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首页> 外文期刊>Journal of Medicinal Chemistry >Methanocarba modification of uracil and adenine nucleotides: high potency of Northern ring conformation at P2Y1, P2Y2, P2Y4, and P2Y11 but not P2Y6 receptors.
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Methanocarba modification of uracil and adenine nucleotides: high potency of Northern ring conformation at P2Y1, P2Y2, P2Y4, and P2Y11 but not P2Y6 receptors.

机译：尿嘧啶和腺嘌呤核苷酸的甲氨基甲酸酯修饰：在P2Y1，P2Y2，P2Y4和P2Y11而不是P2Y6受体上的Northern环构象具有很高的效力。

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The potency of nucleotide antagonists at P2Y1 receptors was enhanced by replacing the ribose moiety with a constrained carbocyclic ring (Nandanan, et al. J. Med. Chem. 2000, 43, 829-842). We have now synthesized ring-constrained methanocarba analogues (in which a fused cyclopropane moiety constrains the pseudosugar ring) of adenine and uracil nucleotides, the endogenous activators of P2Y receptors. Methanocarba-adenosine 5'-triphosphate (ATP) was fixed in either a Northern (N) or a Southern (S) conformation, as defined in the pseudorotational cycle. (N)-Methanocarba-uridine was prepared from the 1-amino-pseudosugar ring by treatment with beta-ethoxyacryloyl cyanate and cyclization to form the uracil ring. Phosphorylation was carried out at the 5'-hydroxyl group through a multistep process: Reaction with phosphoramidite followed by oxidation provided the 5'-monophosphates, which then were treated with 1,1'-carbonyldiimidazole for condensation with additional phosphate groups. The ability of the analogues to stimulate phospholipase C through activation of turkey P2Y1 or human P2Y1, P2Y2, P2Y4, P2Y6, and P2Y11 receptors stably expressed in astrocytoma cells was measured. At recombinant human P2Y1 and P2Y2 receptors, (N)-methanocarba-ATP was 138- and 41-fold, respectively, more potent than racemic (S)-methanocarba-ATP as an agonist. (N)-methanocarba-ATP activated P2Y11 receptors with a potency similar to ATP. (N)-Methanocarba-uridine 5'-triphosphate (UTP) was equipotent to UTP as an agonist at human P2Y2 receptors and also activated P2Y4 receptors with an EC(50) of 85 nM. (N)-Methanocarba-uridine 5'-diphosphate (UDP) was inactive at the hP2Y6 receptor. The vascular effects of (N)-methanocarba-UTP and (N)-methanocarba-UDP were studied in a model of the rat mesenteric artery. The triphosphate was more potent than UTP in inducing a dilatory P2Y4 response (pEC(50) = 6.1 +/- 0.2), while the diphosphate was inactive as either an agonist or antagonist in a P2Y6 receptor-mediated contractile response. Our results suggest that new nucleotide agonists may be designed on the basis of the (N) conformation that favors selectivity for P2Y1, P2Y2, P2Y4, and P2Y11 receptors.
机译：通过用受约束的碳环取代核糖部分来增强核苷酸拮抗剂在P2Y1受体上的效力（Nandanan，et al.J.Med.Chem.2000，43，829-842）。现在，我们合成了腺嘌呤和尿嘧啶核苷酸（P2Y受体的内源性激活剂）的环受限的甲氨基甲酸酯类似物（其中稠合的环丙烷部分约束了假糖环）。甲氨基甲腺苷5'-三磷酸（ATP）固定在Northern（N）或Southern（S）构象中，如假旋转循环中所定义。通过用β-乙氧基丙烯酰基氰酸酯处理并环化以形成尿嘧啶环，由1-氨基-伪糖环制备（N）-甲氨基脲。通过多步过程在5'-羟基上进行磷酸化：与亚磷酰胺反应，然后氧化，得到5'-单磷酸酯，然后将其用1,1'-羰基二咪唑处理以与其他磷酸酯基缩合。测量了类似物通过激活在星形细胞瘤细胞中稳定表达的火鸡P2Y1或人类P2Y1，P2Y2，P2Y4，P2Y6和P2Y11受体刺激磷脂酶C的能力。在重组人P2Y1和P2Y2受体上，（N）-甲氨基甲酰-ATP分别是外消旋（S）-甲氨基甲酰-ATP的138倍和41倍。 （N）-甲氨基甲酸-ATP激活的P2Y11受体，其活性类似于ATP。 （N）-Methanocarba-uridine 5'-triphosphate（UTP）与UTP等价地作为人类P2Y2受体的激动剂，并以85 nM的EC（50）激活P2Y4受体。 （N）-Methanocarba-uridine 5'-diphosphate（UDP）在hP2Y6受体上没有活性。在大鼠肠系膜动脉模型中研究了（N）-美甲脲-UTP和（N）-美甲脲-UDP的血管作用。在诱导扩张性P2Y4反应（pEC（50）= 6.1 +/- 0.2）方面，三磷酸盐比UTP更有效，而二磷酸盐在P2Y6受体介导的收缩反应中作为激动剂或拮抗剂无效。我们的结果表明，可以基于有利于P2Y1，P2Y2，P2Y4和P2Y11受体选择性的（N）构象设计新的核苷酸激动剂。

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