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Synthesis and Evaluation of the First Fluorescent Antagonists of the Human P2Y 2 Receptor Based on AR-C118925.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2018 Apr 12; Vol. 61 (7), pp. 3089-3113. Date of Electronic Publication: 2018 Mar 28. - Publication Year :
- 2018
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Abstract
- The human P2Y <subscript>2</subscript> receptor ( hP2Y <subscript>2</subscript> R) is a G-protein-coupled receptor that shows promise as a therapeutic target for many important conditions, including for antimetastatic cancer and more recently for idiopathic pulmonary fibrosis. As such, there is a need for new hP2Y <subscript>2</subscript> R antagonists and molecular probes to study this receptor. Herein, we report the development of a new series of non-nucleotide hP2Y <subscript>2</subscript> R antagonists, based on the known, non-nucleotide hP2Y <subscript>2</subscript> R antagonist AR-C118925 (1), leading to the discovery of a series of fluorescent ligands containing different linkers and fluorophores. One of these conjugates, 98, displayed micromolar affinity for hP2Y <subscript>2</subscript> R (p K <subscript>d</subscript> = 6.32 ± 0.10, n = 17) in a bioluminescence-energy-transfer (BRET) assay. Confocal microscopy with this ligand revealed displaceable membrane labeling of astrocytoma cells expressing untagged hP2Y <subscript>2</subscript> R. These properties make 98 one of the first tools for studying hP2Y <subscript>2</subscript> R distribution and organization.
- Subjects :
- Astrocytoma metabolism
Cell Line
Dibenzocycloheptenes chemistry
Humans
Ligands
Microscopy, Confocal
Molecular Probes
Protein Binding
Pyrimidinones chemistry
Recombinant Proteins chemistry
Structure-Activity Relationship
Dibenzocycloheptenes pharmacology
Fluorescent Dyes chemical synthesis
Fluorescent Dyes pharmacology
Purinergic P2 Receptor Antagonists chemical synthesis
Purinergic P2 Receptor Antagonists pharmacology
Pyrimidinones pharmacology
Receptors, Purinergic P2Y2 drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 61
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 29558126
- Full Text :
- https://doi.org/10.1021/acs.jmedchem.8b00139