2. Academic Validation
  3. Design of (R)-3-(5-Thienyl)carboxamido-2-aminopropanoic Acid Derivatives as Novel NMDA Receptor Glycine Site Agonists: Variation in Molecular Geometry to Improve Potency and Augment GluN2 Subunit-Specific Activity

Design of (R)-3-(5-Thienyl)carboxamido-2-aminopropanoic Acid Derivatives as Novel NMDA Receptor Glycine Site Agonists: Variation in Molecular Geometry to Improve Potency and Augment GluN2 Subunit-Specific Activity

  • J Med Chem. 2025 Feb 13;68(3):3572-3590. doi: 10.1021/acs.jmedchem.4c02715.
Fabao Zhao 1 2,  Unai Atxabal 1,  Sofia Mariottini 1,  Feng Yi 3,  James S Lotti 3,  Michael S Layeux 3,  Chandler Currier 3,  Matthew P Maderia 3,  Lauren E Cornelison 3,  Carly M Anderson 3,  Eric P Schultz 3,  Zhucheng Zhang 1,  Liyang Jiang 2,  Zhen Gao 2,  Na Liu 1 2,  Erica L Woodahl 4,  Lennart Bunch 1,  Kasper B Hansen 3,  Rasmus P Clausen 1
Affiliations

Affiliations

  • 1 Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, DK-2100, Denmark.
  • 2 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 250012 Jinan, Shandong P. R. China.
  • 3 Center for Structural and Functional Neuroscience, Center for Biomolecular Structure and Dynamics, Division of Biological Sciences, University of Montana, Missoula, Montana 59812, United States.
  • 4 L.S. Skaggs Institute for Health Innovation, Department of Biomedical and Pharmaceutical Sciences, University of Montana, Missoula, Montana 59812, United States.
PMID: 39847708 DOI: 10.1021/acs.jmedchem.4c02715
Abstract

NMDA Receptor ligands have therapeutic potential in neurological and psychiatric disorders. We designed (R)-3-(5-thienyl)carboxamido-2-aminopropanoic acid derivatives with nanomolar agonist potencies at NMDA Receptor subtypes (GluN12/A-D). These compounds are superagonists at GluN1/2C compared to glycine and partial to full agonists at GluN1/2A and GluN1/2D but display functional antagonism at GluN1/2B due to low agonist efficacy. Notably, 8d display 864% agonist efficacy at GluN1/2C relative to glycine, and 8j has high potency at GluN1/2A (0.018 μM), GluN1/2C (0.0029 μM), and GluN1/2D (0.016 μM). We evaluated the binding mode in the glycine site using molecular modeling and mutagenesis. In vitro absorption, distribution, metabolism, and excretion (ADME) assays predict high metabolic stability but poor blood-brain barrier permeability. However, an ester prodrug for the carboxylate group of 7j display moderately high blood-brain barrier permeability. The thiophenecarboxamide agonists expand the synthetic pharmacology of NMDA receptors and provide structural insights that facilitate the design of GluN1 agonists with GluN2 subunit-specific activity.

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