title: Enantiomerically Pure 2-Methyltetrahydro-3-benzazepin-1-ols Selectively Blocking GluN2B Subunit Containing N-Methyl-D-aspartate Receptors.
abstract: A chiral pool synthesis was developed to obtain all four stereoisomeric 2-methyl-3-(4-phenylbutyl)tetrahydro-3-benzazepin-1-ols 21, 31, and 32 in a seven- to eight-step sequence. The phenols 32 reveal slightly higher GluN2B affinity than the methyl ethers 21. The GluN2B affinity increases in the order (1R,2S) < (1S,2S) < (1S,2R) < (1R,2R). The stereoisomeric phenols (R,R)-32 and (S,R)-32 show the highest GluN2B affinity and the highest cytoprotective activity. Both compounds represent GluN2B selective allosteric NMDA receptor antagonists. Docking of the 3-benzazepin-1-ols into the ifenprodil binding site of the crystallized GluN1b/GluN2B N-terminal domains led to free binding energies, which correlate nicely with the experimentally determined GluN2B affinities. The similar GluN2B affinity of the stereoisomeric phenols (S,S)-32, (R,R)-32, and (S,R)-32 is explained by different binding modes of the 3-benzazepine scaffold. The benzyl ethers 31 reveal unexpectedly high GluN2B affinity but do not show cytoprotective effects. The additional benzyl moiety of 31 binds into a previously unrecognized lipophilic subpocket.
authors.affiliation: †Institut für Pharmazeutische und Medizinische Chemie der Universität Münster, Corrensstraße 48, D-48149 Münster, Germany.
authors.forename: Bastian
authors.initials: B
authors.lastname: Tewes
authors.affiliation: †Institut für Pharmazeutische und Medizinische Chemie der Universität Münster, Corrensstraße 48, D-48149 Münster, Germany.
authors.forename: Bastian
authors.initials: B
authors.lastname: Frehland
authors.affiliation: †Institut für Pharmazeutische und Medizinische Chemie der Universität Münster, Corrensstraße 48, D-48149 Münster, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Schepmann
authors.affiliation: ‡Institut für Pharmazie, Martin-Luther-Universität Halle-Wittenberg, Wolfgang-Langenbeck-Strasse 4, D-06120 Halle/Saale, Germany.
authors.forename: Dina
authors.initials: D
authors.lastname: Robaa
authors.affiliation: ‡Institut für Pharmazie, Martin-Luther-Universität Halle-Wittenberg, Wolfgang-Langenbeck-Strasse 4, D-06120 Halle/Saale, Germany.
authors.forename: Tanaporn
authors.initials: T
authors.lastname: Uengwetwanit
authors.affiliation: §Institut für Pharmazie der Friedrich-Schiller-Universität Jena, Semmelweisstraße 10, D-07743 Jena, Germany.
authors.forename: Friedemann
authors.initials: F
authors.lastname: Gaube
authors.affiliation: §Institut für Pharmazie der Friedrich-Schiller-Universität Jena, Semmelweisstraße 10, D-07743 Jena, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Winckler
authors.affiliation: ‡Institut für Pharmazie, Martin-Luther-Universität Halle-Wittenberg, Wolfgang-Langenbeck-Strasse 4, D-06120 Halle/Saale, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Sippl
authors.affiliation: †Institut für Pharmazeutische und Medizinische Chemie der Universität Münster, Corrensstraße 48, D-48149 Münster, Germany.|∥Cells-in-Motion Cluster of Excellence (EXC 1003-CiM), Universität Münster, 48149 Münster, Germany.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Wünsch
mesh_terms: D001552:Benzazepines / Q000737:chemistry / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000737:chemistry / Q000494:pharmacology*; D062105:Molecular Docking Simulation; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D001552:Benzazepines; D018691:Excitatory Amino Acid Antagonists; C121001:NR2B NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate