Development of Potent and Selective Antagonists for the UTP-Activated P2Y4 Receptor
| Autor: | Younis Baqi, Aliaa Abdelrahman, Vigneshwaran Namasivayam, Muhammad Rafehi, Christa E. Müller, Alexander Neumann, Theodor Hanck, Enas M. Malik |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
P2Y receptor Chemistry Allosteric regulation Antagonist Pharmacology 03 medical and health sciences 030104 developmental biology Biochemistry Docking (molecular) Drug Discovery Enzyme-linked receptor Molecular Medicine Receptor Glucagon-like peptide 1 receptor Protease-activated receptor 2 |
| Zdroj: | Journal of Medicinal Chemistry. 60:3020-3038 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/acs.jmedchem.7b00030 |
| Popis: | P2Y4 is a Gq protein-coupled receptor activated by uridine-5′-triphosphate (UTP), which is widely expressed in the body, e.g., in intestine, heart, and brain. No selective P2Y4 receptor antagonist has been described so far. Therefore, we developed and optimized P2Y4 receptor antagonists based on an anthraquinone scaffold. Potency was assessed by a fluorescence-based assay measuring inhibition of UTP-induced intracellular calcium release in 1321N1 astrocytoma cells stably transfected with the human P2Y4 receptor. The most potent compound of the present series, sodium 1-amino-4-[4-(2,4-dimethylphenylthio)phenylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate (PSB-16133, 61) exhibited an IC50 value of 233 nM, selectivity versus other P2Y receptor subtypes, and is thought to act as an allosteric antagonist. A receptor homology model was built and docking studies were performed to analyze ligand–receptor interactions. Compound 64 (PSB-1699, sodium 1-amino-4-[4-(3-pyridin-3-ylmethylthio)phenylamino]-9,10-di... |
| Databáze: | OpenAIRE |
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