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@article{1790420,
author = {Gorecki, Lukas and Misiachna, Anna and Damborský, Jiří and Dolezal, Rafael and Korabecny, Jan and Cejkova, Lada and Hakenova, Kristina and Chvojkova, Marketa and Karasova Zdarova, Jana and Prchal, Lukas and Novak, Martin and Kolcheva, Marharyta and Kortus, Stepan and Vales, Karel and Horak, Martin and Soukup, Ondřej},
article_location = {PARIS},
article_number = {July 2021},
doi = {http://dx.doi.org/10.1016/j.ejmech.2021.113434},
keywords = {QSAR; Acetylcholinesterase; Electrophysiology; Glutamate receptor; Ion channel; Pharmacology; in vivo; Tacrine},
language = {eng},
issn = {0223-5234},
journal = {European Journal of Medicinal Chemistry},
title = {Structure-activity relationships of dually-acting acetylcholinesterase inhibitors derived from tacrine on N-methyl-D-Aspartate receptors},
url = {https://www.sciencedirect.com/science/article/pii/S022352342100283X?via%3Dihub},
volume = {219},
year = {2021}
}
TY - JOUR
ID - 1790420
AU - Gorecki, Lukas - Misiachna, Anna - Damborský, Jiří - Dolezal, Rafael - Korabecny, Jan - Cejkova, Lada - Hakenova, Kristina - Chvojkova, Marketa - Karasova Zdarova, Jana - Prchal, Lukas - Novak, Martin - Kolcheva, Marharyta - Kortus, Stepan - Vales, Karel - Horak, Martin - Soukup, Ondřej
PY - 2021
TI - Structure-activity relationships of dually-acting acetylcholinesterase inhibitors derived from tacrine on N-methyl-D-Aspartate receptors
JF - European Journal of Medicinal Chemistry
VL - 219
IS - July 2021
SP - 1-16
EP - 1-16
PB - ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
SN - 02235234
KW - QSAR
KW - Acetylcholinesterase
KW - Electrophysiology
KW - Glutamate receptor
KW - Ion channel
KW - Pharmacology
KW - in vivo
KW - Tacrine
UR - https://www.sciencedirect.com/science/article/pii/S022352342100283X?via%3Dihub
N2 - 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 mu M. 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.
ER -
GORECKI, Lukas, Anna MISIACHNA, Jiří DAMBORSKÝ, Rafael DOLEZAL, Jan KORABECNY, Lada CEJKOVA, Kristina HAKENOVA, Marketa CHVOJKOVA, Jana KARASOVA ZDAROVA, Lukas PRCHAL, Martin NOVAK, Marharyta KOLCHEVA, Stepan KORTUS, Karel VALES, Martin HORAK and Ondřej SOUKUP. Structure-activity relationships of dually-acting acetylcholinesterase inhibitors derived from tacrine on N-methyl-D-Aspartate receptors. \textit{European Journal of Medicinal Chemistry}. PARIS: ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER, 2021, vol.~219, July 2021, p.~1-16. ISSN~0223-5234. Available from: https://dx.doi.org/10.1016/j.ejmech.2021.113434.
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