Pyrimidine Ribonucleotides with Enhanced Selectivity as P2Y6 Receptor Agonists: Novel 4-Alkyloxyimino, (S)-Methanocarba, and 5′-Triphosphate γ-Ester Modificationsa

The P2Y 6 receptor is a cytoprotective G protein-coupled receptor (GPCR) activated by UDP (EC 50 , 0.30 μM). We compared and combined modifications to enhance P2Y 6 receptor agonist selectivity, including ribose ring constraint, 5-iodo and 4-alkyloxyimino modifications, and phosphate modifications s...

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Published inJournal of medicinal chemistry Vol. 53; no. 11; pp. 4488 - 4501
Main Authors Maruoka, Hiroshi, Barrett, Matthew O., Ko, Hyojin, Tosh, Dilip K., Melman, Artem, Burianek, Lauren E., Balasubramanian, Ramachandran, Berk, Barkin, Costanzi, Stefano, Harden, T. Kendall, Jacobson, Kenneth A.
Format Journal Article
LanguageEnglish
Published 10.06.2010
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Summary:The P2Y 6 receptor is a cytoprotective G protein-coupled receptor (GPCR) activated by UDP (EC 50 , 0.30 μM). We compared and combined modifications to enhance P2Y 6 receptor agonist selectivity, including ribose ring constraint, 5-iodo and 4-alkyloxyimino modifications, and phosphate modifications such as α,β-methylene and extension of the terminal phosphate group into γ-esters of UTP analogues. The conformationally constrained (S)-methanocarba UDP is a full agonist (EC 50 0.042 μM). 4-Methoxyimino modification of pyrimidine enhanced P2Y 6 , preserved P2Y 2 and P2Y 4 , and abolished P2Y 14 receptor potency, in the appropriate nucleotide. N 4 -Benzyloxy-CDP ( 15 , MRS2964) and N 4 -methoxy-Cp 3 U ( 23 , MRS2957) were potent, selective P2Y 6 receptor agonists (EC 50 0.026 μM and 0.012 μM, respectively). A hydrophobic binding region near the nucleobase was explored with receptor modeling and docking. UTP-γ-aryl and cycloalkyl phosphoesters displayed only intermediate P2Y 6 receptor potency, but had enhanced stability in acid and cell membranes. UTP-glucose was inactive, but its (S)-methanocarba analogue and N 4 -methoxy-cytidine 5′-triphospho-γ-[1]glucose were active (EC 50 of 2.47 μM and 0.18 μM, respectively). Thus, the potency, selectivity, and stability of pyrimidine nucleotides as P2Y 6 receptor agonists may be enhanced by modest structural changes.
Bibliography:present address: Clarkson Univ., Potsdam, NY.
Permanent address: Yeditepe University, Istanbul, Turkey.
present address: Gwangju Institute of Science and Technology 216 Cheomdan-gwagiro, Buk-gu, Gwangju 500-712, Republic of Korea.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm100287t