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Derivatives of (R)-3-(5-Furanyl)carboxamido-2-aminopropanoic Acid as Potent NMDA Receptor Glycine Site Agonists with GluN2 Subunit-Specific Activity

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    Article

    Derivatives of (R)-3-(5-Furanyl)carboxamido-2-aminopropanoic Acid as Potent NMDA Receptor Glycine Site Agonists with GluN2 Subunit-Specific Activity
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    • Fabao Zhao
      Fabao Zhao
      Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, Copenhagen DK-2200, Denmark
      More by Fabao Zhao
    • Unai Atxabal
      Unai Atxabal
      Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, Copenhagen DK-2200, Denmark
      More by Unai Atxabal
    • Sofia Mariottini
      Sofia Mariottini
      Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, Copenhagen DK-2200, Denmark
      More by Sofia Mariottini
    • Feng Yi
      Feng Yi
      Center for Structural and Functional Neuroscience, Center for Biomolecular Structure and Dynamics, Division of Biological Sciences, University of Montana, Missoula, Montana 59812, United States
      More by Feng Yi
    • James S. Lotti
      James S. Lotti
      Center for Structural and Functional Neuroscience, Center for Biomolecular Structure and Dynamics, Division of Biological Sciences, University of Montana, Missoula, Montana 59812, United States
      More by James S. Lotti
    • Nirvan Rouzbeh
      Nirvan Rouzbeh
      Center for Structural and Functional Neuroscience, Center for Biomolecular Structure and Dynamics, Division of Biological Sciences, University of Montana, Missoula, Montana 59812, United States
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    • Na Liu
      Na Liu
      Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, Copenhagen DK-2200, Denmark
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    • Lennart Bunch
      Lennart Bunch
      Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, Copenhagen DK-2200, Denmark
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      Orcidhttps://orcid.org/0000-0002-0180-4639
    • Kasper B. Hansen*
      Kasper B. Hansen
      Center for Structural and Functional Neuroscience, Center for Biomolecular Structure and Dynamics, Division of Biological Sciences, University of Montana, Missoula, Montana 59812, United States
      *Email: [email protected]. Phone: (+1) 4062434820.
      More by Kasper B. Hansen
      Orcidhttps://orcid.org/0000-0002-3303-4819
    • Rasmus P. Clausen*
      Rasmus P. Clausen
      Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, Copenhagen DK-2200, Denmark
      *Email: [email protected]. Phone: (+45) 35336566.
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      Orcidhttps://orcid.org/0000-0001-9466-9431
    Other Access OptionsSupporting Information (5)

    Journal of Medicinal Chemistry

    Cite this: J. Med. Chem. 2022, 65, 1, 734–746
    Click to copy citationCitation copied!
    https://doi.org/10.1021/acs.jmedchem.1c01810
    Published December 17, 2021
    Copyright © 2021 American Chemical Society
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    Abstract

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    NMDA receptors mediate glutamatergic neurotransmission and are therapeutic targets due to their involvement in a variety of psychiatric and neurological disorders. Here, we describe the design and synthesis of a series of (R)-3-(5-furanyl)carboxamido-2-aminopropanoic acid analogues 8a–s as agonists at the glycine (Gly) binding site in the GluN1 subunit, but not GluN3 subunits, of NMDA receptors. These novel analogues display highly variable potencies and agonist efficacies among the NMDA receptor subtypes (GluN1/2A–D) in a manner dependent on the GluN2 subunit. Notably, compound 8p is identified as a potent partial agonist at GluN1/2C (EC50 = 0.074 μM) with an agonist efficacy of 28% relative to activation by Gly and virtually no agonist activity at GluN1/2A, GluN1/2B, and GluN1/2D. Thus, these novel agonists can modulate the activity of specific NMDA receptor subtypes by replacing the full endogenous agonists Gly or d-serine (d-Ser), thereby providing new opportunities in the development of novel therapeutic agents.

    Copyright © 2021 American Chemical Society

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    Supporting Information

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    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.jmedchem.1c01810.

    • Purity traces of all final compounds and extended version of Table 1 with sample size, Hill slopes, and standard deviations (PDF)

    • Docking pose of 8h (PDB)

    • Docking pose of 8k (PDB)

    • Docking pose of 8p (PDB)

    • Molecular formula strings (CSV)

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    Cited By

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    This article is cited by 3 publications.

    1. Erhad Ascic, Mauro Marigo, Laurent David, Kjartan Frisch Herrik, Morten Grupe, Charlotte Hougaard, Arne Mørk, Christopher R. Jones, Lassina Badolo, Kristen Frederiksen, Harrie C. M. Boonen, Henrik Sindal Jensen, John Paul Kilburn. Advancements in NMDA Receptor-Targeted Antidepressants: From d-Cycloserine Discovery to Preclinical Efficacy of Lu AF90103. Journal of Medicinal Chemistry 2024, 67 (22) , 20135-20155. https://doi.org/10.1021/acs.jmedchem.4c01477
    2. He Chen, Yuanping Dong, Yun Wu, Feng Yi. Targeting NMDA receptor signaling for therapeutic intervention in brain disorders. Reviews in the Neurosciences 2023, Article ASAP.
    3. Fabao Zhao, Georgios Mazis, Feng Yi, James S. Lotti, Michael S. Layeux, Eric P. Schultz, Lennart Bunch, Kasper B. Hansen, Rasmus P. Clausen. Discovery of (R)-2-amino-3-triazolpropanoic acid derivatives as NMDA receptor glycine site agonists with GluN2 subunit-specific activity. Frontiers in Chemistry 2022, 10 https://doi.org/10.3389/fchem.2022.1008233
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    Journal of Medicinal Chemistry

    Cite this: J. Med. Chem. 2022, 65, 1, 734–746
    Click to copy citationCitation copied!
    https://doi.org/10.1021/acs.jmedchem.1c01810
    Published December 17, 2021
    Copyright © 2021 American Chemical Society
    Request reuse permissions

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