TY - JOUR
T1 - Discovery and Characterization of Biased Allosteric Agonists of the Chemokine Receptor CXCR3
AU - Milanos, Lampros
AU - Brox, Regine
AU - Frank, Theresa
AU - Poklukar, Gašper
AU - Palmisano, Ralf
AU - Waibel, Reiner
AU - Einsiedel, Jürgen
AU - Dürr, Maximilian
AU - Ivanović-Burmazović, Ivana
AU - Larsen, Olav
AU - Hjortø, Gertrud Malene
AU - Rosenkilde, Mette Marie
AU - Tschammer, Nuska
PY - 2016
Y1 - 2016
N2 - 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.
AB - 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.
U2 - 10.1021/acs.jmedchem.5b01965
DO - 10.1021/acs.jmedchem.5b01965
M3 - Journal article
C2 - 26862767
AN - SCOPUS:84961172231
VL - 59
SP - 2222
EP - 2243
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 5
ER -