title: Structure-activity relationship of uridine 5'-diphosphoglucose analogues as agonists of the human P2Y14 receptor.
abstract: UDP-glucose (UDPG) and derivatives are naturally occurring agonists of the Gi protein-coupled P2Y14 receptor, which occurs in the immune system. We synthesized and characterized pharmacologically novel analogues of UDPG modified on the nucleobase, ribose, and glucose moieties, as the basis for designing novel ligands in conjunction with modeling. The recombinant human P2Y14 receptor expressed in COS-7 cells was coupled to phospholipase C through an engineered Galpha-q/i protein. Most modifications of the uracil or ribose moieties abolished activity; this is among the least permissive P2Y receptors. However, a 2-thiouracil modification in 15 (EC50 49 +/- 2 nM) enhanced the potency of UDPG (but not UDP-glucuronic acid) by 7-fold. 4-Thio analogue 13 was equipotent to UDPG, but S-alkylation was detrimental. Compound 15 was docked in a rhodposin-based receptor homology model, which correctly predicted potent agonism of UDP-fructose, UDP-mannose, and UDP-inositol. The hexose moiety of UDPG interacts with multiple H-bonding and charged residues and provides a fertile region for agonist modification.
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: Hyojin
authors.initials: H
authors.lastname: Ko
authors.forename: Ingrid
authors.initials: I
authors.lastname: Fricks
authors.forename: Andrei A
authors.initials: AA
authors.lastname: Ivanov
authors.forename: T Kendall
authors.initials: TK
authors.lastname: Harden
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Jacobson
mesh_terms: D000818:Animals; D001665:Binding Sites; D019556:COS Cells; D002522:Chlorocebus aethiops; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D058910:Purinergic P2 Receptor Agonists; D018048:Receptors, Purinergic P2; D011994:Recombinant Proteins / Q000819:agonists; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014532:Uridine Diphosphate Glucose / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: C518528:P2Y14 receptor, human; D058910:Purinergic P2 Receptor Agonists; D018048:Receptors, Purinergic P2; D011994:Recombinant Proteins; D014532:Uridine Diphosphate Glucose