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

Lampros Milanos; Regine Brox; Theresa Frank; Gašper Poklukar; Ralf Palmisano; Reiner Waibel; Jürgen Einsiedel; Maximilian Dürr; Ivana Ivanović-Burmazović; Olav Larsen; Gertrud Malene Hjortø; Mette Marie Rosenkilde; Nuska Tschammer

doi:10.1021/acs.jmedchem.5b01965

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

Lampros Milanos, Regine Brox, Theresa Frank, Gašper Poklukar, Ralf Palmisano, Reiner Waibel, Jürgen Einsiedel, Maximilian Dürr, Ivana Ivanović-Burmazović, Olav Larsen, Gertrud Malene Hjortø, Mette Marie Rosenkilde, Nuska Tschammer^*

^*Corresponding author for this work

Department of Neuroscience

14 Citations (Scopus)

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.

Original language	English
Journal	Journal of Medicinal Chemistry
Volume	59
Issue number	5
Pages (from-to)	2222-2243
Number of pages	22
ISSN	0022-2623
DOIs	https://doi.org/10.1021/acs.jmedchem.5b01965
Publication status	Published - 2016

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Milanos, L., Brox, R., Frank, T., Poklukar, G., Palmisano, R., Waibel, R., Einsiedel, J., Dürr, M., Ivanović-Burmazović, I., Larsen, O., Hjortø, G. M., Rosenkilde, M. M., & Tschammer, N. (2016). Discovery and Characterization of Biased Allosteric Agonists of the Chemokine Receptor CXCR3. Journal of Medicinal Chemistry, 59(5), 2222-2243. https://doi.org/10.1021/acs.jmedchem.5b01965

Milanos, L, Brox, R, Frank, T, Poklukar, G, Palmisano, R, Waibel, R, Einsiedel, J, Dürr, M, Ivanović-Burmazović, I, Larsen, O , Hjortø, GM, Rosenkilde, MM & Tschammer, N 2016, 'Discovery and Characterization of Biased Allosteric Agonists of the Chemokine Receptor CXCR3', Journal of Medicinal Chemistry, vol. 59, no. 5, pp. 2222-2243. https://doi.org/10.1021/acs.jmedchem.5b01965

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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.",

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doi = "10.1021/acs.jmedchem.5b01965",

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T1 - Discovery and Characterization of Biased Allosteric Agonists of the Chemokine Receptor CXCR3

AU - Milanos, Lampros

AU - Brox, Regine

AU - Frank, Theresa

AU - Poklukar, Gašper

AU - Palmisano, Ralf

AU - Waibel, Reiner

AU - Einsiedel, Jürgen

AU - Dürr, Maximilian

AU - Ivanović-Burmazović, Ivana

AU - Larsen, Olav

AU - Hjortø, Gertrud Malene

AU - Rosenkilde, Mette Marie

AU - Tschammer, Nuska

PY - 2016

Y1 - 2016

N2 - 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.

AB - 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.

U2 - 10.1021/acs.jmedchem.5b01965

DO - 10.1021/acs.jmedchem.5b01965

M3 - Journal article

C2 - 26862767

AN - SCOPUS:84961172231

SN - 0022-2623

VL - 59

SP - 2222

EP - 2243

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 5

ER -

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

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