Model-Based Discovery of Synthetic Agonists for the Zn2+-Sensing G-Protein-Coupled Receptor 39 (GPR39) Reveals Novel Biological Functions.

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Thomas M. Frimurer, Franziska Mende, Anne-Sofie Graae, Maja S. Engelstoft, Kristoffer L. Egerod, Rie Nygaard, Lars-Ole Gerlach, Jakob Bondo Hansen, Thue W. Schwartz, Birgitte. Holst

The G-protein coupled receptor 39 (GPR39) is a G protein-coupled receptor activated by Zn2. We used a homol. model-based approach to identify small-mol. pharmacol. tool compds. for the receptor. The method focused on a putative binding site in GPR39 for synthetic ligands and knowledge of ligand binding to other receptors with similar binding pockets to select iterative series of mini-libraries. These libraries were cherry-picked from all com. available synthetic compds. A total of only 520 compds. were tested in vitro, making this method broadly applicable for tool compd. development. The compds. of the initial library were inactive when tested alone, but lead compds. were identified using Zn2 as an allosteric enhancer. Highly selective, highly potent Zn2-independent GPR39 agonists were found in subsequent mini-libraries. These agonists identified GPR39 as a novel regulator of gastric somatostatin secretion. [on SciFinder(R)]
Original languageEnglish
JournalJournal of Medicinal Chemistry
Volume60
Issue number3
Pages (from-to)886-898
Number of pages13
ISSN0022-2623
DOIs
Publication statusPublished - 2017

    Research areas

  • pharmacophore screening GPR39 receptor gastric mucosa somatostatin secretion

ID: 174463411