{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,23]],"date-time":"2026-01-23T07:55:59Z","timestamp":1769154959647,"version":"3.49.0"},"reference-count":0,"publisher":"Cell Physiol Biochem Press GmbH and Co KG","issue":"S3","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cell Physiol Biochem"],"abstract":"<jats:p>The NMDA receptor plays a key role in the pathogenesis of neurodegenerative disorders including Alzheimer's and Huntington's disease, as well as depression and drug or alcohol dependence. Due to its participation in these pathologies, the development of selective modulators for this ion channel is a promising strategy for rational drug therapy. The prototypical negative allosteric modulator ifenprodil inhibits selectively GluN2B subunit containing NMDA receptors. It was conformationally restricted as 2-methyl-3-(4-phenylbutyl)-2,3,4,5-tetrahydro-1H-3-benzazepine-1,7-diol, which showed high GluN2B affinity and inhibitory activity. For a better understanding of the relevance of the functional groups and structural elements, the substituents of this 3-benzazepine were removed successively (deconstruction). Then, additional structural elements were introduced (reconstruction) with the aim to analyze, which additional modifications were tolerated by the GluN2B receptor. The GluN2B affinity was recorded in radioligand receptor binding studies with the radioligand [3H]ifenprodil. The activity of the ligands was determined in two-electrode voltage clamp experiments using Xenopus laevis oocytes transfected with cRNA encoding the GluN1-1a and GluN2B subunits of the NMDA receptor. Docking studies showed the crucial interactions with the NMDA receptor protein. The deconstruction approach showed that removal of the methyl moiety and the phenolic OH moiety in 7-positon resulted in almost the same GluN2B affinity as the parent 3-benzazepine. A considerably reduced GluN2B affinity was found for the 3-benzazepine without further substituents. However, removal of one or both OH moieties led to considerably reduced NMDA receptor inhibition. Introduction of a NO2 moiety or bioisosteric replacement of the phenol by a benzoxazolone resulted in comparable GluN2B affinity, but almost complete loss of inhibitory activity. An O-atom, a carbonyl moiety or a F-atom in the tetramethylene spacer led to 6-7-fold reduced ion channel inhibition.<\/jats:p>","DOI":"10.33594\/000000335","type":"journal-article","created":{"date-parts":[[2021,3,2]],"date-time":"2021-03-02T21:59:28Z","timestamp":1614722368000},"page":"1-13","source":"Crossref","is-referenced-by-count":5,"title":["Deconstruction - Reconstruction: Analysis of the Crucial Structural Elements of GluN2B-Selective, Negative Allosteric NMDA Receptor Modulators with 3-Benzazepine Scaffold"],"prefix":"10.33594","volume":"55","member":"19235","published-online":{"date-parts":[[2020,3,3]]},"container-title":["Cellular Physiology and Biochemistry"],"original-title":[],"deposited":{"date-parts":[[2021,3,2]],"date-time":"2021-03-02T21:59:30Z","timestamp":1614722370000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.cellphysiolbiochem.com\/Articles\/000335\/"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,3,3]]},"references-count":0,"journal-issue":{"issue":"S3","published-online":{"date-parts":[[2020,3,3]]}},"URL":"https:\/\/doi.org\/10.33594\/000000335","relation":{},"ISSN":["1015-8987","1421-9778"],"issn-type":[{"value":"1015-8987","type":"print"},{"value":"1421-9778","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,3,3]]}}}