{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T21:20:43Z","timestamp":1783977643122,"version":"3.55.0"},"reference-count":26,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2022,3,24]],"date-time":"2022-03-24T00:00:00Z","timestamp":1648080000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["T32GM099608"],"award-info":[{"award-number":["T32GM099608"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000052","name":"NIH Office of the Director","doi-asserted-by":"publisher","award":["R21NS110647 CounterACT Program"],"award-info":[{"award-number":["R21NS110647 CounterACT Program"]}],"id":[{"id":"10.13039\/100000052","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000052","name":"NIH Office of the Director","doi-asserted-by":"publisher","award":["U54NS079202 CounterACT Program"],"award-info":[{"award-number":["U54NS079202 CounterACT Program"]}],"id":[{"id":"10.13039\/100000052","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Ann Clin Transl Neurol"],"published-print":{"date-parts":[[2022,5]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>Royal demolition explosive (RDX) can induce seizures in wildlife and humans following release into the environment or after voluntary consumption. During the Vietnam War, RDX intoxication was the most common cause of generalized seizures in US service personnel, and in some sections of the armed forces, eating of RDX has continued as \u201ca dare\u201d to this day. After its mechanism of action was long unknown, RDX was recently shown to be a GABA<jats:sub>A<\/jats:sub> receptor antagonist. We here determined the GABA<jats:sub>A<\/jats:sub> receptor subtype\u2010selectivity of RDX and mapped its functional binding site.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We used whole\u2010cell patch\u2010clamp to determine the potency of RDX on 10 recombinantly expressed GABA<jats:sub>A<\/jats:sub> receptors and mapped the RDX binding site using a combination of Rosetta molecular modeling and site\u2010directed mutagenesis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>RDX was found to reversibly inhibit the <jats:italic>\u03b1<\/jats:italic>1<jats:italic>\u03b2<\/jats:italic>2<jats:italic>\u03b3<\/jats:italic>2 GABA<jats:sub>A<\/jats:sub> receptor with an IC<jats:sub>50<\/jats:sub> of 23\u2009<jats:italic>\u03bc<\/jats:italic>mol\/L (95% CI 15.1\u201333.3\u2009<jats:italic>\u03bc<\/jats:italic>mol\/L), whereas <jats:italic>\u03b1<\/jats:italic>4 and <jats:italic>\u03b1<\/jats:italic>6 containing GABA<jats:sub>A<\/jats:sub> receptor combinations were 4\u201310\u2010fold less sensitive. RDX is binding to the noncompetitive antagonist (NCA) site in the pore. In a molecular model based on the cryo\u2010EM structure of the resting state of the <jats:italic>\u03b1<\/jats:italic>1<jats:italic>\u03b2<\/jats:italic>2<jats:italic>\u03b3<\/jats:italic>2 receptor, RDX forms two hydrogen bonds with the threonines at the T6\u2019 ring and makes hydrophobic interactions with the valine and alanine in 2\u2032 position of the <jats:italic>\u03b1<\/jats:italic>1 or <jats:italic>\u03b2<\/jats:italic>2 subunits.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>Our findings characterize the mechanism of action of RDX at the atomistic level and suggest that RDX\u2010induced seizures should be susceptible to treatment with GABA<jats:sub>A<\/jats:sub> modulating drugs such as benzodiazepines, barbiturates, propofol, or neurosteroids.<\/jats:p><\/jats:sec>","DOI":"10.1002\/acn3.51536","type":"journal-article","created":{"date-parts":[[2022,3,24]],"date-time":"2022-03-24T23:39:21Z","timestamp":1648165161000},"page":"600-609","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["The seizure\u2010inducing plastic explosive <scp>RDX<\/scp> inhibits the <i>\u03b1<\/i>1<i>\u03b2<\/i>2<i>\u03b3<\/i>2 <scp>GABA<sub>A<\/sub><\/scp> receptor"],"prefix":"10.1002","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9122-930X","authenticated-orcid":false,"given":"Brandon","family":"Pressly","sequence":"first","affiliation":[{"name":"Department of Pharmacology School of Medicine University of California  Davis California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8871-4814","authenticated-orcid":false,"given":"Ruth 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of California  Davis California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,3,24]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1001\/archinte.1969.00300220078015"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-021-00909-4"},{"key":"e_1_2_7_4_1","unstructured":"EPA US.Toxicological review of hexahydro\u20101 3 5\u2010trinitro\u20101 3 5\u2010triazine (RDX).EPA\/635\/R\u201018\/211Fa. 2018;www.epa.gov\/iris:CASRN121\u2010182\u2010124."},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1897\/08-419.1"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10646-012-1019-8"},{"key":"e_1_2_7_7_1","first-page":"21","article-title":"Toxocity and potential dangers of cyclotrimethylenetrinitramine","volume":"31","author":"Von Oettingen WF","year":"1949","journal-title":"J Ind Hyg 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