Department of Chemistry, Gonda-Goldschmied Medical Research Center, Bar-Ilan University, Ramat-Gan 52900, Israel.
J Med Chem. 2010 Feb 25;53(4):1673-85. doi: 10.1021/jm901450d.
P2Y nucleotide receptors (P2Y-Rs) play important physiological roles. However, most of the P2Y-R subtypes are still lacking potent and selective agonists and antagonists. Based on data mining analysis of binding interactions in 44 protein-uridine nucleos(t)ides complexes, we designed uracil nucleotides, substituted at the C5/C6 position. All C6-substituted derivatives were inactive at the P2Y(2,4,6)-Rs, while out of the C5-substituted analogues, only 5-OMe-UD(T)P showed activity. To rationalize the data, the ionization and conformation of these analogues were evaluated. The pK(a) values of most analogues substituted at the C5/C6 positions were unaltered compared to UTP (pK(a) 9.42), except for 5-F-UTP nucleotide (pK(a) 7.85). C6-substituted analogues adopt the syn or high-syn conformations, which are disfavored by the receptors, while 5-OMe-UD(T)P adopt the favored anti conformation. Furthermore, 5-OMe-UDP adopts the S sugar puckering, which is the conformation preferred by the P2Y(6)-R, but not the P2Y(2)- or P2Y(4)-Rs. 5-OMe-UDP fulfills the conformational and H-bonding requirements of P2Y(6)-R, thus, making a potent P2Y(6)-R agonist (EC(50) 0.08 microM), more than UDP (EC(50) 0.14 microM).
P2Y 核苷酸受体（P2Y-Rs）发挥着重要的生理作用。然而，大多数 P2Y-R 亚型仍然缺乏有效且选择性的激动剂和拮抗剂。基于对 44 个蛋白-尿苷核苷（t）复合物结合相互作用的数据挖掘分析，我们设计了在 C5/C6 位置取代的尿嘧啶核苷酸。所有 C6 取代衍生物在 P2Y（2、4、6）-Rs 中均无活性，而在 C5 取代的类似物中，只有 5-OMe-UD（T）P 显示出活性。为了合理分析这些数据，评估了这些类似物的离子化和构象。与 UTP（pK(a) 9.42）相比，除了 5-F-UTP 核苷酸（pK(a) 7.85）外，大多数在 C5/C6 位置取代的类似物的 pK(a) 值没有改变。C6 取代的类似物采用 syn 或高 syn 构象，这是受体不喜欢的，而 5-OMe-UD（T）P 采用有利的反式构象。此外，5-OMe-UDP 采用 S 糖构象，这是 P2Y（6）-R 所偏好的构象，但不是 P2Y（2）-或 P2Y（4）-Rs 所偏好的构象。5-OMe-UDP 满足了 P2Y（6）-R 的构象和氢键要求，因此，成为一种有效的 P2Y（6）-R 激动剂（EC（50）0.08 μM），比 UDP（EC（50）0.14 μM）更有效。
