학술논문
Impact of hydroxy moieties at the benzo[7]annulene ring system of GluN2B ligands: Design, synthesis and biological evaluation.
Document Type
Academic Journal
Author
Temme L; Institut für Pharmazeutische und Medizinische Chemie der Universität Münster, Corrensstraße 48, 48149 Münster, Germany; Cells-in-Motion Cluster of Excellence (EXC 1003 - CiM), Westfälische Wilhelms-Universität Münster, Germany.; Börgel F; Institut für Pharmazeutische und Medizinische Chemie der Universität Münster, Corrensstraße 48, 48149 Münster, Germany.; Schepmann D; Institut für Pharmazeutische und Medizinische Chemie der Universität Münster, Corrensstraße 48, 48149 Münster, Germany.; Robaa D; Institut für Pharmazie der Martin-Luther-Universität Halle-Wittenberg, Wolfgang-Langenbeck-Straße 4, 06120 Halle (Saale), Germany.; Sippl W; Institut für Pharmazie der Martin-Luther-Universität Halle-Wittenberg, Wolfgang-Langenbeck-Straße 4, 06120 Halle (Saale), Germany.; Daniliuc C; Organisch-chemisches Institut der Westfälischen Wilhelms-Universität, Münster, Corrensstraße 40, 48149 Münster, Germany.; Wünsch B; Institut für Pharmazeutische und Medizinische Chemie der Universität Münster, Corrensstraße 48, 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: Elsevier Science Country of Publication: England NLM ID: 9413298 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1464-3391 (Electronic) Linking ISSN: 09680896 NLM ISO Abbreviation: Bioorg Med Chem Subsets: MEDLINE
Subject
Language
English
Abstract
In this study, the impact of one or two hydroxy moieties at the benzo[7]annulene scaffold on the GluN2B affinity and cytoprotective activity was analyzed. The key intermediate for the synthesis of OH-substituted benzo[7]annulenamines 11-13 and 17 was the epoxyketone 8. Reductive epoxide opening of 8 resulted with high regioselectivity in the 5-hydroxyketone 9 (Pd(OAc) 2 , HCO 2 H, phosphane ligand) or the 6-hydroxyketone 10 (H 2 , Pd/C), whereas hydrolysis in aqueous dioxane led to the dihydroxyketone 14. Reductive amination of these ketones with primary amines and NaBH(OAc) 3 afforded the benzo[7]annulenamines 11-13 and 17. In receptor binding studies 5-OH derivatives 11 and 12 showed higher GluN2B affinity than 6-OH derivatives 13, which in turn were more active than 5,6-di-OH derivative 17a. The same order was found for the cytoprotective activity of the ligands. The tertiary amine 12a with one OH moiety in 5-position represents the most promising GluN2B negative allosteric modulator with a binding affinity of K i = 49 nM and a cytoprotective activity of IC 50 = 580 nM. In the binding pocket 12a shows a crucial H-bond between the benzylic OH moiety and the backbone carbonyl O-atom of Ser132 (GluN1b). It was concluded that a 5-OH moiety is essential for the inhibition of the NMDA receptor associated ion channel, whereas a OH moiety in 6-position is detrimental for binding and inhibition. An OH or CH 2 OH moiety at 2-position results in binding at the ifenprodil binding site, but very weak ion channel inhibition.
(Copyright © 2019 Elsevier Ltd. All rights reserved.)
(Copyright © 2019 Elsevier Ltd. All rights reserved.)