title: Chemical subtleties in small-molecule modulation of peptide receptor function: the case of CXCR3 biaryl-type ligands.
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 ortho-substituents play an important role in determining agonist efficacies. Compounds 38 (VUF11222) and 39 (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.
authors.affiliation: Leiden/Amsterdam Center for Drug Research, Division of Medicinal Chemistry, Faculty of Sciences, VU University Amsterdam, The Netherlands.
authors.forename: Maikel
authors.initials: M
authors.lastname: Wijtmans
authors.forename: Danny J
authors.initials: DJ
authors.lastname: Scholten
authors.forename: Luc
authors.initials: L
authors.lastname: Roumen
authors.forename: Meritxell
authors.initials: M
authors.lastname: Canals
authors.forename: Hans
authors.initials: H
authors.lastname: Custers
authors.forename: Marjolein
authors.initials: M
authors.lastname: Glas
authors.forename: Marlies C A
authors.initials: MC
authors.lastname: Vreeker
authors.forename: Frans J J
authors.initials: FJ
authors.lastname: de Kanter
authors.forename: Chris
authors.initials: C
authors.lastname: de Graaf
authors.forename: Martine J
authors.initials: MJ
authors.lastname: Smit
authors.forename: Iwan J P
authors.initials: IJ
authors.lastname: de Esch
authors.forename: Rob
authors.initials: R
authors.lastname: Leurs
mesh_terms: D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D054367:Receptors, CXCR3 / Q000737:chemistry*; D018000:Receptors, Peptide / Q000187:drug effects*; D054852:Small Molecule Libraries; D013329:Structure-Activity Relationship
chemical_list: C515187:CXCR3 protein, human; D008024:Ligands; D054367:Receptors, CXCR3; D018000:Receptors, Peptide; D054852:Small Molecule Libraries