학술논문
Negative allosteric modulators of the GluN2B NMDA receptor with phenylethylamine structure embedded in ring-expanded and ring-contracted scaffolds.
Document Type
Academic Journal
Author
Temme L; Institut für Pharmazeutische und Medizinische Chemie der Universität Münster, Corrensstraße 48, D-48149, Münster, Germany; Cells-in-Motion Cluster of Excellence (EXC 1003 - CiM), Westfälische Wilhelms-Universität, Münster, Germany.; Bechthold E; Institut für Pharmazeutische und Medizinische Chemie der Universität Münster, Corrensstraße 48, D-48149, Münster, Germany.; Schreiber JA; Institut für Pharmazeutische und Medizinische Chemie der Universität Münster, Corrensstraße 48, D-48149, Münster, Germany; Cells-in-Motion Cluster of Excellence (EXC 1003 - CiM), Westfälische Wilhelms-Universität, Münster, Germany; Institut für Pharmazie der Martin-Luther-Universität Halle-Wittenberg, Wolfgang-Langenbeck-Straße 4, 06120, Halle (Saale), Germany.; Gawaskar S; Institut für Pharmazeutische und Medizinische Chemie der Universität Münster, Corrensstraße 48, D-48149, Münster, Germany; Cells-in-Motion Cluster of Excellence (EXC 1003 - CiM), Westfälische Wilhelms-Universität, Münster, Germany.; Schepmann D; Institut für Pharmazeutische und Medizinische Chemie der Universität Münster, Corrensstraße 48, D-48149, Münster, Germany.; Robaa D; Cellular Electrophysiology and Molecular Biology, Institute for Genetics of Heart Diseases (IfGH), Department of Cardiovascular Medicine, University Hospital Münster, Robert-Koch-Str. 45, D-48149, Münster, Germany.; Sippl W; Cellular Electrophysiology and Molecular Biology, Institute for Genetics of Heart Diseases (IfGH), Department of Cardiovascular Medicine, University Hospital Münster, Robert-Koch-Str. 45, D-48149, Münster, Germany.; Seebohm G; Institut für Pharmazie der Martin-Luther-Universität Halle-Wittenberg, Wolfgang-Langenbeck-Straße 4, 06120, Halle (Saale), Germany.; Wünsch B; Institut für Pharmazeutische und Medizinische Chemie der 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.
Source
Publisher: Editions Scientifiques Elsevier Country of Publication: France NLM ID: 0420510 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1768-3254 (Electronic) Linking ISSN: 02235234 NLM ISO Abbreviation: Eur J Med Chem Subsets: MEDLINE
Subject
Language
English
Abstract
A set of GluN2B NMDA receptor antagonists with conformationally restricted phenylethylamine substructure was prepared and pharmacologically evaluated. The phenylethylamine substructure was embedded in ring expanded 3-benzazocines 4 as well as ring-contracted tetralinamines 6 and indanamines 7. The ligands 4, 6 and 7 were synthesized by reductive alkylation of secondary amine 11, reductive amination of ketones 12 and 16 and nucleophilic substitution of nosylates 14 and 17. The moderate GluN2B affinity of 3-benzazocine 4d (K i = 32 nM) translated into moderate cytoprotective activity (IC 50 = 890 nM) and moderate ion channel inhibition (60% at 10 μM) in two-electrode voltage clamp experiments with GluN1a/GluN2B expressing oocytes. Although some of the tetralinamines 6 and indanamines 7 showed very high GluN2B affinity (e.g. K i (7f) = 3.2 nM), they could not inhibit glutamate/glycine inducted cytotoxicity. The low cytoprotective activity of 3-benzazocines 4, tetralinamines 6 and indanamines 7 was attributed to the missing OH moiety at the benzene ring and/or in benzylic position. Docking studies showed that the novel GluN2B ligands adopt similar binding poses as Ro 25-6981 with the central H-bond interaction between the protonated amino moiety of the ligands and the carbamoyl moiety of Gln110. However, due to the lack of a second H-bond forming group, the ligands can adopt two binding poses within the ifenprodil binding pocket.
Competing Interests: Declaration of competing interest The authors declare no conflict of interest.
(Copyright © 2020 Elsevier Masson SAS. All rights reserved.)
Competing Interests: Declaration of competing interest The authors declare no conflict of interest.
(Copyright © 2020 Elsevier Masson SAS. All rights reserved.)