title: Synthesis and structure-activity relationship of uracil nucleotide derivatives towards the identification of human P2Y6 receptor antagonists.
abstract: P2Y6 receptor (P2Y6-R) is involved in various physiological and pathophysiological events. With a view to set rules for the design of UDP-based reversible P2Y6-R antagonists as potential drugs, we established structure-activity relationship of UDP analogues, bearing modifications at the uracil ring, ribose moiety, and the phosphate chain. For instance, C5-phenyl- or 3-NMe-uridine-5'-α,β-methylene-diphosphonate, 16 and 23, or lack of 2'-OH, in 12-15, resulted in loss of both agonist and antagonist activity toward hP2Y6-R. However, uridylyl phosphosulfate, 19, selectively inhibited hP2Y6-R (IC50 112 μM) versus P2Y2/4-Rs. In summary, we have established a comprehensive SAR for hP2Y6-R ligands towards the development of hP2Y6-R antagonists.
authors.affiliation: Department of Chemistry, Bar Ilan University, Ramat Gan 52900, Israel.
authors.forename: Diana
authors.initials: D
authors.lastname: Meltzer
authors.affiliation: Department of Chemistry, Bar Ilan University, Ramat Gan 52900, Israel.
authors.forename: Ophir
authors.initials: O
authors.lastname: Ethan
authors.affiliation: Department of Anatomy and Cellular Biology, Université de Sherbrooke, rue Jean-Mignault, Sherbrooke 3201, QC, Canada.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Arguin
authors.affiliation: Department of Chemistry, Bar Ilan University, Ramat Gan 52900, Israel.
authors.forename: Yael
authors.initials: Y
authors.lastname: Nadel
authors.affiliation: Department of Chemistry, Bar Ilan University, Ramat Gan 52900, Israel.
authors.forename: Ortal
authors.initials: O
authors.lastname: Danino
authors.affiliation: Centre de Recherche en Rhumatologie et Immunologie, Université Laval, Québec, QC, Canada.
authors.forename: Joanna
authors.initials: J
authors.lastname: Lecka
authors.affiliation: Centre de Recherche en Rhumatologie et Immunologie, Université Laval, Québec, QC, Canada.
authors.forename: Jean
authors.initials: J
authors.lastname: Sévigny
authors.affiliation: Department of Anatomy and Cellular Biology, Université de Sherbrooke, rue Jean-Mignault, Sherbrooke 3201, QC, Canada.
authors.forename: Fernand-Pierre
authors.initials: FP
authors.lastname: Gendron
authors.affiliation: Department of Chemistry, Bar Ilan University, Ramat Gan 52900, Israel. Electronic address: bilha.fischer@biu.ac.il.
authors.forename: Bilha
authors.initials: B
authors.lastname: Fischer
mesh_terms: D006801:Humans; D015394:Molecular Structure; D018048:Receptors, Purinergic P2 / Q000737:chemistry*; D013329:Structure-Activity Relationship; D014500:Uracil Nucleotides / Q000138:chemical synthesis* / Q000737:chemistry
chemical_list: D018048:Receptors, Purinergic P2; D014500:Uracil Nucleotides; C099845:purinoceptor P2Y6
keywords: Antagonist; Human P2Y(6) receptor; Structure–activity relationship (SAR); UDP