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dc.contributor.author
Bettini, Ezio
dc.contributor.author
Stahl, Stephen M.
dc.contributor.author
De Martin, Sara
dc.contributor.author
Mattarei, Andrea
dc.contributor.author
Sgrignani, Jacopo
dc.contributor.author
Carignani, Corrado
dc.contributor.author
Nola, Selena
dc.contributor.author
Locatelli, Patrizia
dc.contributor.author
Pappagallo, Marco
dc.contributor.author
Inturrisi, Charles E.
dc.contributor.author
Bifari, Francesco
dc.contributor.author
Cavalli, Andrea
dc.contributor.author
Alimonti, Andrea
dc.contributor.author
Pani, Luca
dc.contributor.author
Fava, Maurizio
dc.contributor.author
Traversa, Sergio
dc.contributor.author
Folli, Franco
dc.contributor.author
Manfredi, Paolo L.
dc.date.accessioned
2024-02-02T10:56:16Z
dc.date.available
2024-02-02T10:56:16Z
dc.date.issued
2022-08
dc.identifier.issn
1424-8247
dc.identifier.other
10.3390/ph15080997
en_US
dc.identifier.uri
http://hdl.handle.net/20.500.11850/657265
dc.identifier.doi
10.3929/ethz-b-000568721
dc.description.abstract
Excessive Ca2+ currents via N-methyl-D-aspartate receptors (NMDARs) have been implicated in many disorders. Uncompetitive NMDAR channel blockers are an emerging class of drugs in clinical use for major depressive disorder (MDD) and other neuropsychiatric diseases. The pharmacological characterization of uncompetitive NMDAR blockers in clinical use may improve our understanding of NMDAR function in physiology and pathology. REL-1017 (esmethadone-HCl), a novel uncompetitive NMDAR channel blocker in Phase 3 trials for the treatment of MDD, was characterized together with dextromethorphan, memantine, (±)-ketamine, and MK-801 in cell lines over-expressing NMDAR subtypes using fluorometric imaging plate reader (FLIPR), automated patch-clamp, and manual patch-clamp electrophysiology. In the absence of Mg2+, NMDAR subtypes NR1-2D were most sensitive to low, sub-μM glutamate concentrations in FLIPR experiments. FLIPR Ca2+ determination demonstrated low μM affinity of REL-1017 at NMDARs with minimal subtype preference. In automated and manual patch-clamp electrophysiological experiments, REL-1017 exhibited preference for the NR1-2D NMDAR subtype in the presence of 1 mM Mg2+ and 1 μM L-glutamate. Tau off and trapping characteristics were similar for (±)-ketamine and REL-1017. Results of radioligand binding assays in rat cortical neurons correlated with the estimated affinities obtained in FLIPR assays and in automated and manual patch-clamp assays. In silico studies of NMDARs in closed and open conformation indicate that REL-1017 has a higher preference for docking and undocking the open-channel conformation compared to ketamine. In conclusion, the pharmacological characteristics of REL-1017 at NMDARs, including relatively low affinity at the NMDAR, NR1-2D subtype preference in the presence of 1 mM Mg2+, tau off and degree of trapping similar to (±)-ketamine, and preferential docking and undocking of the open NMDAR, could all be important variables for understanding the rapid-onset antidepressant effects of REL-1017 without psychotomimetic side effects.
en_US
dc.format
application/pdf
en_US
dc.language.iso
en
en_US
dc.publisher
MDPI
en_US
dc.rights.uri
http://creativecommons.org/licenses/by/4.0/
dc.subject
REL-1017
en_US
dc.subject
esmethadone HCL
en_US
dc.subject
N-methyl-D-aspartate receptor (NMDAR)
en_US
dc.subject
dextromethadone
en_US
dc.subject
d-methadone
en_US
dc.subject
ketamine
en_US
dc.subject
memantine
en_US
dc.subject
dextromethorphan
en_US
dc.subject
MK-801
en_US
dc.subject
major depressive disorder (MDD)
en_US
dc.title
Pharmacological Comparative Characterization of REL-1017 (Esmethadone-HCl) and Other NMDAR Channel Blockers in Human Heterodimeric N-Methyl-D-Aspartate Receptors
en_US
dc.type
Journal Article
dc.rights.license
Creative Commons Attribution 4.0 International
dc.date.published
2022-08-13
ethz.journal.title
Pharmaceuticals
ethz.journal.volume
15
en_US
ethz.journal.issue
8
en_US
ethz.pages.start
997
en_US
ethz.size
22 p.
en_US
ethz.version.deposit
publishedVersion
en_US
ethz.identifier.wos
ethz.identifier.scopus
ethz.publication.place
Basel
en_US
ethz.publication.status
published
en_US
ethz.leitzahl
ETH Zürich::00002 - ETH Zürich::00012 - Lehre und Forschung::00007 - Departemente::02070 - Dep. Gesundheitswiss. und Technologie / Dep. of Health Sciences and Technology::02540 - Institut für Translationale Medizin / Institute of Translational Medicine::09703 - Alimonti, Andrea / Alimonti, Andrea
ethz.leitzahl.certified
ETH Zürich::00002 - ETH Zürich::00012 - Lehre und Forschung::00007 - Departemente::02070 - Dep. Gesundheitswiss. und Technologie / Dep. of Health Sciences and Technology::02540 - Institut für Translationale Medizin / Institute of Translational Medicine::09703 - Alimonti, Andrea / Alimonti, Andrea
ethz.date.deposited
2022-09-05T03:03:57Z
ethz.source
BATCH
ethz.source
WOS
ethz.eth
yes
en_US
ethz.availability
Open access
en_US
ethz.rosetta.installDate
2024-02-02T10:56:18Z
ethz.rosetta.lastUpdated
2025-02-14T07:24:40Z
ethz.rosetta.versionExported
true
dc.identifier.olduri
http://hdl.handle.net/20.500.11850/656961
dc.identifier.olduri
http://hdl.handle.net/20.500.11850/568721
ethz.COinS
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