2. Academic Validation
  3. An Agonist Radioligand for the Proinflammatory Lipid-Activated G Protein-Coupled Receptor GPR84 Providing Structural Insights

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

  • J Med Chem. 2020 Mar 12;63(5):2391-2410. doi: 10.1021/acs.jmedchem.9b01339.
Meryem Köse 1,  Thanigaimalai Pillaiyar 1,  Vigneshwaran Namasivayam 1,  Elisabetta De Filippo 1,  Katharina Sylvester 1,  Trond Ulven 2,  Ivar von Kügelgen 3,  Christa E Müller 1
Affiliations

Affiliations

  • 1 PharmaCenter Bonn, Pharmaceutical Institute, Department of Pharmaceutical and Medicinal Chemistry, University of Bonn, An der Immenburg 4, D-53121 Bonn, Germany.
  • 2 Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark.
  • 3 Department of Pharmacology and Toxicology, Pharma Center Bonn, Sigmund-Freud-Str. 25, D-53127 Bonn, Germany.
PMID: 31721581 DOI: 10.1021/acs.jmedchem.9b01339
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.

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