NPY PEPTIDOMIMETICS--DESIGN, SYNTHESIS AND EVALUATION

NPY 肽模拟物——设计、合成和评估

• 批准号: 2270978
• 负责人: MICHAEL B DOUGHTY
• 金额: $ 20.75万
• 依托单位: UNIVERSITY OF KANSAS LAWRENCE
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-02-01 至 1999-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2270978
• 关键词: benzodiazepines; chemical structure function; circular dichroism; conformation; inhibitor /antagonist; laboratory mouse; laboratory rat; neuropeptide Y; neuropeptide receptor; nuclear magnetic resonance spectroscopy; peptide analog; peptide chemical synthesis; peptide hormone analog; protein structure; receptor sensitivity; stimulant /agonist; synthetic peptide

Neuropeptide Y (NPY), a thirty-six amino acid peptide neurotransmitter with sequence homologies to the endocrine hormones of the pancreatic polypeptide and PYY families, is thought to fold into a compact, globular structure in solution. In earlier studies we identified benextramine (1) as an NPY receptor antagonist based on its chemical similarities to a NPY pharmacophore model. In addition, we synthesized SC3117 (2), SC3199 (3) and CC2137 (4) as NPY functional group mimetics and characterized them as mild to potent, Y(2)-selective NPY receptor antagonists in the rat femoral artery. This proposal extends on our rational design of NPY receptor non-peptide antagonists and is based on the hypothesis that benextramine is a functional group mimetic of the NPY pharmacophore. First, we propose a direct test for the NPY structural model by synthesis of conformationally restricted analogs of the peptide agonists NPY(13-36) and NPY. The conformational properties of these peptides will be assessed by circular dichroism and (1)H-NMR spectroscopy. Second, we propose SAR studies on the NPY functional group mimetics 2-4. We will test the contribution of the following chemical and structural features to Y(2)-receptor selectivity and potency: i) stereochemistry, ii) the "outer" amines, iii) the basicity versus hydrogen bonding properties of the guanidines, and iv) symmetry. These third generation antagonists of the NPY receptor have been designed with regards to increasing their membrane partition properties, potency and selectivity. Third, we outline an approach to the design of Y(1)-selective peptidomimetics. These appropriately substituted benzodiazepines attempt to mimic the conformation restriction which in peptide agonists confer Y(1)-selectivity. Each of these peptide and non-peptide analogs of NPY will be tested for receptor binding potency, intrinsic activity and competitive antagonist activity in tissues with homogeneous receptor populations representative of the Y(1) and Y(2) NPY receptors and the variant types of each, and in tissues with heterogeneous NPY receptor populations that are physiologically relevant NPY's in vivo activities. These NPY receptor antagonists have relevance as tools for elucidating the in vivo role of NPY in the peripheral and central nervous systems, and as drugs (or appropriate leads for the development of drugs) for the treatment of cardiovascular disease and eating disorders, including obesity, anorexia nervosa, and bulimia.

神经肽Y（neuropeptide Y，NPY）是一种由36个氨基酸组成的肽类神经递质 与胰腺的内分泌激素序列同源 多肽和PYY家族，被认为折叠成紧凑的， 溶液中的球状结构。 在早期的研究中， benextramine（1）作为一种NPY受体拮抗剂， 与NPY药效团模型相似。 此外，我们还合成了 SC 3117（2）、SC 3199（3）和CC 2137（4）作为NPY官能团模拟物 并将其描述为轻度至强效的Y（2）选择性NPY受体 拮抗剂在大鼠股动脉。 这一建议延伸到我们的 NPY受体非肽类拮抗剂的合理设计， 假设benextramine是一种功能基团模拟物， NPY药效团。 首先，我们提出了一个直接测试神经肽Y 通过合成构象限制类似物的结构模型 肽激动剂NPY（13-36）和NPY。 构象 这些肽的性质将通过圆二色性来评估， （1）1H-NMR光谱。 第二，我们建议对NPY进行SAR研究 官能团模拟物2-4。 我们将测试 Y（2）受体选择性的化学和结构特征 和效力：i）立体化学，ii）“外部”胺，iii） 胍的碱度与氢键性质，以及iv） 对称性 这些第三代NPY受体拮抗剂具有 在设计时考虑到增加它们的膜分配 性质、效力和选择性。 第三，我们概述了一种方法， Y（1）-选择性肽模拟物的设计。 这些适当 取代的苯并二氮杂卓试图模仿构象 在肽激动剂中赋予Y（1）-选择性的限制。 每个 这些肽和非肽类似物的NPY将被测试， 受体结合效力、内在活性和竞争性拮抗剂 在具有同质受体群体的组织中的活性 代表Y（1）和Y（2）NPY受体和变体类型 在具有异质性NPY受体群体的组织中， 与神经肽Y在体内的生理活性相关。 这些NPY 受体拮抗剂作为阐明免疫抑制的工具具有相关性， NPY在外周和中枢神经系统中的体内作用， 药物（或药物开发的适当线索）， 治疗心血管疾病和饮食失调，包括 肥胖症、神经性厌食症和贪食症。