Structure-activity relationships of dinucleotides: Potent and selective agonists of P2Y receptors.
Structure-activity relationships of dinucleotides: Potent and selective agonists of P2Y receptors.
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DOI：
10.1007/s11302-005-0648-2
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发表时间：
2005-06
影响因子：
3.5
通讯作者：
Yerxa, Benjamin R
中科院分区：
文献类型：
--
作者：
Shaver, Sammy R;Rideout, Janet L;Pendergast, William;Douglass, James G;Brown, Edward G;Boyer, Jose L;Patel, Roshni I;Redick, Catherine C;Jones, Arthur C;Picher, Maryse;Yerxa, Benjamin R
二核苷多磷酸作为嘌呤能P2 Y受体的激动剂，介导多种细胞过程。对称的、天然存在的嘌呤二核苷酸存在于大多数活细胞中，它们的作用是众所周知的。然而，不对称嘌呤二核苷酸和所有含嘧啶的二核苷酸并不常见，因此它们的作用还不清楚。为了对这些二核苷酸的活性和特异性进行彻底检查，开发了一种稳健的合成方法，以允许操纵二核苷酸的核苷以及磷酸链长度。含腺苷的二核苷酸对P2 Y1表现出一定水平的活性，而含尿苷的二核苷酸对P2 Y2和P2 Y 6具有一定水平的激动剂应答。连接磷酸链的长度决定了不同的特异性;二磷酸被二核苷三磷酸最准确地模拟，三磷酸最类似于二核苷四磷酸。这些二核苷酸的药理活性和相对代谢稳定性的报告，其潜在的治疗应用进行了讨论。
Dinucleoside polyphosphates act as agonists on purinergic P2Y receptors to mediate a variety of cellular processes. Symmetrical, naturally occurring purine dinucleotides are found in most living cells and their actions are generally known. Unsymmetrical purine dinucleotides and all pyrimidine containing dinucleotides, however, are not as common and therefore their actions are not well understood. To carry out a thorough examination of the activities and specificities of these dinucleotides, a robust method of synthesis was developed to allow manipulation of either nucleoside of the dinucleotide as well as the phosphate chain lengths. Adenosine containing dinucleotides exhibit some level of activity on P2Y1 while uridine containing dinucleotides have some level of agonist response on P2Y2 and P2Y6. The length of the linking phosphate chain determines a different specificity; diphosphates are most accurately mimicked by dinucleoside triphosphates and triphosphates most resemble dinucleoside tetraphosphates. The pharmacological activities and relative metabolic stabilities of these dinucleotides are reported with their potential therapeutic applications being discussed.