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

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.