{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T20:40:50Z","timestamp":1792269650096,"version":"4.4.0"},"reference-count":46,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2022,8,13]],"date-time":"2022-08-13T00:00:00Z","timestamp":1660348800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Relmada Therapeutics","award":["VDD9974"],"award-info":[{"award-number":["VDD9974"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>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, (\u00b1)-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-\u03bcM glutamate concentrations in FLIPR experiments. FLIPR Ca2+ determination demonstrated low \u03bcM 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 \u03bcM L-glutamate. Tau off and trapping characteristics were similar for (\u00b1)-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 (\u00b1)-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.<\/jats:p>","DOI":"10.3390\/ph15080997","type":"journal-article","created":{"date-parts":[[2022,8,15]],"date-time":"2022-08-15T03:33:20Z","timestamp":1660534400000},"page":"997","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["Pharmacological Comparative Characterization of REL-1017 (Esmethadone-HCl) and Other NMDAR Channel Blockers in Human Heterodimeric N-Methyl-D-Aspartate Receptors"],"prefix":"10.3390","volume":"15","author":[{"given":"Ezio","family":"Bettini","sequence":"first","affiliation":[{"name":"In Vitro Pharmacology Department, Aptuit, An Evotec Company, 37135 Verona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen M.","family":"Stahl","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, VAMC (SD), University of California, San Diego, CA 92093, USA"},{"name":"Neuroscience Education Institute, Carlsbad, CA 92008, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6398-8237","authenticated-orcid":false,"given":"Sara","family":"De Martin","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical and Pharmacological Sciences, University of Padua, 35122 Padua, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2023-0749","authenticated-orcid":false,"given":"Andrea","family":"Mattarei","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical and Pharmacological Sciences, University of Padua, 35122 Padua, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8633-1032","authenticated-orcid":false,"given":"Jacopo","family":"Sgrignani","sequence":"additional","affiliation":[{"name":"Institute for Research in Biomedicine (IRB), Universit\u00e0 della Svizzera Italiana (USI), 6500 Bellinzona, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Corrado","family":"Carignani","sequence":"additional","affiliation":[{"name":"In Vitro Pharmacology Department, Aptuit, An Evotec Company, 37135 Verona, 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USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2028-3012","authenticated-orcid":false,"given":"Francesco","family":"Bifari","sequence":"additional","affiliation":[{"name":"Department of Medical Biotechnology and Translational Medicine, University of Milan, 20122 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Cavalli","sequence":"additional","affiliation":[{"name":"Institute for Research in Biomedicine (IRB), Universit\u00e0 della Svizzera Italiana (USI), 6500 Bellinzona, Switzerland"},{"name":"Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Alimonti","sequence":"additional","affiliation":[{"name":"Department of Health Sciences and Technology, ETH Zurich, 8092 Zurich, Switzerland"},{"name":"Institute of Oncology Research, Southern Switzerland, 6500 Bellinzona, Switzerland"},{"name":"The Institute of Oncology Research, Universit\u00e0 della Svizzera Italiana, 6500 Bellinzona, Switzerland"},{"name":"Veneto Institute of Molecular Medicine, 35129 Padua, Italy"},{"name":"Department of Medicine, Zurich University, 8006 Zurich, Switzerland"},{"name":"Department of Medicine\u2014DIMED, University of Padua, 35122 Padua, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9273-2839","authenticated-orcid":false,"given":"Luca","family":"Pani","sequence":"additional","affiliation":[{"name":"Relmada Therapeutics, Coral Gables, FL 33134, USA"},{"name":"Department of Psychiatry and Behavioral Sciences, School of Medicine, University of Miami, Miami, FL 33136, USA"},{"name":"Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, 41121 Modena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maurizio","family":"Fava","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Massachusetts General Hospital, Boston, MA 02114, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sergio","family":"Traversa","sequence":"additional","affiliation":[{"name":"Relmada Therapeutics, Coral Gables, FL 33134, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Franco","family":"Folli","sequence":"additional","affiliation":[{"name":"Department of Health Sciences, University of Milan, 20122 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paolo L.","family":"Manfredi","sequence":"additional","affiliation":[{"name":"Relmada Therapeutics, Coral Gables, FL 33134, 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