Chemical Subtleties in
Small-Molecule Modulation of
Peptide Receptor Function: The Case of CXCR3 Biaryl-Type Ligands
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Abstract
The G protein-coupled chemokine receptor CXCR3 plays
a role in
numerous inflammatory events. The endogenous ligands for the chemokine
receptors are peptides, but in this study we disclose small-molecule
ligands that are able to activate CXCR3. A class of biaryl-type compounds
that is assembled by convenient synthetic routes is described as a
new class of CXCR3 agonists. Intriguingly, structure–activity
relationship and structure–function relationship studies reveal
that subtle chemical modifications on the outer aryl ring (e.g., either
the size or position of a halogen atom) result in a full spectrum
of agonist efficacies on CXCR3. Quantum mechanics calculations and
nuclear Overhauser effect spectroscopy NMR studies suggest that the
biaryl dihedral angle and the electronic nature of <i>ortho</i>-substituents play an important role in determining agonist efficacies.
Compounds <b>38</b> (VUF11222) and <b>39</b> (VUF11418)
are the first reported nonpeptidomimetic agonists on CXCR3, rendering
them highly useful chemical tools for detailed assessment of CXCR3
activation as well as for studying downstream CXCR3 signaling