title: Structure-activity relationships of uridine 5'-diphosphate analogues at the human P2Y6 receptor.
abstract: The structure-activity relationships and molecular modeling of the uracil nucleotide activated P2Y6 receptor have been studied. Uridine 5'-diphosphate (UDP) analogues bearing substitutions of the ribose moiety, the uracil ring, and the diphosphate group were synthesized and assayed for activity at the human P2Y6 receptor. The uracil ring was modified at the 4 position, with the synthesis of 4-substituted-thiouridine 5'-diphosphate analogues, as well as at positions 2, 3, and 5. The effect of modifications at the level of the phosphate chain was studied by preparing a cyclic 3',5'-diphosphate analogue, a 3'-diphosphate analogue, and several dinucleotide diphosphates. 5-Iodo-UDP 32 (EC50 = 0.15 microM) was equipotent to UDP, while substitutions of the 2'-hydroxyl (amino, azido) greatly reduce potency. The 2- and 4-thio analogues, 20 and 21, respectively, were also relatively potent in comparison to UDP. However, most other modifications greatly reduced potency. Molecular modeling indicates that the beta-phosphate of 5'-UDP and analogues is essential for the establishment of electrostatic interactions with two of the three conserved cationic residues of the receptor. Among 4-thioether derivatives, a 4-ethylthio analogue 23 displayed an EC50 of 0.28 microM, indicative of favorable interactions predicted for a small 4-alkylthio moiety with the aromatic ring of Y33 in TM1. The activity of analogue 19 in which the ribose was substituted with a 2-oxabicyclohexane ring in a rigid (S)-conformation (P = 126 degrees , 1'-exo) was consistent with molecular modeling. These results provide a better understanding of molecular recognition at the P2Y6 receptor and will be helpful in designing selective and potent P2Y6 receptor ligands.
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: Pedro
authors.initials: P
authors.lastname: Besada
authors.forename: Dae Hong
authors.initials: DH
authors.lastname: Shin
authors.forename: Stefano
authors.initials: S
authors.lastname: Costanzi
authors.forename: Hyojin
authors.initials: H
authors.lastname: Ko
authors.forename: Christophe
authors.initials: C
authors.lastname: Mathé
authors.forename: Julien
authors.initials: J
authors.lastname: Gagneron
authors.forename: Gilles
authors.initials: G
authors.lastname: Gosselin
authors.forename: Savitri
authors.initials: S
authors.lastname: Maddileti
authors.forename: T Kendall
authors.initials: TK
authors.lastname: Harden
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Jacobson
mesh_terms: D045744:Cell Line, Tumor; D006801:Humans; D008958:Models, Molecular; D058910:Purinergic P2 Receptor Agonists; D018048:Receptors, Purinergic P2 / Q000187:drug effects*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014530:Uridine Diphosphate / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D058910:Purinergic P2 Receptor Agonists; D018048:Receptors, Purinergic P2; C099845:purinoceptor P2Y6; D014530:Uridine Diphosphate