P2Y-Purinergic Receptors

描述(申请人提供)：核苷酸和核苷酸糖以受调控的方式从可兴奋和不可兴奋的细胞中释放出来，并作为细胞外信号分子调节一系列非常广泛的生理反应，从神经传递到上皮离子转运再到血小板聚集。至少有15种不同的P2受体识别细胞外核苷酸为其同源激动剂，其中8种包括代谢性G蛋白偶联的P2Y受体家族。虽然从P2Y受体发出的信号在几乎所有的组织中传递重要的生理和病理生理反应，但对这些受体的作用的生理和分子理解一直滞后，这主要是由于缺乏可靠的分子来明确地探测单个受体亚型的作用。一种血小板ADP激活的P2Y12受体的拮抗剂(氯吡格雷；Plavix)已经在现代治疗中产生了巨大的影响，临床上针对其他G蛋白偶联的P2Y受体的药物的潜力非常大，但尚未实现。我们的研究项目已经开发并应用了第一批选择性和高亲和力的激动剂、拮抗剂和放射配体来研究P2Y1受体。这些分子中的几个现在已经商业化，是许多实验室用来阐明这一研究领域的机制的关键试剂。我们研究的长期目标是确定每一个核苷酸激活的P2Y受体的亚型选择性激动剂和拮抗剂，并应用这些分子来增加对P2Y受体依赖信号的分子、生理和病理生理学的理解。我们最近在确定尿苷核苷酸激活的P2Y2、P2Y4和P2Y6受体以及核苷酸激活的P2Y14受体的结构和活性关系方面取得了相当大的进展。这一进展为开发选择性的、高亲和力的这些受体拮抗剂提供了新的见解。我们提出的研究计划将在重要的新方向上扩展这些发现。在第一个特定目标中，我们将合成和表征UTP激活的P2Y2和P2Y4受体的选择性高亲和力激动剂和拮抗剂。在第二个特定目标中，我们将合成和表征核苷酸糖激活的P2Y14受体的选择性高亲和力激动剂和拮抗剂，以及UDP激活的P2Y6受体的激动剂。这项研究的完成将提供急需的分子工具来选择性地激活和阻断尿苷核苷酸和核苷酸糖激活的高亲和力和选择性的P2Y受体。 公共卫生相关性本研究中研究的药物靶标在人体生理学和许多影响心血管系统、肺、脑和其他组织的疾病中发挥关键作用。FDA批准的受体受体之一的拮抗剂(氯吡格雷；Plavix)对人类健康的影响是巨大的。我们预计，进一步了解这组重要信号蛋白中的其他受体将导致类似的重要治疗剂。

DESCRIPTION (provided by applicant): Nucleotides and nucleotide sugars are released in regulated fashion from both excitable and non- excitable cells and act as extracellular signaling molecules to regulate a remarkably broad array of physiological responses ranging from neurotransmission to epithelial ion transport to platelet aggregation. At least fifteen different P2 receptors recognize extracellular nucleotides as their cognate agonists, and eight of these comprise the family of metabotropic G protein-coupled P2Y receptors. Although signals emanating from P2Y receptors convey important physiological and pathophysiological responses in essentially all tissues, physiological and molecular understanding of the action of these receptors has lagged, largely due to lack of reliable molecules to probe unambiguously the actions of single receptor subtypes. An antagonist (clopidogrel; Plavix) of the platelet ADP-activated P2Y12 receptor has made an enormous impact in modern therapeutics, and the potential for drugs that clinically target other G protein-coupled P2Y receptors is both very large and as yet unrealized. Our research program has developed and applied the first selective and high affinity agonists, antagonists, and radioligands for the study of P2Y1 receptors. Several of these molecules are now commercially available and are key reagents used by many laboratories to elucidate mechanism in this field of research. The long-term goal of our research is to identify subtype-selective agonists and antagonists for each of the nucleotide-activated P2Y receptors and to apply these molecules to increase molecular, physiological, and pathophysiological understanding of P2Y-receptor-dependent signaling. We recently have made considerable progress in defining structure activity relationships at the uridine nucleotide- activated P2Y2, P2Y4, and P2Y6 receptors and at the nucleotide sugar-activated P2Y14 receptor. Included in this progress is promising new insight for development of selective, high affinity antagonists of these receptors. Our proposed research plan will expand on these discoveries in important new directions. In the first specific aim we will synthesize and characterize selective high affinity agonists and antagonists of the UTP-activated P2Y2 and P2Y4 receptors. In the second specific aim we will synthesize and characterize selective high affinity agonists and antagonists of the nucleotide sugar-activated P2Y14 receptor and agonists of the UDP-activated P2Y6 receptor. Completion of the research described here will provide much-needed molecular tools to selectively activate and block uridine nucleotide- and nucleotide sugar-activated P2Y receptors with high affinity and selectivity. PUBLIC HEALTH RELEVANCE The drug targets studied in this research fulfill key roles in human physiology and in many diseases that affect the cardiovascular system, lung, brain, and other tissues. The impact on human health of an FDA-approved antagonist (clopidogrel; Plavix) of one of the receptors in the class of signaling proteins under study in this research program has been enormous. We anticipate that furthering the basic understanding of other receptors in this group of important signaling proteins will lead to similarly important therapeutic agents.