Ligand-Biased and Probe-Dependent Modulation of Chemokine Receptor CXCR3 Signaling by Negative Allosteric Modulators
Bernat V, Brox R, Heinrich M, Auberson YP, Tschammer N (2015)
Publication Status: Published
Publication Type: Journal article, Original article
Publication year: 2015
Journal
Publisher: John Wiley and Sons Ltd
Book Volume: 10
Pages Range: 566-574
Journal Issue: 3
Abstract
Over the last decade, functional selectivity (or ligand bias) has evolved from being a peculiar phenomenon to being recognized as an essential feature of synthetic ligands that target Gprotein-coupled receptors (GPCRs). The CXC chemokine receptor3 (CXCR3) is an outstanding platform to study various aspects of biased signaling, because nature itself uses functional selectivity to manipulate receptor signaling. At the same time, CXCR3 is an attractive therapeutic target in the treatment of autoimmune diseases and cancer. Herein we report the discovery of an 8-azaquinazolinone derivative (N-{1-[3-(4-ethoxyphenyl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl]ethyl}-4-(4-fluorobutoxy)-N-[(1-methylpiperidin-4-yl)methyl]butanamide, 1b) that can inhibit CXC chemokine11 (CXCL11)-dependent Gprotein activation over β-arrestin recruitment with 187-fold selectivity. This compound also demonstrates probe-dependent activity, that is, it inhibits CXCL11- over CXCL10-mediated Gprotein activation with 12-fold selectivity. Together with a previously reported biased negative allosteric modulator from our group, the present study provides additional information on the molecular requirements for allosteric modulation of CXCR3. How amazing can 1b? The chemokine receptor CXCR3 is an outstanding platform to study various aspects of allosteric modulation. Herein we report the discovery of a small molecule (compound 1b) that can inhibit CXCL11-dependent Gprotein activation over β-arrestin recruitment with 187-fold selectivity. Compound 1b also demonstrates probe-dependent activity: it inhibits CXCL11- over CXCL10-mediated Gprotein activation with 12-fold selectivity.
Authors with CRIS profile
Viachaslau Bernat
Regine Brox Lehrstuhl für Pharmazeutische Chemie Markus Heinrich Professur für Pharmazeutische Chemie Nuska Tschammer Lehrstuhl für Pharmazeutische Chemie
Regine Brox Lehrstuhl für Pharmazeutische Chemie Markus Heinrich Professur für Pharmazeutische Chemie Nuska Tschammer Lehrstuhl für Pharmazeutische Chemie
Involved external institutions
Switzerland (CH)How to cite
APA:
Bernat, V., Brox, R., Heinrich, M., Auberson, Y.P., & Tschammer, N. (2015). Ligand-Biased and Probe-Dependent Modulation of Chemokine Receptor CXCR3 Signaling by Negative Allosteric Modulators. ChemMedChem, 10(3), 566-574. https://doi.org/10.1002/cmdc.201402507
MLA:
Bernat, Viachaslau, et al. "Ligand-Biased and Probe-Dependent Modulation of Chemokine Receptor CXCR3 Signaling by Negative Allosteric Modulators." ChemMedChem 10.3 (2015): 566-574.
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