title: Development of Potent and Selective Antagonists for the UTP-Activated P2Y4Receptor.
abstract: P2Y4is a Gqprotein-coupled receptor activated by uridine-5'-triphosphate (UTP), which is widely expressed in the body, e.g., in intestine, heart, and brain. No selective P2Y4receptor antagonist has been described so far. Therefore, we developed and optimized P2Y4receptor 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 P2Y4receptor. 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 IC50value 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-dioxo-9,10-dihydroanthracene-2-sulfonate) represents the most selective P2Y4receptor antagonist known to date. Compounds 61 and 64 are therefore anticipated to become useful tools for studying this scarcely investigated receptor.
authors.affiliation: PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, Pharmaceutical Sciences Bonn (PSB), University of Bonn , An der Immenburg 4, D-53121 Bonn, Germany.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Rafehi
authors.affiliation: PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, Pharmaceutical Sciences Bonn (PSB), University of Bonn , An der Immenburg 4, D-53121 Bonn, Germany.
authors.forename: Enas M
authors.identifier: 0000-0003-4563-3584
authors.initials: EM
authors.lastname: Malik
authors.affiliation: PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, Pharmaceutical Sciences Bonn (PSB), University of Bonn , An der Immenburg 4, D-53121 Bonn, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Neumann
authors.affiliation: PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, Pharmaceutical Sciences Bonn (PSB), University of Bonn , An der Immenburg 4, D-53121 Bonn, Germany.
authors.forename: Aliaa
authors.initials: A
authors.lastname: Abdelrahman
authors.affiliation: PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, Pharmaceutical Sciences Bonn (PSB), University of Bonn , An der Immenburg 4, D-53121 Bonn, Germany.
authors.forename: Theodor
authors.initials: T
authors.lastname: Hanck
authors.affiliation: PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, Pharmaceutical Sciences Bonn (PSB), University of Bonn , An der Immenburg 4, D-53121 Bonn, Germany.
authors.forename: Vigneshwaran
authors.initials: V
authors.lastname: Namasivayam
authors.affiliation: PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, Pharmaceutical Sciences Bonn (PSB), University of Bonn , An der Immenburg 4, D-53121 Bonn, Germany.
authors.forename: Christa E
authors.identifier: 0000-0002-0013-6624
authors.initials: CE
authors.lastname: Müller
authors.affiliation: Department of Chemistry, Faculty of Science, Sultan Qaboos University , PO Box 36, Postal Code 123, Muscat, Oman.
authors.forename: Younis
authors.identifier: 0000-0002-9659-8419
authors.initials: Y
authors.lastname: Baqi
mesh_terms: D000880:Anthraquinones / Q000737:chemistry* / Q000494:pharmacology*; D055808:Drug Discovery; D006801:Humans; D062105:Molecular Docking Simulation; D058919:Purinergic P2 Receptor Antagonists / Q000737:chemistry* / Q000494:pharmacology*; D018048:Receptors, Purinergic P2 / Q000737:chemistry / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014544:Uridine Triphosphate / Q000378:metabolism*
chemical_list: D000880:Anthraquinones; D058919:Purinergic P2 Receptor Antagonists; D018048:Receptors, Purinergic P2; C104749:purinoceptor P2Y4; D014544:Uridine Triphosphate