Covalent Allosteric Probe for the Metabotropic Glutamate Receptor 2: Design, Synthesis, and Pharmacological Characterization

Maarten L.J. Doornbos, Xuesong Wang, Sophie C. Vermond, Luc Peeters, Laura Pérez-Benito, Andrés A. Trabanco, Hilde Lavreysen, José María Cid, Laura H. Heitman, Gary Tresadern, Adriaan P. Ijzerman

    Research output: Contribution to journalArticleResearch

    12 Citations (Scopus)

    Abstract

    © 2018 American Chemical Society. Covalent labeling of G protein-coupled receptors (GPCRs) by small molecules is a powerful approach to understand binding modes, mechanism of action, pharmacology, and even facilitate structure elucidation. We report the first covalent positive allosteric modulator (PAM) for a class C GPCR, the mGlu 2 receptor. Three putatively covalent mGlu 2 PAMs were designed and synthesized. Pharmacological characterization identified 2 to bind the receptor covalently. Computational modeling combined with receptor mutagenesis revealed T791 7.29×30 as the likely position of covalent interaction. We show how this covalent ligand can be used to characterize the PAM binding mode and that it is a valuable tool compound in studying receptor function and binding kinetics. Our findings advance the understanding of the mGlu 2 PAM interaction and suggest that 2 is a valuable probe for further structural and chemical biology approaches.
    Original languageEnglish
    Pages (from-to)223-233
    JournalJournal of Medicinal Chemistry
    Volume62
    DOIs
    Publication statusPublished - 1 Oct 2019

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