Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 59, Issue 5, Pages 2222-2243Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.5b01965
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Funding
- Graduate Training School of German Research Foundation (DFG) [GRK1910]
- Friedrich-Alexander University of Erlangen-Nurnberg (Emerging Field Initiative: Medicinal Redox Inorganic Chemistry)
- Novo Nordisk Fonden [NNF12OC0001900] Funding Source: researchfish
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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 beta-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 beta-arrestin 2 recruitment. Concomitant structure activity relationship studies indicated very steep structure activity relationships, which steer the ligand bias between the beta-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.
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