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

Journal of Medicinal Chemistry
Maarten L J DoornbosAdriaan P IJzerman

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 mGlu2 receptor. Three putatively covalent mGlu2 PAMs were designed and synthesized. Pharmacological characterization identified 2 to bind the receptor covalently. Computational modeling combined with receptor mutagenesis revealed T7917.29×30 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 mGlu2 PAM interaction and suggest that 2 is a valuable probe for further structural and chemical biology approaches.

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Citations

Mar 23, 2019·Angewandte Chemie·Daniel PetzoldBurkhard König
Mar 23, 2019·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Claudia Llinas Del TorrentGary Tresadern
Jan 23, 2021·RSC Medicinal Chemistry·Lyn H Jones, Jeffery W Kelly
Feb 19, 2021·Journal of Medicinal Chemistry·Natalia V Ortiz ZacaríasLaura H Heitman
Aug 21, 2020·European Journal of Medicinal Chemistry·Yuemin BianXiang-Qun Xie
Mar 15, 2019·Journal of Medicinal Chemistry·Xue YangAdriaan P IJzerman
May 6, 2019·Journal of Medicinal Chemistry·Gaochan WuPeng Zhan
Feb 6, 2019·Journal of Medicinal Chemistry·Quinn CoughlinDario Doller
Mar 19, 2020·ACS Medicinal Chemistry Letters·Ana Isabel de LucasJosé María Cid

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Methods Mentioned

BETA
column chromatography
Transfection
transfections
scraping
scintillation spectrometry
Assay

Software Mentioned

ConfGen
Chemstation
- Agilent Data Browser
MOE
Glide
Protein Preparation
PROPKA
MassLynx
- Openlynx
GraphPad

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