Somatostatin Receptor-Selective Agonists and Antagonists

描述(申请人提供)：生长抑素(SRIF)不仅是一个主要的 内分泌激素和生长激素的生理抑制剂，胰高血糖素和 胰岛素可以分泌，但也有多种其他功能。SRIF类似物 用于治疗几种病理情况，通过调节或 靶向五个已知的膜相关受体亚型中的一个或多个 (sst1-5)。这些不同生物的实际功能、分布和特性 受体及其作用机制尚未完全了解，部分原因是， 由于缺乏有效和选择性的激动剂和拮抗剂，以及固有的 现有技术的局限性。跟进现有线索 以及从核磁共振波谱、计算机模拟和 体外结合和功能分析，我们将设计、合成和 用具有激动剂和已定义结构的SRIF类似物表征 五种受体亚型的拮抗剂特性。因为关键的 Sst2和Sst5在抑制胰高血糖素和胰岛素中的作用 分别介绍了分泌物及其在糖尿病中的作用，我们将重点介绍 Sst2选择性激动剂和sst5选择性拮抗剂的研究进展。 同样，任何或所有SRIF受体的配体将用于 某些癌症的受体靶向闪烁成像和放射性核素治疗。 初步研究表明，这种多肽类似物是可以获得的 使用有理和有限的组合方法。我们会调查的 我们铅受限激动剂和拮抗剂的溶液构象 用光谱和计算方法了解多肽/受体 相互作用(结构研究)。使用这些信息，我们将确定 受体、配体和特定氨基酸的结构基序 负责选择性结合和转导，并设计改进的SRIF 也可以标记的激动剂和拮抗剂(药理学研究)。 利用这种方法，我们成功地设计出了有效的和选择性的sst1。 激动剂和sst3选择性拮抗剂。另外，我们有很有希望的线索 用于开发Sst2和Sst5选择性配体以及Sst4选择性配体 使用在β-甲基化氨基中发现的微妙构象限制的激动剂 酸和贝蒂达米诺酸。我们将确定这些类似物的人类目标 并调查一些精选的SRIF类似物作为潜在药物的用处 或了解相关病理生理状态的工具。几名调查人员 (附上10封信)热情提出在生物领域进行合作 我们的sst选择性类似物的(体内和体外)表征 论证了产生sst选择性配体的意义。

DESCRIPTION (provided by applicant): Somatostatin (SRIF) is not only a major endocrine hormone and physiological inhibitor of growth hormone, glucagon, and insulin secretions but has a variety of other functions as well. SRIF analogs are used in the treatment of several pathological conditions by modulating or targeting one or more of the five known membrane-associated receptor subtypes (sst1-5). The actual function, distribution, and specificity of these different receptors and their mechanism of action are not fully understood due, in part, to the lack of potent and selective agonists and antagonists and inherent limitations of techniques presently available. Following up on existing leads and information derived from NMR spectroscopy, computer simulations, and binding and functional assays in vitro, we will design, synthesize, and characterize SRIF analogs with defined structures that have agonist and antagonist properties for the five receptor subtypes. Because of the critical role played by sst2 and sst5 in the inhibition of glucagon and insulin secretion, respectively, and their role in diabetes, we will emphasize the development of sst2-selective agonists and sst5-selective antagonists. Similarly, ligands to any or all SRIF receptors will be used for receptor-targeted scintigraphy and radionuclide therapy of certain cancers. Preliminary investigations demonstrate that such peptide analogs are accessible using both rational and limited combinatorial approaches. We will investigate the solution conformation of our lead constrained agonists and antagonists using spectroscopic and computational approaches to understand peptide/receptor interactions (structural studies). Using this information, we will identify structural motifs of both receptors and ligands and specific amino acids responsible for selective binding and transduction and design improved SRIF agonists and antagonists that could also be labeled (pharmacological studies). Using this approach, we have successfully designed potent and selective sst1 agonists and sst3-selective antagonists. Additionally, we have promising leads for the development of sst2- and sst5-selective ligands and of sst4-selective agonists using subtle conformational constraints found in beta-methylated amino acids and betidamino acids. We will identify the human targets of those analogs and investigate the usefulness of some selected SRIF analogs as potential drugs or tools to understand related pathophysiological states. Several investigators (10 letters attached) enthusiastically offered to collaborate in the biological (in vivo and in vitro) characterization of our sst-selective analogs demonstrating the significance of generating sst-selective ligands.