{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,11]],"date-time":"2025-11-11T12:38:01Z","timestamp":1762864681694},"reference-count":22,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2009,2,2]],"date-time":"2009-02-02T00:00:00Z","timestamp":1233532800000},"content-version":"vor","delay-in-days":1920,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[2003,11]]},"abstract":"<jats:p>\n<jats:list list-type=\"explicit-label\">\n<jats:list-item><jats:p>Investigation into the modulatory effects of chlormethiazole at human recombinant <jats:italic>\u03b3<\/jats:italic>\u2010aminobutyric acid A receptor (GABA<jats:sub>A<\/jats:sub>) and <jats:italic>N<\/jats:italic>\u2010methyl\u2010<jats:sc>D<\/jats:sc>\u2010aspartate (NMDA) receptors was undertaken to gain insight into its mechanism of action and determine if the drug exhibited any subtype\u2010selective activity.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Despite a structural similarity to the <jats:italic>\u03b2<\/jats:italic>\u2010subunit\u2010selective compound loreclezole, chlormethiazole did not show any difference in maximum efficacy and only a slight difference in EC<jats:sub>50<\/jats:sub> in its potentiating action at <jats:italic>\u03b1<\/jats:italic>1<jats:italic>\u03b2<\/jats:italic>1<jats:italic>\u03b3<\/jats:italic>2 and <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 subtypes with preference for <jats:italic>\u03b1<\/jats:italic>1<jats:italic>\u03b2<\/jats:italic>1<jats:italic>\u03b3<\/jats:italic>2.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Similar to the previously reported subtype\u2010dependent activity of pentobarbital, chlormethiazole elicited a significantly greater degree of maximum potentiation on receptors lacking a <jats:italic>\u03b3<\/jats:italic>2 subunit, and also those receptors containing an <jats:italic>\u03b1<\/jats:italic>4 or <jats:italic>\u03b1<\/jats:italic>6 subunit. This also demonstrates that chlormethiazole does not act <jats:italic>via<\/jats:italic> the benzodiazepine binding site.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Unlike pentobarbital and propofol, chlormethiazole elicited only a slight direct GABA<jats:sub>A<\/jats:sub> receptor activation at concentrations up to 1 m<jats:sc>M<\/jats:sc>. In addition, the drug did not potentiate anaesthetic\u2010mediated currents elicited by pentobarbital or propofol, suggesting that chlormethiazole may be acting <jats:italic>via<\/jats:italic> an anaesthetic binding site.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Chlormethiazole produced weak nonselective inhibition of human NMDA NR1a+NR2A and NR1a+NR2B receptors. IC<jats:sub>50<\/jats:sub>'s were approximately 500 <jats:italic>\u03bc<\/jats:italic><jats:sc>M<\/jats:sc> that likely exceed the therapeutic dose range for chlormethiazole, indicating that the primary mechanism of the compounds <jats:italic>in vivo<\/jats:italic> activity is <jats:italic>via<\/jats:italic> GABA<jats:sub>A<\/jats:sub> receptors.<\/jats:p><\/jats:list-item>\n<\/jats:list>\n<\/jats:p><jats:p><jats:italic>British Journal of Pharmacology<\/jats:italic> (2003) <jats:bold>140<\/jats:bold>, 1045\u20131050. doi:<jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"doi\" xlink:href=\"10.1038\/sj.bjp.0705540\">10.1038\/sj.bjp.0705540<\/jats:ext-link><\/jats:p>","DOI":"10.1038\/sj.bjp.0705540","type":"journal-article","created":{"date-parts":[[2003,11,12]],"date-time":"2003-11-12T20:52:59Z","timestamp":1068670379000},"page":"1045-1050","update-policy":"http:\/\/dx.doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Activity of chlormethiazole at human recombinant GABA<sub>A<\/sub> and NMDA receptors"],"prefix":"10.1111","volume":"140","author":[{"given":"Marcello","family":"Usala","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sally Anne","family":"Thompson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paul J","family":"Whiting","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Keith A","family":"Wafford","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2009,2,2]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/0306-3623(88)90047-X"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0197-0186(99)00037-6"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476-5381.1995.tb14949.x"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476-5381.1989.tb16893.x"},{"key":"e_1_2_6_6_1","first-page":"742","article-title":"Intravenous chlormethiazole","volume":"48","author":"FULTON B.","year":"1992","journal-title":"Br. 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