Počet záznamů: 1
Structure-activity relationships of dually-acting acetylcholinesterase inhibitors derived from tacrine on N-methyl-d-Aspartate receptors
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SYSNO ASEP 0542659 Druh ASEP J - Článek v odborném periodiku Zařazení RIV J - Článek v odborném periodiku Poddruh J Článek ve WOS Název Structure-activity relationships of dually-acting acetylcholinesterase inhibitors derived from tacrine on N-methyl-d-Aspartate receptors Tvůrce(i) 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)Číslo článku 113434 Zdroj.dok. European Journal of Medicinal Chemistry. - : Elsevier - ISSN 0223-5234
Roč. 219, 5 July (2021)Poč.str. 16 s. Jazyk dok. eng - angličtina Země vyd. FR - Francie Klíč. slova QSAR ; acetylcholinesterase ; electrophysiology ; glutamate receptor ; ion channel ; pharmacology ; in vivo ; tacrine Vědní obor RIV FR - Farmakologie a lékárnická chemie Obor OECD Pharmacology and pharmacy CEP EF16_025/0007444 GA MZd - Ministerstvo zdravotnictví Způsob publikování Open access Institucionální podpora FGU-C - RVO:67985823 UT WOS 000646945500020 EID SCOPUS 85104312152 DOI 10.1016/j.ejmech.2021.113434 Anotace 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. Pracoviště Fyziologický ústav Kontakt Lucie Trajhanová, lucie.trajhanova@fgu.cas.cz, Tel.: 241 062 400 Rok sběru 2022 Elektronická adresa https://doi.org/10.1016/j.ejmech.2021.113434
Počet záznamů: 1