Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 16, Issue 12, Pages 6319-6332Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2008.05.013
Keywords
uracil nucleotide; G protein-coupled receptor; phospholipase C; UDP; UTP; dinucleotide; structure-activity relationships
Funding
- Intramural NIH HHS [Z01 DK031116-20] Funding Source: Medline
- NIGMS NIH HHS [R01 GM038213, GM38213] Funding Source: Medline
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The phosphate, uracil, and ribose moieties of uracil nucleotides were varied structurally for evaluation of agonist activity at the human P2Y(2), P2Y(4), and P2Y(6) receptors. The 2-thio modi. cation, found previously to enhance P2Y2 receptor potency, could be combined with other favorable modi. cations to produce novel molecules that exhibit high potencies and receptor selectivities. Phosphonomethylene bridges introduced for stability in analogues of UDP, UTP, and uracil dinucleotides markedly reduced potency. Truncation of dinucleotide agonists of the P2Y(2) receptor, in the form of Up(4)-sugars, indicated that a terminal uracil ring is not essential for moderate potency at this receptor and that specific SAR patterns are observed at this distal end of the molecule. Key compounds reported in this study include 9, alpha, beta-methylene-UDP, a P2Y(6) receptor agonist; 30, Up(4)-phenyl ester and 34, Up(4)-[1] glucose, selective P2Y(2) receptor agonists; dihalomethylene phosphonate analogues 16 and 41, selective P2Y(2) receptor agonists; 43, the 2-thio analogue of INS37217 (P-1-(uridine-5')-P-4-(2'-deoxycytidine-5') tetraphosphate), a potent and selective P2Y(2) receptor agonist. Published by Elsevier Ltd.
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