{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,16]],"date-time":"2025-10-16T19:48:53Z","timestamp":1760644133575,"version":"build-2065373602"},"reference-count":40,"publisher":"Wiley","issue":"23","license":[{"start":{"date-parts":[[2018,11,14]],"date-time":"2018-11-14T00:00:00Z","timestamp":1542153600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["WU 176\/14-1"],"award-info":[{"award-number":["WU 176\/14-1"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["chemistry-europe.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["ChemMedChem"],"published-print":{"date-parts":[[2018,12,6]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The 4\u2010benzylpiperidine moiety is a central structural element of potent <jats:italic>N<\/jats:italic>\u2010methyl\u2010<jats:sc>d<\/jats:sc>\u2010aspartate (NMDA) receptor antagonists containing the GluN2B subunit. To obtain novel GluN2B ligands suitable for positron emission tomography, the benzylpiperidine moiety was replaced with fluorinated \u03c9\u2010phenylalkylamino groups. For this purpose three primary propyl\u2010 and butylamines <jats:bold>7\u2009a<\/jats:bold>\u2013<jats:bold>c<\/jats:bold> and one butyraldehyde <jats:bold>7\u2009d<\/jats:bold> bearing a fluorine atom and an \u03c9\u2010phenyl moiety were prepared in 3\u2010 to 7\u2010step syntheses. Compounds <jats:bold>7\u2009a<\/jats:bold>\u2013<jats:bold>d<\/jats:bold> were attached to various scaffolds of potent GluN2B antagonists (scaffold hopping) instead of the original 4\u2010benzylpiperidine moiety. Although benzoxazol\u20102\u2010ones and indoles with a benzylpiperidine moiety show high GluN2B affinity, the corresponding fluorophenylalkylamine derivatives did not result in high Glu2B affinity. Moderate GluN2B affinity was observed for a 3\u2010(fluoroalkyl)\u2010substituted tetrahydro\u20101<jats:italic>H<\/jats:italic>\u20103\u2010benzazepine (<jats:italic>K<\/jats:italic><jats:sub>i<\/jats:sub>=239\u2005n<jats:sc>m<\/jats:sc>). However, high GluN2B affinity was obtained for the tetrahydro\u20105<jats:italic>H<\/jats:italic>\u2010benzo[7]annulen\u20107\u2010amines <jats:bold>12\u2009a<\/jats:bold>\u2013<jats:bold>c<\/jats:bold> (<jats:italic>K<\/jats:italic><jats:sub>i<\/jats:sub>=17\u201330\u2005n<jats:sc>m<\/jats:sc>). Docking studies resulted in the same binding pose for <jats:bold>12\u2009a<\/jats:bold> as for the lead compound Ro\u200525\u20106981. It can be concluded that some GluN2B ligands (benzoxazolones, indoles) do not tolerate replacement of the 4\u2010benzylpiperidine moiety with flexible fluorinated phenylalkyl side chains, but other scaffolds such as tetrahydro\u20103\u2010benzazepines and \u2010benzo[7]annulenes retain interaction with NMDA receptors containing the GluN2B subunit.<\/jats:p>","DOI":"10.1002\/cmdc.201800566","type":"journal-article","created":{"date-parts":[[2018,10,12]],"date-time":"2018-10-12T12:10:52Z","timestamp":1539346252000},"page":"2522-2529","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Replacement of the Benzylpiperidine Moiety with Fluorinated Phenylalkyl Side Chains for the Development of GluN2B Receptor Ligands"],"prefix":"10.1002","volume":"13","author":[{"given":"Simone","family":"Thum","sequence":"first","affiliation":[{"name":"Institut f\u00fcr Pharmazeutische und Medizinische Chemie Westf\u00e4lische Wilhelms-Universit\u00e4t M\u00fcnster  Corrensstra\u00dfe 48 48149 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-Universit\u00e4t M\u00fcnster  Corrensstra\u00dfe 48 48149 M\u00fcnster Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dmitrii V.","family":"Kalinin","sequence":"additional","affiliation":[{"name":"Institut f\u00fcr Pharmazeutische und Medizinische Chemie Westf\u00e4lische Wilhelms-Universit\u00e4t M\u00fcnster  Corrensstra\u00dfe 48 48149 M\u00fcnster Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Simon M.","family":"Ametamey","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Applied Biosciences Institute of Pharmaceutical Sciences ETH Zurich  Vladimir-Prelog-Weg 1-5\/10 8093 Z\u00fcrich Switzerland"}],"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-Universit\u00e4t M\u00fcnster  Corrensstra\u00dfe 48 48149 M\u00fcnster Germany"},{"name":"Cells-in-Motion Cluster of Excellence (EXC\u20051003\u2013CiM) Westf\u00e4lische Wilhelms-Universit\u00e4t M\u00fcnster  48149 M\u00fcnster Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2018,11,14]]},"reference":[{"key":"e_1_2_7_1_1","doi-asserted-by":"crossref","first-page":"992","DOI":"10.1126\/science.1251915","volume":"344","author":"Karakas E.","year":"2014","journal-title":"Science"},{"key":"e_1_2_7_2_1","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1016\/j.neuropharm.2008.06.063","volume":"56","author":"Collingridge G. 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