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

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Standard

Discovery and Characterization of Biased Allosteric Agonists of the Chemokine Receptor CXCR3. / Milanos, Lampros; Brox, Regine; Frank, Theresa; Poklukar, Gašper; Palmisano, Ralf; Waibel, Reiner; Einsiedel, Jürgen; Dürr, Maximilian; Ivanović-Burmazović, Ivana; Larsen, Olav; Hjortø, Gertrud Malene; Rosenkilde, Mette Marie; Tschammer, Nuska.

I: Journal of Medicinal Chemistry, Bind 59, Nr. 5, 2016, s. 2222-2243.

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt

Harvard

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, bind 59, nr. 5, s. 2222-2243. https://doi.org/10.1021/acs.jmedchem.5b01965

APA

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

Vancouver

Milanos L, Brox R, Frank T, Poklukar G, Palmisano R, Waibel R o.a. Discovery and Characterization of Biased Allosteric Agonists of the Chemokine Receptor CXCR3. Journal of Medicinal Chemistry. 2016;59(5):2222-2243. https://doi.org/10.1021/acs.jmedchem.5b01965

Author

Milanos, Lampros ; Brox, Regine ; Frank, Theresa ; Poklukar, Gašper ; Palmisano, Ralf ; Waibel, Reiner ; Einsiedel, Jürgen ; Dürr, Maximilian ; Ivanović-Burmazović, Ivana ; Larsen, Olav ; Hjortø, Gertrud Malene ; Rosenkilde, Mette Marie ; Tschammer, Nuska. / Discovery and Characterization of Biased Allosteric Agonists of the Chemokine Receptor CXCR3. I: Journal of Medicinal Chemistry. 2016 ; Bind 59, Nr. 5. s. 2222-2243.

Bibtex

@article{ddd5e0e7ef574ba98c6555cd7da7cee8,
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.",
author = "Lampros Milanos and Regine Brox and Theresa Frank and Ga{\v s}per Poklukar and Ralf Palmisano and Reiner Waibel and J{\"u}rgen Einsiedel and Maximilian D{\"u}rr and Ivana Ivanovi{\'c}-Burmazovi{\'c} and Olav Larsen and Hjort{\o}, {Gertrud Malene} and Rosenkilde, {Mette Marie} and Nuska Tschammer",
year = "2016",
doi = "10.1021/acs.jmedchem.5b01965",
language = "English",
volume = "59",
pages = "2222--2243",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "5",

}

RIS

TY - JOUR

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

VL - 59

SP - 2222

EP - 2243

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 5

ER -

ID: 179316032