{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T08:02:49Z","timestamp":1753862569540,"version":"3.41.2"},"reference-count":53,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2022,5,23]],"date-time":"2022-05-23T00:00:00Z","timestamp":1653264000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["WU 176"],"award-info":[{"award-number":["WU 176"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Archiv der Pharmazie"],"published-print":{"date-parts":[[2022,9]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Tricyclic tetrahydrooxazolo[4,5\u2010<jats:italic>h<\/jats:italic>]\u2010[3]benzazepin\u20109\u2010ols <jats:bold>22<\/jats:bold> were designed as phenol bioisosteres of tetrahydro\u20103\u2010benzazepine\u20101,7\u2010diols. Key features of the synthesis are the introduction of the trifluoromethylsulfonyl and allyl protective groups at the heterocyclic N\u2010atoms. Two methods were developed to convert the triflyl\u2010protected ketone <jats:bold>16<\/jats:bold> into tricyclic alcohols <jats:bold>21<\/jats:bold> bearing various N\u2010substituents. According to the first method, trifluoromethanesulfinate was removed by K<jats:sub>2<\/jats:sub>CO<jats:sub>3<\/jats:sub>. Following the selective reduction of the imino moiety of <jats:bold>17<\/jats:bold> with NaBH(OAc)<jats:sub>3<\/jats:sub> afforded the aminoketone <jats:bold>18<\/jats:bold>, which was reductively alkylated and reduced. According to the second method, both the imine and the ketone of the iminoketone <jats:bold>17<\/jats:bold> were reduced with NaBH<jats:sub>4<\/jats:sub> to yield the aminoalcohol <jats:bold>20<\/jats:bold>, which was alkylated or reductively alkylated to form tertiary amines <jats:bold>21f\u201321r<\/jats:bold>. In the last step, the allyl protective group of <jats:bold>21<\/jats:bold> was removed with RhCl<jats:sub>3<\/jats:sub> and HCl to obtain oxazolones <jats:bold>22<\/jats:bold>. In receptor binding studies using [<jats:sup>3<\/jats:sup>H]ifenprodil as radioligand ketone, <jats:bold>22m<\/jats:bold> showed the highest GluN2B affinity (<jats:italic>K<\/jats:italic><jats:sub>i<\/jats:sub>\u2009=\u200988\u2009nM). However, a reduced affinity toward\u00a0GluN2B subunit\u2010containing <jats:italic>N<\/jats:italic>\u2010methyl\u2010\n<jats:sc>d<\/jats:sc>\u2010aspartate\u00a0(NMDA) receptors was observed for oxazolones <jats:bold>22<\/jats:bold> compared to bioisosteric 3\u2010benzazepine\u20101,7\u2010diols. High selectivity of <jats:bold>22m<\/jats:bold> for the ifenprodil binding site of GluN2B\u2010NMDA receptors over the 1\u2010(1\u2010phenylcyclohexyl)piperidine binding site and \u03c3<jats:sub>2<\/jats:sub> receptors was observed, but only negligible selectivity over \u03c3<jats:sub>1<\/jats:sub> receptors. In two\u2010electrode voltage clamp experiments, the 4\u2010phenylbutyl derivative <jats:bold>22d<\/jats:bold> (<jats:italic>K<\/jats:italic><jats:sub>i<\/jats:sub>\u2009=\u2009422\u2009nM) demonstrated 80% inhibition of ion flux at a concentration of 1\u2009\u00b5M. The differences in GluN2B affinity and inhibitory activity are explained by docking studies. In conclusion, <jats:bold>22d<\/jats:bold> is regarded as a novel scaffold of highly potent GluN1\/GluN2B antagonists.<\/jats:p>","DOI":"10.1002\/ardp.202200147","type":"journal-article","created":{"date-parts":[[2022,5,24]],"date-time":"2022-05-24T03:44:35Z","timestamp":1653363875000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Phenol\u2014Benzoxazolone bioisosteres: Synthesis and biological evaluation of tricyclic GluN2B\u2010selective <i>N<\/i>\u2010methyl\u2010<scp>d<\/scp>\u2010aspartate receptor antagonists"],"prefix":"10.1002","volume":"355","author":[{"given":"Alexander","family":"Markus","sequence":"first","affiliation":[{"name":"Institut f\u00fcr Pharmazeutische und Medizinische Chemie Westf\u00e4lische Wilhelms\u2010Universit\u00e4t M\u00fcnster  M\u00fcnster Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3847-7539","authenticated-orcid":false,"given":"Julian A.","family":"Schreiber","sequence":"additional","affiliation":[{"name":"Institut f\u00fcr Pharmazeutische und Medizinische Chemie Westf\u00e4lische Wilhelms\u2010Universit\u00e4t M\u00fcnster  M\u00fcnster Germany"},{"name":"Department of Cardiovascular Medicine, Cellular Electrophysiology and Molecular Biology, Institute for Genetics of Heart Diseases (IfGH) University Hospital M\u00fcnster  M\u00fcnster Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3952-320X","authenticated-orcid":false,"given":"Gunnar","family":"Goerges","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, Cellular Electrophysiology and Molecular Biology, Institute for Genetics of Heart Diseases (IfGH) University Hospital M\u00fcnster  M\u00fcnster Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bastian","family":"Frehland","sequence":"additional","affiliation":[{"name":"Institut f\u00fcr Pharmazeutische und Medizinische Chemie Westf\u00e4lische Wilhelms\u2010Universit\u00e4t M\u00fcnster  M\u00fcnster Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guiscard","family":"Seebohm","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, Cellular Electrophysiology and Molecular Biology, Institute for Genetics of Heart Diseases (IfGH) University Hospital M\u00fcnster  M\u00fcnster Germany"},{"name":"GRK 2515, Chemical Biology of Ion Channels (Chembion) Westf\u00e4lische Wilhelms\u2010Universit\u00e4t M\u00fcnster  M\u00fcnster Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dirk","family":"Schepmann","sequence":"additional","affiliation":[{"name":"Institut f\u00fcr Pharmazeutische und Medizinische Chemie Westf\u00e4lische Wilhelms\u2010Universit\u00e4t M\u00fcnster  M\u00fcnster Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9030-8417","authenticated-orcid":false,"given":"Bernhard","family":"W\u00fcnsch","sequence":"additional","affiliation":[{"name":"Institut f\u00fcr Pharmazeutische und Medizinische Chemie Westf\u00e4lische Wilhelms\u2010Universit\u00e4t M\u00fcnster  M\u00fcnster Germany"},{"name":"GRK 2515, Chemical Biology of Ion Channels (Chembion) Westf\u00e4lische Wilhelms\u2010Universit\u00e4t M\u00fcnster  M\u00fcnster Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2022,5,23]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2008.06.063"},{"issue":"1","key":"e_1_2_7_3_1","first-page":"7","volume":"51","author":"Dingledine R.","year":"1999","journal-title":"Pharmacol. 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