Somatostatin Receptor-Selective Agonists and Antagonists

描述（由申请人提供）：生长抑素（SRIF）不仅是一种主要的 内分泌激素和生长激素、胰高血糖素的生理抑制剂， 胰岛素分泌，但也具有多种其他功能。SRIF类似物 用于治疗多种病理状况， 靶向五种已知膜相关受体亚型中的一种或多种 （SST 1 -5）。这些不同器官的实际功能、分布和特异性 受体和它们的作用机制还没有被完全理解，部分原因是， 缺乏有效的和选择性的激动剂和拮抗剂， 现有技术的局限性。跟进现有线索 和信息来自核磁共振光谱，计算机模拟， 结合和体外功能测定，我们将设计，合成， 表征具有确定结构的SRIF类似物，其具有激动剂和 这五种受体亚型的拮抗剂特性。由于关键的 SST 2和SST 5在胰高血糖素和胰岛素抑制中的作用 分泌，分别，和它们在糖尿病中的作用，我们将强调 SST 2选择性激动剂和SST 5选择性拮抗剂的开发。 类似地，任何或所有SRIF受体的配体将用于 受体靶向放射性造影术和某些癌症的放射性核素治疗。 初步研究表明，这种肽类似物是可获得的， 使用理性的和有限的组合方法。我们将调查 我们的先导限制性激动剂和拮抗剂的溶液构象 使用光谱和计算方法来理解肽/受体 结构研究（Structural Studies）利用这些信息，我们将 受体和配体以及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 激动剂和拮抗剂也可以被标记（药理学研究）。 利用这种方法，我们成功地设计了有效的和选择性的sst 1 激动剂和SST 3选择性拮抗剂。另外，我们有很好的线索 用于开发SST 2-和SST 5-选择性配体和SST 4-选择性配体 使用在β-甲基化氨基中发现的微妙构象约束的激动剂 酸和甜菜氨酸。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 或者理解相关病理生理状态的工具。几名研究者 (10附信）热情地提出在生物学方面进行合作， (in体内和体外）表征我们的SST-选择性类似物 证明了产生SST-选择性配体的重要性。

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.