Synthesis and evaluation of the first fluorescent antagonists of the human P2Y2 receptor based on AR-C118925

Conroy, Sean and Kindon, Nicholas and Glenn, Jacqueline and Stoddart, Leigh A. and Lewis, Richard James and Hill, Stephen J. and Kellam, Barrie and Stocks, Michael J. (2018) Synthesis and evaluation of the first fluorescent antagonists of the human P2Y2 receptor based on AR-C118925. Journal of Medicinal Chemistry, 61 (7). pp. 3089-3113. ISSN 1520-4804

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The human P2Y2 receptor (hP2Y2R) is a G protein-coupled receptor that shows promise as a therapeutic target for many important conditions including anti-metastatic cancer therapy and more recently for the treatment of idiopathic pulmonary fibrosis. As such, there is a need for new hP2Y2R antagonists and molecular probes to study this receptor. Herein, we report the development of a new series of non-nucleotide hP2Y2R antagonists leading to the discovery of a series of fluorescent ligands containing different linkers and fluorophores based on the known, non-nucleotide hP2Y2R antagonist AR-C118925 (1). One of these conjugates 98 displayed micromolar affinity for the hP2Y2R (pKd = 6.32 ± 0.10; n=17) using a bioluminescence energy transfer (BRET) assay. Confocal microscopy with this ligand revealed displaceable membrane labeling of astrocytoma cells expressing un-tagged hP2Y2R. These properties, make 98 one of the first tools for studying hP2Y2R distribution and organization.

Item Type: Article
Keywords: P2Y2R, antagonists, fluorescence, BRET, G Protein-Coupled Receptor, GPCR
Schools/Departments: University of Nottingham, UK > Faculty of Medicine and Health Sciences > School of Life Sciences
University of Nottingham, UK > Faculty of Science > School of Pharmacy
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Depositing User: Eprints, Support
Date Deposited: 21 Mar 2018 14:00
Last Modified: 09 Jul 2018 09:30

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