Somatostatin Receptor-Selective Agonists and Antagonists

生长抑素受体选择性激动剂和拮抗剂

• 批准号: 6887348
• 负责人: JEAN E RIVIER
• 金额: $ 46.93万
• 依托单位: SALK INSTITUTE FOR BIOLOGICAL STUDIES
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-01 至 2007-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6887348
• 关键词: autoradiography; capillary electrophoresis; cell line; clinical research; computer simulation; diabetes mellitus; drug design /synthesis /production; electrospray ionization mass spectrometry; high performance liquid chromatography; hormone receptor; inhibitor /antagonist; ligands; matrix assisted laser desorption ionization; neoplasm /cancer diagnosis; neoplasm /cancer radionuclide therapy; neuropeptide receptor; nuclear magnetic resonance spectroscopy; peptide hormone analog; peptide structure; radiotracer; receptor binding; site directed mutagenesis; somatostatin; stimulant /agonist

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.

描述（由申请人提供）：Somatostatin（SRIF）不仅是主要 生长激素，胰血糖素和生理抑制剂的内分泌激素和生理抑制剂 胰岛素分泌，但也具有多种其他功能。 SRIF类似物 通过调节或 靶向五个已知膜相关受体亚型中的一个或多个 （SST1-5）。这些不同的实际功能，分布和特异性 受体及其作用机理尚未完全理解，部分原因是 由于缺乏强大而有选择性的激动剂和对手以及固有的 目前可用的技术局限性。跟进现有潜在客户 以及来自NMR光谱，计算机模拟和 在体外结合和功能分析，我们将设计，合成，并 表征具有具有激动剂和的定义结构的SRIF类似物 五个受体亚型的拮抗特性。因为关键 SST2和SST5在抑制胰高血糖素和胰岛素中扮演的角色 分泌分别及其在糖尿病中的作用，我们将强调 SST2选择性激动剂和SST5选择性拮抗剂的发展。 同样，将使用任何SRIF受体的配体用于 某些癌症的受体靶向闪烁显像和放射性核素治疗。 初步研究表明，这种肽类似物是可以访问的 使用合理和有限的组合方法。我们将调查 我们的铅受约束激动剂和拮抗剂的溶液构象 使用光谱和计算方法来了解肽/受体 相互作用（结构研究）。使用此信息，我们将确定 受体和配体的结构基序以及特定的氨基酸 负责选择性结合和转导以及设计改进的SRIF 也可以标记的激动剂和拮抗剂（药理学研究）。 使用这种方法，我们已经成功设计了有力和选择性的SST1 激动剂和SST3选择性拮抗剂。此外，我们有希望的线索 为了开发SST2-和SST5选择配体以及SST4选择性的配体 激动剂使用在β-甲基化氨基中发现的微妙构象约束 酸和β苯甲酸。我们将确定这些类似物的人类目标 并研究一些选定的SRIF类似物作为潜在药物的有用性 或了解相关病理生理状态的工具。几个调查人员 （附带的10封信）热情地提出要在生物学中进行合作 （体内和体外）表征我们的SST选择性类似物 证明产生SST选择配体的重要性。