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[摘要]：The P2Y(6) receptor is a cytoprotective G-protein-coupled receptor (GPCR) activated by UDP (EC50 = 0.30 mu M). 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 alpha,beta-methylene and extension of the terminal phosphate group into gamma-esters of UTP analogues. The conformationally constrained (S)-methanocarba-UDP is a full agonist (EC50 = 0.042 mu M). 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-Cp3U Cp3U (12, MRS2957) were potent, selective P2Y(6) receptor agonists (EC50 of 0.026 and 0.012 mu M, respectively). A hydrophobic binding region near the nucleobase was explored with receptor modeling and docking. UTP-gamma-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-methoxycytidine 5'-triphospho-gamma-[1]glucose were active (EC50 of 2.47 and 0.18 mu M, respectively). Thus, the potency, selectivity, and stability of pyrimidine nucleotides as P2Y(6) receptor agonists may be enhanced by modest structural changes. |
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