Covalent Allosteric Probe for the Metabotropic Glutamate Receptor 2 : Design, Synthesis, and Pharmacological Characterization
Doornbos, Maarten L. J. (Leiden University)
Wang, Xuesong (Leiden University)
Vermond, Sophie C. (Leiden University)
Peeters, Luc (Janssen Research and Development)
Pérez-Benito, Laura (Universitat Autònoma de Barcelona)
Trabanco, Andrés A. (Janssen Research and Development)
Lavreysen, Hilde (Janssen Research and Development)
Cid, José María (Janssen Research and Development)
Heitman, Laura H. (Leiden University)
Tresadern, Gary (Janssen Research and Development)
IJzerman, Adriaan P. (Leiden University)

Date:	2018
Abstract:	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 receptor. Three putatively covalent mGlu 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 PAM interaction and suggest that 2 is a valuable probe for further structural and chemical biology approaches.
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, i la comunicació pública de l'obra, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original. No es permet la creació d'obres derivades.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Published in:	Journal of medicinal chemistry, Vol. 62 (march 2018) , p. 223-233, ISSN 1520-4804

DOI: 10.1021/acs.jmedchem.8b00051
PMID: 29494768

11 p, 2.5 MB

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