An Agonist Radioligand for the Proinflammatory Lipid-Activated G Protein-Coupled Receptor GPR84 Providing Structural Insights

Research output: Contribution to journal › Journal article › Research › peer-review

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An Agonist Radioligand for the Proinflammatory Lipid-Activated G Protein-Coupled Receptor GPR84 Providing Structural Insights. / Köse, Meryem; Pillaiyar, Thanigaimalai; Namasivayam, Vigneshwaran; De Filippo, Elisabetta; Sylvester, Katharina; Ulven, Trond; Von Kügelgen, Ivar; Müller, Christa E.

In: Journal of Medicinal Chemistry, Vol. 63, No. 5, 12.03.2020, p. 2391-2410.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Köse, M, Pillaiyar, T, Namasivayam, V, De Filippo, E, Sylvester, K, Ulven, T, Von Kügelgen, I & Müller, CE 2020, 'An Agonist Radioligand for the Proinflammatory Lipid-Activated G Protein-Coupled Receptor GPR84 Providing Structural Insights', Journal of Medicinal Chemistry, vol. 63, no. 5, pp. 2391-2410. https://doi.org/10.1021/acs.jmedchem.9b01339

APA

Köse, M., Pillaiyar, T., Namasivayam, V., De Filippo, E., Sylvester, K., Ulven, T., Von Kügelgen, I., & Müller, C. E. (2020). An Agonist Radioligand for the Proinflammatory Lipid-Activated G Protein-Coupled Receptor GPR84 Providing Structural Insights. Journal of Medicinal Chemistry, 63(5), 2391-2410. https://doi.org/10.1021/acs.jmedchem.9b01339

Vancouver

Köse M, Pillaiyar T, Namasivayam V, De Filippo E, Sylvester K, Ulven T et al. An Agonist Radioligand for the Proinflammatory Lipid-Activated G Protein-Coupled Receptor GPR84 Providing Structural Insights. Journal of Medicinal Chemistry. 2020 Mar 12;63(5):2391-2410. https://doi.org/10.1021/acs.jmedchem.9b01339

Author

Köse, Meryem ; Pillaiyar, Thanigaimalai ; Namasivayam, Vigneshwaran ; De Filippo, Elisabetta ; Sylvester, Katharina ; Ulven, Trond ; Von Kügelgen, Ivar ; Müller, Christa E. / An Agonist Radioligand for the Proinflammatory Lipid-Activated G Protein-Coupled Receptor GPR84 Providing Structural Insights. In: Journal of Medicinal Chemistry. 2020 ; Vol. 63, No. 5. pp. 2391-2410.

Bibtex

@article{d4cce64ccc3b4e998279b2ee07cf616f,
title = "An Agonist Radioligand for the Proinflammatory Lipid-Activated G Protein-Coupled Receptor GPR84 Providing Structural Insights",
abstract = "The orphan G protein-coupled receptor (GPCR) GPR84 is expressed on immune cells mediating proinflammatory and immunostimulatory effects. In this study, we prepared the fully efficacious, nonbiased GPR84 agonist 6-hexylamino-2,4(1H,3H)-pyrimidinedione (6) in tritium-labeled form ([3H]PSB-1584) by hydrogenation of a hexenyl-substituted precursor with tritium gas. The radioligand was characterized by kinetic, saturation, and competition assays using membranes of Chinese hamster ovary cells recombinantly expressing the human GPR84. [3H]6 reversibly labeled the receptor with high affinity (KD 2.08 nM). Structurally diverse orthosteric and allosteric ligands, including newly designed and synthesized compounds, were studied in competition binding assays. A homology model of GPR84 was generated to perform docking studies rationalizing the experimental data. The radioligand was additionally used for labeling GPR84 in native cells and tissues. [3H]6 constitutes the first GPR84 agonist radioligand representing a powerful tool for this poorly investigated GPCR, which has potential as a future drug target.",
author = "Meryem K{\"o}se and Thanigaimalai Pillaiyar and Vigneshwaran Namasivayam and {De Filippo}, Elisabetta and Katharina Sylvester and Trond Ulven and {Von K{\"u}gelgen}, Ivar and M{\"u}ller, {Christa E.}",
year = "2020",
month = mar,
day = "12",
doi = "10.1021/acs.jmedchem.9b01339",
language = "English",
volume = "63",
pages = "2391--2410",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "5",

}

RIS

TY - JOUR

T1 - An Agonist Radioligand for the Proinflammatory Lipid-Activated G Protein-Coupled Receptor GPR84 Providing Structural Insights

AU - Köse, Meryem

AU - Pillaiyar, Thanigaimalai

AU - Namasivayam, Vigneshwaran

AU - De Filippo, Elisabetta

AU - Sylvester, Katharina

AU - Ulven, Trond

AU - Von Kügelgen, Ivar

AU - Müller, Christa E.

PY - 2020/3/12

Y1 - 2020/3/12

N2 - The orphan G protein-coupled receptor (GPCR) GPR84 is expressed on immune cells mediating proinflammatory and immunostimulatory effects. In this study, we prepared the fully efficacious, nonbiased GPR84 agonist 6-hexylamino-2,4(1H,3H)-pyrimidinedione (6) in tritium-labeled form ([3H]PSB-1584) by hydrogenation of a hexenyl-substituted precursor with tritium gas. The radioligand was characterized by kinetic, saturation, and competition assays using membranes of Chinese hamster ovary cells recombinantly expressing the human GPR84. [3H]6 reversibly labeled the receptor with high affinity (KD 2.08 nM). Structurally diverse orthosteric and allosteric ligands, including newly designed and synthesized compounds, were studied in competition binding assays. A homology model of GPR84 was generated to perform docking studies rationalizing the experimental data. The radioligand was additionally used for labeling GPR84 in native cells and tissues. [3H]6 constitutes the first GPR84 agonist radioligand representing a powerful tool for this poorly investigated GPCR, which has potential as a future drug target.

AB - The orphan G protein-coupled receptor (GPCR) GPR84 is expressed on immune cells mediating proinflammatory and immunostimulatory effects. In this study, we prepared the fully efficacious, nonbiased GPR84 agonist 6-hexylamino-2,4(1H,3H)-pyrimidinedione (6) in tritium-labeled form ([3H]PSB-1584) by hydrogenation of a hexenyl-substituted precursor with tritium gas. The radioligand was characterized by kinetic, saturation, and competition assays using membranes of Chinese hamster ovary cells recombinantly expressing the human GPR84. [3H]6 reversibly labeled the receptor with high affinity (KD 2.08 nM). Structurally diverse orthosteric and allosteric ligands, including newly designed and synthesized compounds, were studied in competition binding assays. A homology model of GPR84 was generated to perform docking studies rationalizing the experimental data. The radioligand was additionally used for labeling GPR84 in native cells and tissues. [3H]6 constitutes the first GPR84 agonist radioligand representing a powerful tool for this poorly investigated GPCR, which has potential as a future drug target.

U2 - 10.1021/acs.jmedchem.9b01339

DO - 10.1021/acs.jmedchem.9b01339

M3 - Journal article

C2 - 31721581

AN - SCOPUS:85076428431

VL - 63

SP - 2391

EP - 2410

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 5

ER -

ID: 239723865