1241964-28-2Relevant academic research and scientific papers
Pyrimidine ribonucleotides with enhanced selectivity as P2Y6 receptor agonists: Novel 4-alkyloxyimino, (S)-methanocarba, and 5′-triphosphate γ-ester modifications
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.
experimental part, p. 4488 - 4501 (2010/10/21)
The P2Y6 receptor is a cytoprotective G-protein-coupled receptor (GPCR) activated by UDP (EC50 = 0.30 μM). We compared and combined modifications to enhance P2Y6 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 P2Y6, preserved P2Y2 and P2Y4, and abolished P2Y14 receptor potency, in the appropriate nucleotide. N 4-Benzyloxy-CDP (15, MRS2964) and N4-methoxy-Cp 3U (23, MRS2957) were potent, selective P2Y6 receptor agonists (EC50 of 0.026 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 P2Y6 receptor potency but had enhanced stability in acid and cell membranes. UTP-glucose was inactive, but its (S)-methanocarba analogue and N4-methoxycytidine 5′-triphospho-γ-[1]glucose were active (EC50 of 2.47 and 0.18 μM, respectively). Thus, the potency, selectivity, and stability of pyrimidine nucleotides as P2Y6 receptor agonists may be enhanced by modest structural changes.
