{"id":3316,"date":"2026-03-17T08:18:41","date_gmt":"2026-03-17T08:18:41","guid":{"rendered":"https:\/\/medicine.nus.edu.sg\/medphc\/?p=3316"},"modified":"2026-03-17T08:18:41","modified_gmt":"2026-03-17T08:18:41","slug":"inhibition-of-glun2b-containing-n-methyl-d-aspartate-receptors-by-radiprodil","status":"publish","type":"post","link":"https:\/\/medicine.nus.edu.sg\/medphc\/publications\/inhibition-of-glun2b-containing-n-methyl-d-aspartate-receptors-by-radiprodil\/","title":{"rendered":"Inhibition of GluN2B-containing N-methyl-D- aspartate receptors by radiprodil"},"content":{"rendered":"<p><img loading=\"lazy\" decoding=\"async\" class=\"alignnone wp-image-3320\" src=\"https:\/\/medicine.nus.edu.sg\/medphc\/wp-content\/uploads\/sites\/33\/2026\/03\/20260317-LCM-1-300x169.jpg\" alt=\"\" width=\"850\" height=\"478\" srcset=\"https:\/\/medicine.nus.edu.sg\/medphc\/wp-content\/uploads\/sites\/33\/2026\/03\/20260317-LCM-1-300x169.jpg 300w, https:\/\/medicine.nus.edu.sg\/medphc\/wp-content\/uploads\/sites\/33\/2026\/03\/20260317-LCM-1-1024x576.jpg 1024w, https:\/\/medicine.nus.edu.sg\/medphc\/wp-content\/uploads\/sites\/33\/2026\/03\/20260317-LCM-1-768x432.jpg 768w, https:\/\/medicine.nus.edu.sg\/medphc\/wp-content\/uploads\/sites\/33\/2026\/03\/20260317-LCM-1.jpg 1280w\" sizes=\"auto, (max-width: 850px) 100vw, 850px\" \/><\/p>\n<h2 id=\"abstract\" class=\"section-heading-2\">ABSTRACT<\/h2>\n<p>N-methyl-D-aspartate (NMDA) receptors mediate a slow, Ca2+-permeable component of excitatory synaptic transmis\u00adsion in the brain and participate in neuronal development and synaptic plasticity. Most NMDA receptors are tetra\u00admeric 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 po\u00adtency 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.<br \/>\nAmong 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 ex\u00adplore 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 dis\u00adability, epilepsy, language disorders and movement disorders. We show that radiprodil is an effective antagonist at &gt;80% of human disease-associated GRIN1 and GRIN2B missense variants tested in vitro (22\/27, equally or more effect\u00adive as wild-type receptors), including variants in the pore-forming region, linker regions and elsewhere that uniform\u00adly 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 de\u00adlays the onset of seizures (458 \u00b1 90 s, versus 207 \u00b1 23 s in the vehicle group) in response to in vivo administration of the chemoconvulsant pentylenetetrazole.<br \/>\nThese 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.<\/p>\n<p>Full Article:\u00a0<a href=\"https:\/\/doi.org\/10.1093\/brain\/awaf355\">https:\/\/doi.org\/10.1093\/brain\/awaf355<\/a><\/p>\n","protected":false},"excerpt":{"rendered":"<p>ABSTRACT N-methyl-D-aspartate (NMDA) receptors mediate a slow, Ca2+-permeable component of excitatory synaptic transmis\u00adsion in the brain and participate in neuronal development and synaptic plasticity. Most NMDA receptors are tetra\u00admeric 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 [&hellip;]<\/p>\n","protected":false},"author":9339,"featured_media":3320,"comment_status":"closed","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"_acf_changed":false,"site-sidebar-layout":"default","site-content-layout":"","ast-site-content-layout":"default","site-content-style":"default","site-sidebar-style":"default","ast-global-header-display":"","ast-banner-title-visibility":"","ast-main-header-display":"","ast-hfb-above-header-display":"","ast-hfb-below-header-display":"","ast-hfb-mobile-header-display":"","site-post-title":"","ast-breadcrumbs-content":"","ast-featured-img":"","footer-sml-layout":"","theme-transparent-header-meta":"default","adv-header-id-meta":"","stick-header-meta":"default","header-above-stick-meta":"","header-main-stick-meta":"","header-below-stick-meta":"","astra-migrate-meta-layouts":"set","ast-page-background-enabled":"default","ast-page-background-meta":{"desktop":{"background-color":"var(--ast-global-color-4)","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""},"tablet":{"background-color":"","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""},"mobile":{"background-color":"","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""}},"ast-content-background-meta":{"desktop":{"background-color":"var(--ast-global-color-5)","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""},"tablet":{"background-color":"var(--ast-global-color-5)","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""},"mobile":{"background-color":"var(--ast-global-color-5)","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""}},"footnotes":""},"categories":[5],"tags":[],"class_list":["post-3316","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-publications"],"acf":[],"yoast_head":"<!-- This site is optimized with the Yoast SEO plugin v26.4 - https:\/\/yoast.com\/wordpress\/plugins\/seo\/ -->\n<title>Inhibition of GluN2B-containing N-methyl-D- aspartate receptors by radiprodil - Pharmacology<\/title>\n<meta name=\"robots\" content=\"index, follow, max-snippet:-1, max-image-preview:large, max-video-preview:-1\" \/>\n<link rel=\"canonical\" href=\"https:\/\/medicine.nus.edu.sg\/medphc\/publications\/inhibition-of-glun2b-containing-n-methyl-d-aspartate-receptors-by-radiprodil\/\" \/>\n<meta property=\"og:locale\" content=\"en_US\" \/>\n<meta property=\"og:type\" content=\"article\" \/>\n<meta property=\"og:title\" content=\"Inhibition of GluN2B-containing N-methyl-D- aspartate receptors by radiprodil - Pharmacology\" \/>\n<meta property=\"og:description\" content=\"ABSTRACT N-methyl-D-aspartate (NMDA) receptors mediate a slow, Ca2+-permeable component of excitatory synaptic transmis\u00adsion in the brain and participate in neuronal development and synaptic plasticity. Most NMDA receptors are tetra\u00admeric 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 [&hellip;]\" \/>\n<meta property=\"og:url\" content=\"https:\/\/medicine.nus.edu.sg\/medphc\/publications\/inhibition-of-glun2b-containing-n-methyl-d-aspartate-receptors-by-radiprodil\/\" \/>\n<meta property=\"og:site_name\" content=\"Pharmacology\" \/>\n<meta property=\"article:published_time\" content=\"2026-03-17T08:18:41+00:00\" \/>\n<meta property=\"og:image\" content=\"https:\/\/medicine.nus.edu.sg\/medphc\/wp-content\/uploads\/sites\/33\/2026\/03\/20260317-LCM-1.jpg\" \/>\n\t<meta property=\"og:image:width\" content=\"1280\" \/>\n\t<meta property=\"og:image:height\" content=\"720\" \/>\n\t<meta property=\"og:image:type\" content=\"image\/jpeg\" \/>\n<meta name=\"author\" content=\"Alan KOH\" \/>\n<meta name=\"twitter:card\" content=\"summary_large_image\" \/>\n<meta name=\"twitter:label1\" content=\"Written by\" \/>\n\t<meta name=\"twitter:data1\" content=\"Alan KOH\" \/>\n\t<meta name=\"twitter:label2\" content=\"Est. reading time\" \/>\n\t<meta name=\"twitter:data2\" content=\"2 minutes\" \/>\n<script type=\"application\/ld+json\" class=\"yoast-schema-graph\">{\"@context\":\"https:\/\/schema.org\",\"@graph\":[{\"@type\":\"Article\",\"@id\":\"https:\/\/medicine.nus.edu.sg\/medphc\/publications\/inhibition-of-glun2b-containing-n-methyl-d-aspartate-receptors-by-radiprodil\/#article\",\"isPartOf\":{\"@id\":\"https:\/\/medicine.nus.edu.sg\/medphc\/publications\/inhibition-of-glun2b-containing-n-methyl-d-aspartate-receptors-by-radiprodil\/\"},\"author\":{\"name\":\"Alan KOH\",\"@id\":\"https:\/\/medicine.nus.edu.sg\/medphc\/#\/schema\/person\/7d3c6eda1bb38ccc10654332cc8ddd5e\"},\"headline\":\"Inhibition of GluN2B-containing N-methyl-D- aspartate receptors by radiprodil\",\"datePublished\":\"2026-03-17T08:18:41+00:00\",\"mainEntityOfPage\":{\"@id\":\"https:\/\/medicine.nus.edu.sg\/medphc\/publications\/inhibition-of-glun2b-containing-n-methyl-d-aspartate-receptors-by-radiprodil\/\"},\"wordCount\":358,\"publisher\":{\"@id\":\"https:\/\/medicine.nus.edu.sg\/medphc\/#organization\"},\"image\":{\"@id\":\"https:\/\/medicine.nus.edu.sg\/medphc\/publications\/inhibition-of-glun2b-containing-n-methyl-d-aspartate-receptors-by-radiprodil\/#primaryimage\"},\"thumbnailUrl\":\"https:\/\/medicine.nus.edu.sg\/medphc\/wp-content\/uploads\/sites\/33\/2026\/03\/20260317-LCM-1.jpg\",\"articleSection\":[\"Publications\"],\"inLanguage\":\"en-US\"},{\"@type\":\"WebPage\",\"@id\":\"https:\/\/medicine.nus.edu.sg\/medphc\/publications\/inhibition-of-glun2b-containing-n-methyl-d-aspartate-receptors-by-radiprodil\/\",\"url\":\"https:\/\/medicine.nus.edu.sg\/medphc\/publications\/inhibition-of-glun2b-containing-n-methyl-d-aspartate-receptors-by-radiprodil\/\",\"name\":\"Inhibition of GluN2B-containing N-methyl-D- aspartate receptors by radiprodil - 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Most NMDA receptors are tetra\u00admeric 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 [&hellip;]","og_url":"https:\/\/medicine.nus.edu.sg\/medphc\/publications\/inhibition-of-glun2b-containing-n-methyl-d-aspartate-receptors-by-radiprodil\/","og_site_name":"Pharmacology","article_published_time":"2026-03-17T08:18:41+00:00","og_image":[{"width":1280,"height":720,"url":"https:\/\/medicine.nus.edu.sg\/medphc\/wp-content\/uploads\/sites\/33\/2026\/03\/20260317-LCM-1.jpg","type":"image\/jpeg"}],"author":"Alan KOH","twitter_card":"summary_large_image","twitter_misc":{"Written by":"Alan KOH","Est. reading time":"2 minutes"},"schema":{"@context":"https:\/\/schema.org","@graph":[{"@type":"Article","@id":"https:\/\/medicine.nus.edu.sg\/medphc\/publications\/inhibition-of-glun2b-containing-n-methyl-d-aspartate-receptors-by-radiprodil\/#article","isPartOf":{"@id":"https:\/\/medicine.nus.edu.sg\/medphc\/publications\/inhibition-of-glun2b-containing-n-methyl-d-aspartate-receptors-by-radiprodil\/"},"author":{"name":"Alan KOH","@id":"https:\/\/medicine.nus.edu.sg\/medphc\/#\/schema\/person\/7d3c6eda1bb38ccc10654332cc8ddd5e"},"headline":"Inhibition of GluN2B-containing N-methyl-D- aspartate receptors by radiprodil","datePublished":"2026-03-17T08:18:41+00:00","mainEntityOfPage":{"@id":"https:\/\/medicine.nus.edu.sg\/medphc\/publications\/inhibition-of-glun2b-containing-n-methyl-d-aspartate-receptors-by-radiprodil\/"},"wordCount":358,"publisher":{"@id":"https:\/\/medicine.nus.edu.sg\/medphc\/#organization"},"image":{"@id":"https:\/\/medicine.nus.edu.sg\/medphc\/publications\/inhibition-of-glun2b-containing-n-methyl-d-aspartate-receptors-by-radiprodil\/#primaryimage"},"thumbnailUrl":"https:\/\/medicine.nus.edu.sg\/medphc\/wp-content\/uploads\/sites\/33\/2026\/03\/20260317-LCM-1.jpg","articleSection":["Publications"],"inLanguage":"en-US"},{"@type":"WebPage","@id":"https:\/\/medicine.nus.edu.sg\/medphc\/publications\/inhibition-of-glun2b-containing-n-methyl-d-aspartate-receptors-by-radiprodil\/","url":"https:\/\/medicine.nus.edu.sg\/medphc\/publications\/inhibition-of-glun2b-containing-n-methyl-d-aspartate-receptors-by-radiprodil\/","name":"Inhibition of GluN2B-containing N-methyl-D- aspartate receptors by radiprodil - 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