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To increase the bioavailability and GluN2B affinity, the phenol of the potent benzazepine\u2010based inhibitor, WMS\u20101410 (<jats:bold>3<\/jats:bold>), was replaced bioisosterically by a benzoxazolone moiety and the phenylbutyl side chain was conformationally restricted in a phenylcyclohexyl substituent. A four\u2010step, one\u2010pot procedure transformed the oxazolo\u2010benzazepine <jats:bold>7<\/jats:bold> into the phenylcyclohexyl derivative <jats:bold>11<\/jats:bold>. The same protocol was applied to the methylated analog <jats:bold>12<\/jats:bold>, which unexpectedly led to ring\u2010contracted oxazolo\u2010isoquinolines <jats:bold>18<\/jats:bold>. This rearrangement was explained by the additional methyl moiety in the 8\u2010position inhibiting the formation of the planar intermediate iminium ion with phenylcyclohexanone. The allyl protective group of <jats:bold>11<\/jats:bold> and <jats:bold>18<\/jats:bold> was removed with RhCl<jats:sub>3<\/jats:sub> and HCl to obtain the tricyclic compounds <jats:bold>5<\/jats:bold> and <jats:bold>19<\/jats:bold> without substituent at the oxazolone ring. The structures of the rearranged products <jats:bold>18<\/jats:bold> and <jats:bold>19<\/jats:bold> were elucidated by X\u2010ray crystal structure analysis. The oxazolo\u2010isoquinoline <jats:italic>trans<\/jats:italic>\u2010<jats:bold>18<\/jats:bold> with allyl moiety (<jats:italic>K<\/jats:italic><jats:sub>i<\/jats:sub>\u2009=\u200989\u2009nM) and the oxazolo\u2010benzazepine <jats:bold>5<\/jats:bold> without substituent at the oxazolone ring (<jats:italic>K<\/jats:italic><jats:sub>i<\/jats:sub>\u2009=\u2009114\u2009nM) showed GluN2B affinity in the same range as the lead compound <jats:bold>3<\/jats:bold>. In two\u2010electrode voltage clamp measurements, <jats:bold>5<\/jats:bold> displayed only weak inhibitory activity.<\/jats:p>","DOI":"10.1002\/ardp.202200225","type":"journal-article","created":{"date-parts":[[2022,7,31]],"date-time":"2022-07-31T04:16:05Z","timestamp":1659240965000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Phenol\u2010benzoxazolone bioisosteres of GluN2B\u2010NMDA receptor antagonists: Unexpected rearrangement during reductive alkylation with phenylcyclohexanone"],"prefix":"10.1002","volume":"355","author":[{"given":"Alexander","family":"Markus","sequence":"first","affiliation":[{"name":"Westf\u00e4lische Wilhelms\u2010Universit\u00e4t M\u00fcnster Institut f\u00fcr Pharmazeutische und Medizinische Chemie  M\u00fcnster Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Julian A.","family":"Schreiber","sequence":"additional","affiliation":[{"name":"Westf\u00e4lische Wilhelms\u2010Universit\u00e4t M\u00fcnster Institut f\u00fcr Pharmazeutische und Medizinische Chemie  M\u00fcnster Germany"},{"name":"University Hospital M\u00fcnster Department of Cardiovascular Medicine, Cellular Electrophysiology and Molecular Biology, Institute for Genetics of Heart Diseases (IfGH)  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":"University Hospital M\u00fcnster Department of Cardiovascular Medicine, Cellular Electrophysiology and Molecular Biology, Institute for Genetics of Heart Diseases (IfGH)  M\u00fcnster Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bastian","family":"Frehland","sequence":"additional","affiliation":[{"name":"Westf\u00e4lische Wilhelms\u2010Universit\u00e4t M\u00fcnster Institut f\u00fcr Pharmazeutische und Medizinische Chemie  M\u00fcnster Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dirk","family":"Schepmann","sequence":"additional","affiliation":[{"name":"Westf\u00e4lische Wilhelms\u2010Universit\u00e4t M\u00fcnster Institut f\u00fcr Pharmazeutische und Medizinische Chemie  M\u00fcnster Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Constantin","family":"Daniliuc","sequence":"additional","affiliation":[{"name":"Westf\u00e4lische Wilhelms\u2010Universit\u00e4t M\u00fcnster Organisch\u2010Chemisches Institut  M\u00fcnster 48149 Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Roland","family":"Fr\u00f6hlich","sequence":"additional","affiliation":[{"name":"Westf\u00e4lische Wilhelms\u2010Universit\u00e4t M\u00fcnster Organisch\u2010Chemisches Institut  M\u00fcnster 48149 Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guiscard","family":"Seebohm","sequence":"additional","affiliation":[{"name":"University Hospital M\u00fcnster Department of Cardiovascular Medicine, Cellular Electrophysiology and Molecular Biology, Institute for Genetics of Heart Diseases (IfGH)  M\u00fcnster Germany"},{"name":"Westf\u00e4lische Wilhelms\u2010Universit\u00e4t M\u00fcnster GRK 2515, Chemical Biology of Ion Channels (Chembion)  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":"Westf\u00e4lische Wilhelms\u2010Universit\u00e4t M\u00fcnster Institut f\u00fcr Pharmazeutische und Medizinische Chemie  M\u00fcnster Germany"},{"name":"Westf\u00e4lische Wilhelms\u2010Universit\u00e4t M\u00fcnster GRK 2515, Chemical Biology of Ion Channels (Chembion)  M\u00fcnster Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2022,7,30]]},"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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