title: Role of the phenolic OH moiety of GluN2B-selective NMDA antagonists with 3-benzazepine scaffold.
abstract: In order to analyze the role of the phenolic OH moiety of ifenprodil (1) and 3-benzazepin-1,7-diol 2 for the affinity and selectivity at GluN2B subunit containing NMDA receptors, the 3-benzazepin-1-ols 3 were designed, synthesized and pharmacologically evaluated and furthermore, the molecular interactions of the phenylbutyl derivative 3c with the GluN2B receptor were investigated. In order to avoid decarbonylation during the intramolecular Friedel-Crafts acylation of 11, the N-atom has to be protected with a trifluoromethylsulfonyl group. The second key step of the synthesis was the removal of the N-triflyl group, which was realized by K2CO3 induced elimination of trifluoromethanelsulfinate (F3CSO2(-)). In receptor binding studies with the radioligand [(3)H]ifenprodil the 3-benzazepin-1-ol 3c revealed a GluN2B affinity of 73 nM indicating that the phenolic OH moiety of 1 and 2 is not essential but favorable for high GluN2B affinity. In docking studies 3-benzazepin-1-ol 3c shows the same binding pose as ifenprodil-keto 1A in the X-ray crystal structure. H-bond interactions and lipophilic interactions of 3c and 1A are very similar.
authors.affiliation: Institut für Pharmazeutische und Medizinische Chemie der Westfälischen Wilhelms-Universität Münster, Corrensstraße 48, D-48149 Münster, Germany; NRW Graduate School of Chemistry, Westfälischen Wilhelms-Universität Münster, Wilhelm-Klemm-Str. 10, D-48149 Münster, Germany.
authors.forename: Sougata
authors.initials: S
authors.lastname: Dey
authors.affiliation: Institut für Pharmazeutische und Medizinische Chemie der Westfälischen Wilhelms-Universität Münster, Corrensstraße 48, D-48149 Münster, Germany; Cells-in-Motion Cluster of Excellence (EXC 1003-CiM), Westfälische Wilhelms-Universität Münster, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Schepmann
authors.affiliation: Institut für Pharmazeutische und Medizinische Chemie der Westfälischen Wilhelms-Universität Münster, Corrensstraße 48, D-48149 Münster, Germany; Cells-in-Motion Cluster of Excellence (EXC 1003-CiM), Westfälische Wilhelms-Universität Münster, Germany. Electronic address: wuensch@uni-muenster.de.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Wünsch
mesh_terms: D001552:Benzazepines / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D006801:Humans; D007700:Kinetics; D062105:Molecular Docking Simulation; D010636:Phenols / Q000737:chemistry*; D010880:Piperidines / Q000737:chemistry / Q000378:metabolism; D017434:Protein Structure, Tertiary; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014316:Tritium / Q000737:chemistry
chemical_list: D001552:Benzazepines; C121001:NR2B NMDA receptor; D010636:Phenols; D010880:Piperidines; D016194:Receptors, N-Methyl-D-Aspartate; D014316:Tritium; C010739:ifenprodil
keywords: Conformational restriction; Docking; GluN2B selective NMDA receptor antagonist; N-Triflyl deprotection; NMDA receptor; Radioligand receptor binding studies; Tetrahydro-3-benzazepin-1-ol