QSAR study revealed statistically significant model for the data obtained for inhibition of GluN1/Glu2B at −60 mV expressed as IC50 values, and for relative inhibition of GluN1/Glu2A at +40 mV caused by a concentration of 100 μM. The models can be utilized for a ligand-based virtual screening to detect potential candidates for inhibition of GluN1/Glu2A and/or GluN1/Glu2B subtypes. Using in vivo experiments in rats we observed that unlike MK-801, the tested novel compounds did not induce hyperlocomotion in open field, and also did not impair prepulse inhibition of startle response, suggesting minimal induction of psychotomimetic side effects. We conclude that tacrine derivatives are promising compounds since they are centrally available subtype-specific inhibitors of the NMDARs without detrimental behavioral side-effects. 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.ejmech.2021.113434
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