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Discovery and Characterization of Biased Allosteric Agonists of the Chemokine Receptor CXCR3

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posted on 10.02.2016, 00:00 by Lampros Milanos, Regine Brox, Theresa Frank, Gašper Poklukar, Ralf Palmisano, Reiner Waibel, Jürgen Einsiedel, Maximilian Dürr, Ivana Ivanović-Burmazović, Olav Larsen, Gertrud Malene Hjortø, Mette Marie Rosenkilde, Nuska Tschammer
In this work we report a design, synthesis, and detailed functional characterization of unique strongly biased allosteric agonists of CXCR3 that contain tetrahydroisoquinoline carboxamide cores. Compound 11 (FAUC1036) is the first strongly biased allosteric agonist of CXCR3 that selectively induces weak chemotaxis and leads to receptor internalization and the β-arrestin 2 recruitment with potency comparable to that of the chemokine CXCL11 without any activation of G proteins. A subtle structural change (addition of a methoxy group, 14 (FAUC1104)) led to a contrasting biased allosteric partial agonist that activated solely G proteins, induced chemotaxis, but failed to induce receptor internalization or β-arrestin 2 recruitment. Concomitant structure–activity relationship studies indicated very steep structure–activity relationships, which steer the ligand bias between the β-arrestin 2 and G protein pathway. Overall, the information presented provides a powerful platform for further development and rational design of strongly biased allosteric agonists of CXCR3.