Pharmacological characterization of a small-molecule agonist for the chemokine receptor CXCR3

Danny J Scholten, Meritxell Canals, Maikel Wijtmans, Sabrina de Munnik, Phong Thanh Nguyen, Dennis Verzijl, Iwan J P de Esch, Henry F Vischer, Martine J Smit, Rob Leurs

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BACKGROUND AND PURPOSE The chemokine receptor CXCR3 is a GPCR found predominantly on activated T cells. CXCR3 is activated by three endogenous peptides; CXCL9, CXCL10 and CXCL11. Recently, a small-molecule agonist, VUF10661, has been reported in the literature and synthesized in our laboratory. The aim of the present study was to provide a detailed pharmacological characterization of VUF10661 by comparing its effects with those of CXCL11. EXPERIMENTAL APPROACH Agonistic properties of VUF10661 were assessed in a chemotaxis assay with murine L1.2 cells transiently transfected with cDNA encoding the human CXCR3 receptor and in binding studies, with [ 125I]-CXCL10 and [ 125I]-CXCL11, on membrane preparations from HEK293 cells stably expressing CXCR3. [ 35S]-GTPI?S binding was used to determine its potency to induce CXCR3-mediated G protein activation and BRET-based assays to investigate its effects on intracellular cAMP levels and I?-arrestin recruitment. KEY RESULTS VUF10661 acted as a partial agonist in CXCR3-mediated chemotaxis, bound to CXCR3 in an allosteric fashion in ligand binding assays and activated G i proteins with the same efficacy as CXCL11 in the [ 35S]-GTPI?S binding and cAMP assay, while it recruited more I?-arrestin1 and I?-arrestin2 to CXCR3 receptors than the chemokine. CONCLUSIONS AND IMPLICATIONS VUF10661, like CXCL11, activates both G protein-dependent and -independent signalling via the CXCR3 receptor, but probably exerts its effects from an allosteric binding site that is different from that for CXCL11. It could stabilize different receptor and/or I?-arrestin conformations leading to differences in functional output. Such ligand-biased signalling might offer interesting options for the therapeutic use of CXCR3 agonists.
Original languageEnglish
Pages (from-to)898 - 911
Number of pages14
JournalBritish Journal of Pharmacology
Issue number3
Publication statusPublished - 2012
Externally publishedYes

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Scholten, D. J., Canals, M., Wijtmans, M., de Munnik, S., Nguyen, P. T., Verzijl, D., de Esch, I. J. P., Vischer, H. F., Smit, M. J., & Leurs, R. (2012). Pharmacological characterization of a small-molecule agonist for the chemokine receptor CXCR3. British Journal of Pharmacology, 166(3), 898 - 911.