| Abstract
| - The structure−activity relationships and molecular modeling of the uracil nucleotide activated P2Y6 receptorhave been studied. Uridine 5‘-diphosphate (UDP) analogues bearing substitutions of the ribose moiety, theuracil 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‘-diphosphateanalogues, as well as at positions 2, 3, and 5. The effect of modifications at the level of the phosphate chainwas studied by preparing a cyclic 3‘,5‘-diphosphate analogue, a 3‘-diphosphate analogue, and severaldinucleotide diphosphates. 5-Iodo-UDP 32 (EC50 = 0.15 μM) was equipotent to UDP, while substitutionsof 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 β-phosphate of 5‘-UDP and analogues is essential for the establishmentof electrostatic interactions with two of the three conserved cationic residues of the receptor. Among4-thioether derivatives, a 4-ethylthio analogue 23 displayed an EC50 of 0.28 μM, indicative of favorableinteractions predicted for a small 4-alkylthio moiety with the aromatic ring of Y33 in TM1. The activity ofanalogue 19 in which the ribose was substituted with a 2-oxabicyclohexane ring in a rigid (S)-conformation(P = 126°, 1‘-exo) was consistent with molecular modeling. These results provide a better understanding ofmolecular recognition at the P2Y6 receptor and will be helpful in designing selective and potent P2Y6 receptorligands.
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