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

Lampros M, Brox R, Frank T, Poklukar G, Palmisano R, Waibel R, Einsiedel J, Dürr M, Ivanovic-Burmazovic I, Larsen O, Hjorto GM, Rosenkilde MM, Tschammer N (2016)


Publication Status: Published

Publication Type: Journal article

Publication year: 2016

Journal

Book Volume: 59

Pages Range: 2222-43

Journal Issue: 5

DOI: 10.1021/acs.jmedchem.5b01965

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.

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How to cite

APA:

Lampros, M., Brox, R., Frank, T., Poklukar, G., Palmisano, R., Waibel, R.,... Tschammer, N. (2016). Discovery and Characterization of Biased Allosteric Agonists of the Chemokine Receptor CXCR3. Journal of Medicinal Chemistry, 59(5), 2222-43. https://doi.org/10.1021/acs.jmedchem.5b01965

MLA:

Lampros, Milanos, et al. "Discovery and Characterization of Biased Allosteric Agonists of the Chemokine Receptor CXCR3." Journal of Medicinal Chemistry 59.5 (2016): 2222-43.

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