Impact of hydroxy moieties at the benzo[7]annulene ring system of GluN2B ligands: Design,synthesis and biological evaluation |
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| Institution: | 1. Institut für Pharmazeutische und Medizinische Chemie der Universität Münster, Corrensstraße 48, 48149 Münster, Germany;2. Cells-in-Motion Cluster of Excellence (EXC 1003 – CiM), Westfälische Wilhelms-Universität Münster, Germany;3. Institut für Pharmazie der Martin-Luther-Universität Halle-Wittenberg, Wolfgang-Langenbeck-Straße 4, 06120 Halle (Saale), Germany;4. Organisch-chemisches Institut der Westfälischen Wilhelms-Universität, Münster, Corrensstraße 40, 48149 Münster, Germany;1. Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, 600 Forbes Avenue, Pittsburgh, PA 15282, United States;2. Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, 421 E. Canfield Street, Detroit, MI 48201, United States;3. Department of Oncology, Wayne State University School of Medicine, Detroit, MI 48201, United States;4. Department of Pharmacology, Wayne State University School of Medicine, Detroit, MI 48201, United States;1. School of Medicine, China Medical University, Taichung 404, Taiwan;2. Department of Chemistry, National Tsing Hua University, Hsinchu 30013, Taiwan;3. Agricultural Biotechnology Research Center, Academia Sinica, Taipei 115, Taiwan;4. Division of Radiotherapy, Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan;5. Department of Radiation Oncology, China Medical University Hospital, Taichung 404, Taiwan;6. Department of Biomedical Imaging and Radiological Science, China Medical University, Taichung 404, Taiwan;7. Department of Anesthesiology, China Medical University Hospital, Taichung, Taiwan;8. School of Medicine, College of Medicine, China Medical University, Taichung, Taiwan;9. Center for General Education, Chang Gung University, Taoyuan 33302, Taiwan;10. Development Center for Biotechnology, 101, Lane 169, Kangning St., Xizhi District, New Taipei City 22180, Taiwan;11. Nuclear Science & Technology Development Center, National Tsing Hua University, Hsinchu 30013, Taiwan;1. Auckland Cancer Society Research Centre, School of Medical Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand;2. Institute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, IL 60612, USA;3. Global Alliance for TB Drug Development, 40 Wall St, New York 10005, USA |
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| Abstract: | In this study, the impact of one or two hydroxy moieties at the benzo7]annulene scaffold on the GluN2B affinity and cytoprotective activity was analyzed. The key intermediate for the synthesis of OH-substituted benzo7]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, HCO2H, phosphane ligand) or the 6-hydroxyketone 10 (H2, 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 benzo7]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 Ki = 49 nM and a cytoprotective activity of IC50 = 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 CH2OH moiety at 2-position results in binding at the ifenprodil binding site, but very weak ion channel inhibition. |
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| Keywords: | NMDA receptor Ifenprodil binding site Negative allosteric modulators GluN2B selective antagonists Docking studies Selectivity Cytoprotective activity Structure-affinity relationships Structure-activity relationships Metabolic stability |
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