title: Discovery and Characterization of Biased Allosteric Agonists of the Chemokine Receptor CXCR3.
abstract: 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.
authors: Department of Chemistry and Pharmacy, Medicinal Chemistry, Emil Fischer Center, Friedrich Alexander University , Schuhstraße 19, 91052 Erlangen, Germany.
authors: Lampros
authors: L
authors: Milanos
authors: Department of Chemistry and Pharmacy, Medicinal Chemistry, Emil Fischer Center, Friedrich Alexander University , Schuhstraße 19, 91052 Erlangen, Germany.
authors: Regine
authors: R
authors: Brox
authors: Department of Chemistry and Pharmacy, Medicinal Chemistry, Emil Fischer Center, Friedrich Alexander University , Schuhstraße 19, 91052 Erlangen, Germany.
authors: Theresa
authors: T
authors: Frank
authors: Department of Chemistry and Pharmacy, Medicinal Chemistry, Emil Fischer Center, Friedrich Alexander University , Schuhstraße 19, 91052 Erlangen, Germany.|Faculty of Pharmacy, University of Ljubljana , Aškerčeva 7, 1000 Ljubljana, Slovenia.
authors: Gašper
authors: G
authors: Poklukar
authors: Optical Imaging Center Erlangen, Friedrich Alexander University , Hartmannstraße 14, 91052 Erlangen, Germany.
authors: Ralf
authors: R
authors: Palmisano
authors: Department of Chemistry and Pharmacy, Medicinal Chemistry, Emil Fischer Center, Friedrich Alexander University , Schuhstraße 19, 91052 Erlangen, Germany.
authors: Reiner
authors: R
authors: Waibel
authors: Department of Chemistry and Pharmacy, Medicinal Chemistry, Emil Fischer Center, Friedrich Alexander University , Schuhstraße 19, 91052 Erlangen, Germany.
authors: Jürgen
authors: J
authors: Einsiedel
authors: Department of Chemistry and Pharmacy, Bioorganic Chemistry, Friedrich Alexander University , Egerlandstraße 1, 91058 Erlangen, Germany.
authors: Maximilian
authors: M
authors: Dürr
authors: Department of Chemistry and Pharmacy, Bioorganic Chemistry, Friedrich Alexander University , Egerlandstraße 1, 91058 Erlangen, Germany.
authors: Ivana
authors: I
authors: Ivanović-Burmazović
authors: Department of Neuroscience and Pharmacology, Laboratory for Molecular Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen , Blegdamsvej 3B, DK-2200 Copenhagen N, Denmark.
authors: Olav
authors: O
authors: Larsen
authors: Department of Neuroscience and Pharmacology, Laboratory for Molecular Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen , Blegdamsvej 3B, DK-2200 Copenhagen N, Denmark.
authors: Gertrud Malene
authors: GM
authors: Hjortø
authors: Department of Neuroscience and Pharmacology, Laboratory for Molecular Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen , Blegdamsvej 3B, DK-2200 Copenhagen N, Denmark.
authors: Mette Marie
authors: MM
authors: Rosenkilde
authors: Department of Chemistry and Pharmacy, Medicinal Chemistry, Emil Fischer Center, Friedrich Alexander University , Schuhstraße 19, 91052 Erlangen, Germany.
authors: Nuska
authors: N
authors: Tschammer
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects*; D000818:Animals; D019556:COS Cells; D002465:Cell Movement / Q000187:drug effects; D002522:Chlorocebus aethiops; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D015394:Molecular Structure; D054367:Receptors, CXCR3 / Q000819:agonists* / Q000378:metabolism; D013329:Structure-Activity Relationship; D044005:Tetrahydroisoquinolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C515187:CXCR3 protein, human; D008024:Ligands; D054367:Receptors, CXCR3; D044005:Tetrahydroisoquinolines