title: Ligand-biased and probe-dependent modulation of chemokine receptor CXCR3 signaling by negative allosteric modulators.
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 G protein-coupled receptors (GPCRs). The CXC chemokine receptor 3 (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, 1 b) that can inhibit CXC chemokine 11 (CXCL11)-dependent G protein activation over β-arrestin recruitment with 187-fold selectivity. This compound also demonstrates probe-dependent activity, that is, it inhibits CXCL11- over CXCL10-mediated G protein 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.
authors: Department of Chemistry and Pharmacy, Medicinal Chemistry, Emil Fischer Center, Friedrich Alexander University, Schuhstraße 19, 91052 Erlangen (Germany); Current affiliation: Department of Chemistry, The Scripps Research Institute, 130 Scripps Way, 3A1, 33458 Jupiter, FL (USA).
authors: Viachaslau
authors: V
authors: Bernat
authors: Regine
authors: R
authors: Brox
authors: Markus R
authors: MR
authors: Heinrich
authors: Yves P
authors: YP
authors: Auberson
authors: Nuska
authors: N
authors: Tschammer
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects*; D019390:Arrestins / Q000276:immunology; D001372:Aza Compounds / Q000737:chemistry / Q000494:pharmacology; D054371:Chemokine CXCL11 / Q000037:antagonists & inhibitors; D057809:HEK293 Cells; D006801:Humans; D007155:Immunologic Factors / Q000737:chemistry* / Q000494:pharmacology*; D008024:Ligands; D052999:Quinazolinones / Q000737:chemistry* / Q000494:pharmacology*; D054367:Receptors, CXCR3 / Q000276:immunology*; D015398:Signal Transduction / Q000187:drug effects; D000071557:beta-Arrestins
chemical_list: D019390:Arrestins; D001372:Aza Compounds; D054371:Chemokine CXCL11; D007155:Immunologic Factors; D008024:Ligands; D052999:Quinazolinones; D054367:Receptors, CXCR3; D000071557:beta-Arrestins
keywords: allosteric modulation; chemokine receptor CXCR3; ligand-biased signaling; probe dependence