7-phenoxytacrine is a dually acting drug with neuroprotective efficacy in vivo
The result's identifiers
Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F67985823%3A_____%2F21%3A00543350" target="_blank" >RIV/67985823:_____/21:00543350 - isvavai.cz</a>
Alternative codes found
RIV/00023752:_____/21:43920522 RIV/68378041:_____/21:00543492 RIV/00179906:_____/21:10428061 RIV/60162694:G44__/21:00556998 RIV/00216208:11160/21:10428061
Result on the web
<a href="https://doi.org/10.1016/j.bcp.2021.114460" target="_blank" >https://doi.org/10.1016/j.bcp.2021.114460</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1016/j.bcp.2021.114460" target="_blank" >10.1016/j.bcp.2021.114460</a>
Alternative languages
Result language
angličtina
Original language name
7-phenoxytacrine is a dually acting drug with neuroprotective efficacy in vivo
Original language description
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.
Czech name
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Czech description
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Classification
Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
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OECD FORD branch
30104 - Pharmacology and pharmacy
Result continuities
Project
Result was created during the realization of more than one project. More information in the Projects tab.
Continuities
P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)
Others
Publication year
2021
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
Biochemical Pharmacology
ISSN
0006-2952
e-ISSN
1873-2968
Volume of the periodical
186
Issue of the periodical within the volume
Apr
Country of publishing house
US - UNITED STATES
Number of pages
13
Pages from-to
114460
UT code for WoS article
000640416800002
EID of the result in the Scopus database
2-s2.0-85100905242