{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T05:33:59Z","timestamp":1789450439414,"version":"build-2803163510"},"reference-count":83,"publisher":"Oxford University Press (OUP)","issue":"3","funder":[{"name":"NIH-NINDS","award":["NS111619 S.F.T."],"award-info":[{"award-number":["NS111619 S.F.T."]}]},{"name":"NIH-NINDS","award":["NS11745 H.F."],"award-info":[{"award-number":["NS11745 H.F."]}]},{"name":"NIH-NINDS","award":["113632 H.F."],"award-info":[{"award-number":["113632 H.F."]}]},{"name":"NIH-NIMH","award":["MH085926 H.F."],"award-info":[{"award-number":["MH085926 H.F."]}]},{"name":"NIH-NIMH","award":["MH127404 H.Y."],"award-info":[{"award-number":["MH127404 H.Y."]}]},{"DOI":"10.13039\/100000071","name":"NICHD","doi-asserted-by":"publisher","award":["HD082373 H.Y."],"award-info":[{"award-number":["HD082373 H.Y."]}],"id":[{"id":"10.13039\/100000071","id-type":"DOI","asserted-by":"publisher"}]},{"name":"NIH-NIA","award":["AG072142 S.J.M."],"award-info":[{"award-number":["AG072142 S.J.M."]}]},{"name":"NIH-NIA","award":["AG075444 S.H.L."],"award-info":[{"award-number":["AG075444 S.H.L."]}]},{"name":"NIH-NIA","award":["AG080262 S.H.L."],"award-info":[{"award-number":["AG080262 S.H.L."]}]},{"name":"NIH-NIA","award":["AG083084 S.H.L."],"award-info":[{"award-number":["AG083084 S.H.L."]}]},{"name":"NIH-NIBIB","award":["S10OD034326 S.H.L."],"award-info":[{"award-number":["S10OD034326 S.H.L."]}]},{"name":"GRIN2B Foundation"},{"name":"GRIN Therapeutics"},{"name":"Austin\u2019s Purpose"},{"DOI":"10.13039\/100014370","name":"SFARI","doi-asserted-by":"publisher","award":["732132"],"award-info":[{"award-number":["732132"]}],"id":[{"id":"10.13039\/100014370","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100013356","name":"Cold Spring Harbor Laboratory","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100013356","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Doug Fox Alzheimer\u2019s fund"},{"name":"Heartfelt Wing Alzheimer\u2019s fund"},{"name":"Gertrude and Louis Feil Family Trust"},{"name":"Imagine, Innovate and Impact"},{"DOI":"10.13039\/100007623","name":"Emory University School of Medicine","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007623","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Georgia CTSA NIH","award":["UL1-TR002378"],"award-info":[{"award-number":["UL1-TR002378"]}]},{"name":"NINDS Intramural Research Program"},{"DOI":"10.13039\/100000016","name":"Department of Health and Human Services","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000016","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,3,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>N-methyl-D-aspartate (NMDA) receptors mediate a slow, Ca2+-permeable component of excitatory synaptic transmission in the brain and participate in neuronal development and synaptic plasticity. Most NMDA receptors are tetrameric assemblies of two GluN1 and two GluN2 subunits encoded by five genes (GRIN1 and GRIN2A\u2013GRIN2D), which produce GluN1 and GluN2A\u2013GluN2D subunits. NMDA receptors that contain the GluN2B subunit have unique pharmacological properties, being inhibited by multiple structurally distinct series of biaryl compounds with high potency and selectivity. These agents are of considerable therapeutic interest, given the numerous roles that GluN2B-containing NMDA receptors play in normal brain function and pathological situations.<\/jats:p>\n                  <jats:p>Among GluN2B-selective negative allosteric modulators, radiprodil inhibits NMDA receptors that contain GluN2B with high potency and selectivity and appears to be safe in humans. Here, we evaluate the structural determinants of radiprodil binding to the heterodimeric GluN1\u2013GluN2B amino terminal domain by X-ray crystallography and explore the molecular mechanism of inhibition. A large number of de novo variants have been identified in the GRIN gene family in patients with various neurological and neuropsychiatric conditions, including autism, intellectual disability, epilepsy, language disorders and movement disorders. We show that radiprodil is an effective antagonist at &amp;gt;80% of human disease-associated GRIN1 and GRIN2B missense variants tested in vitro (22\/27, equally or more effective as wild-type receptors), including variants in the pore-forming region, linker regions and elsewhere that uniformly increase NMDA receptor-mediated charge transfer. We show that radiprodil blocks synaptic GluN2B receptors in brain slices acutely isolated from a knock-in mouse line harbouring the gain-of-function variant GluN2B-Ser810Arg associated with early-onset epileptic encephalopathy and intractable seizures in patients. In addition, radiprodil delays the onset of seizures (458 \u00b1 90\u2005s, versus 207 \u00b1 23\u2005s in the vehicle group) in response to in vivo administration of the chemoconvulsant pentylenetetrazole.<\/jats:p>\n                  <jats:p>These data support the potential utility of GluN2B-selective antagonists, such as radiprodil, for clinical treatments of neurological conditions where clinical aetiologies might involve increased current mediated by GluN2B-containing NMDA receptors.<\/jats:p>","DOI":"10.1093\/brain\/awaf355","type":"journal-article","created":{"date-parts":[[2025,9,24]],"date-time":"2025-09-24T12:22:33Z","timestamp":1758716553000},"page":"976-992","source":"Crossref","is-referenced-by-count":6,"title":["Inhibition of GluN2B-containing\n                    <i>N<\/i>\n                    -methyl-\n                    <scp>D-<\/scp>\n                    aspartate receptors by radiprodil"],"prefix":"10.1093","volume":"149","author":[{"given":"Tue G","family":"Banke","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Chemical Biology, Emory University School of Medicine , Atlanta, GA 30322 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael C","family":"Regan","sequence":"additional","affiliation":[{"name":"W.M. Keck Structural Biology Laboratory, Cold Spring Harbor Laboratory , New York, NY 11724 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Riley E","family":"Perszyk","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Chemical Biology, Emory University School of Medicine , Atlanta, GA 30322 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Chemical Biology, Emory University School of Medicine , Atlanta, GA 30322 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Xing","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Chemical Biology, Emory University School of Medicine , Atlanta, GA 30322 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiahui","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Radiology and Imaging Sciences, Emory University , Atlanta, GA 30322 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7417-4917","authenticated-orcid":false,"given":"Sehoon","family":"Won","sequence":"additional","affiliation":[{"name":"Receptor Biology Section, National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health (NIH) , Bethesda, MD 20892 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noriko","family":"Simorowski","sequence":"additional","affiliation":[{"name":"W.M. Keck Structural Biology Laboratory, Cold Spring Harbor Laboratory , New York, NY 11724 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eva S","family":"Diaz","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Chemical Biology, Emory University School of Medicine , Atlanta, GA 30322 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sukhan","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Chemical Biology, Emory University School of Medicine , Atlanta, GA 30322 ,","place":["USA"]},{"name":"Center for Functional Evaluation of Rare Variants (CFERV), Emory University School of Medicine , Atlanta, GA 30322 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Song","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Chemical Biology, Emory University School of Medicine , Atlanta, GA 30322 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Rong","sequence":"additional","affiliation":[{"name":"Department of Radiology and Imaging Sciences, Emory University , Atlanta, GA 30322 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Radiology and Imaging Sciences, Emory University , Atlanta, GA 30322 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmad F","family":"Chaudhary","sequence":"additional","affiliation":[{"name":"Department of Radiology and Imaging Sciences, Emory University , Atlanta, GA 30322 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Chemical Biology, Emory University School of Medicine , Atlanta, GA 30322 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Core, Emory University School of Medicine , Atlanta, GA 30322 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher S","family":"Raymond","sequence":"additional","affiliation":[{"name":"Emory Mouse Transgenic and Gene Targeting Core, Emory University School of Medicine , Atlanta, GA 30322 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chian-Ming","family":"Low","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore , Singapore 117600, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott J","family":"Myers","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Chemical Biology, Emory University School of Medicine , Atlanta, GA 30322 ,","place":["USA"]},{"name":"Center for Functional Evaluation of Rare Variants (CFERV), Emory University School of Medicine , Atlanta, GA 30322 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7282-6539","authenticated-orcid":false,"given":"Katherine W","family":"Roche","sequence":"additional","affiliation":[{"name":"Receptor Biology Section, National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health (NIH) , Bethesda, MD 20892 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1413-6315","authenticated-orcid":false,"given":"Steven H","family":"Liang","sequence":"additional","affiliation":[{"name":"Department of Radiology and Imaging Sciences, Emory University , Atlanta, GA 30322 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3750-9615","authenticated-orcid":false,"given":"Stephen F","family":"Traynelis","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Chemical Biology, 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Sci"},{"key":"2026030512065660000_awaf355-B11","doi-asserted-by":"crossref","first-page":"802","DOI":"10.1016\/j.ajhg.2016.07.013","article-title":"GRIN2D recurrent de novo dominant mutation causes a severe epileptic encephalopathy treatable with NMDA receptor channel blockers","volume":"99","author":"Li","year":"2016","journal-title":"Am J Hum Genet"},{"key":"2026030512065660000_awaf355-B12","doi-asserted-by":"crossref","first-page":"1261","DOI":"10.1016\/j.ajhg.2016.10.002","article-title":"Mechanistic insight into NMDA receptor dysregulation by rare variants in the GluN2A and GluN2B agonist binding domains","volume":"99","author":"Swanger","year":"2016","journal-title":"Am J Hum Genet"},{"key":"2026030512065660000_awaf355-B13","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.cophys.2017.12.013","article-title":"De novo mutations and rare variants occurring in NMDA receptors","volume":"2","author":"XiangWei","year":"2018","journal-title":"Curr Opin 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