title: Human P2Y(14) receptor agonists: truncation of the hexose moiety of uridine-5'-diphosphoglucose and its replacement with alkyl and aryl groups.
abstract: Uridine-5'-diphosphoglucose (UDPG) activates the P2Y(14) receptor, a neuroimmune system GPCR. P2Y(14) receptor tolerates glucose substitution with small alkyl or aryl groups or its truncation to uridine 5'-diphosphate (UDP), a full agonist at the human P2Y(14) receptor expressed in HEK-293 cells. 2-Thiouracil derivatives displayed selectivity for activation of the human P2Y(14) vs the P2Y(6) receptor, such as 2-thio-UDP 4 (EC(50) = 1.92 nM at P2Y(14), 224-fold selectivity vs P2Y(6)) and its beta-propyloxy ester 18. EC(50) values of the beta-methyl ester of UDP and its 2-thio analogue were 2730 and 56 nM, respectively. beta-tert-Butyl ester of 4 was 11-fold more potent than UDPG, but beta-aryloxy or larger, branched beta-alkyl esters, such as cyclohexyl, were less potent. Ribose replacement of UDP with a rigid North or South methanocarba (bicyclo[3.1.0]hexane) group abolished P2Y(14) receptor agonist activity. alpha,beta-Methylene and difluoromethylene groups were well tolerated at the P2Y(14) receptor and are expected to provide enhanced stability in biological systems. alpha,beta-Methylene-2-thio-UDP 11 (EC(50) = 0.92 nM) was 2160-fold selective versus P2Y(6). Thus, these nucleotides and their congeners may serve as important pharmacological probes for the detection and characterization of the P2Y(14) receptor.
authors.affiliation: Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Arijit
authors.initials: A
authors.lastname: Das
authors.forename: Hyojin
authors.initials: H
authors.lastname: Ko
authors.forename: Lauren E
authors.initials: LE
authors.lastname: Burianek
authors.forename: Matthew O
authors.initials: MO
authors.lastname: Barrett
authors.forename: T Kendall
authors.initials: TK
authors.lastname: Harden
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Jacobson
mesh_terms: D000478:Alkylation; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006601:Hexoses / Q000737:chemistry*; D006801:Humans; D008968:Molecular Conformation; D058910:Purinergic P2 Receptor Agonists; D018048:Receptors, Purinergic P2 / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014532:Uridine Diphosphate Glucose / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D006601:Hexoses; C518528:P2Y14 receptor, human; D058910:Purinergic P2 Receptor Agonists; D018048:Receptors, Purinergic P2; D014532:Uridine Diphosphate Glucose