STRUCTURE/ACTIVITY STUDIES OF NPY

NPY 的结构/活性研究

• 批准号: 2900775
• 负责人: AMBIKAIPAKAN BALASUBRAMANIAM
• 金额: $ 23.68万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-04-01 至 2001-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2900775
• 关键词: adenylate cyclase; aminoacid analog; anorexic agent; drug design /synthesis /production; drug screening /evaluation; enzyme activity; laboratory rat; neuropeptide Y; neuropeptide receptor; neuropeptides; peptide analog; peptide chemical synthesis; protein sequence; protein structure function; receptor binding; tissue /cell culture; vasoconstrictors

Neuropeptide Y(NPY), a 36-residue peptide amide isolated from porcine brain, is a member of a family of homologous hormones including peptide YY and pancreatic polypeptide. NPY is widely distributed in the central and peripheral nervous system and occurs in higher concentrations in mammalian brain and heart than any other peptide isolated to date. NPY has been implicated in a number of central and peripheral regulatory roles and is now considered as one of the most potent vasopressor and orexigenic peptides. It has also been shown to inhibit coronary flow, contractility and heart rate in isolated hearts. These observations and the findings that NPY levels are elevated in the plasma of hypertensive rats, patients with congestive heart failure (CHF) and pheochromocytoma, and in the hypothalamus of obese rats suggest that NPY sequence may be modulated for therapeutic use. Investigations have shown that nearly the entire sequence of NPY is required to elicit pressor and orexigenic responses and that these effects are mediated by the same class of receptors (Y-1). Furthermore, we have shown that NPY actions on the heart are mediated by atypical receptors and that NPY (18-36) is a competitive cardiac NPY receptor antagonist. It is therefore proposed to synthesize analogs of NPY and NPY (18-36), and investigate the receptor affinities and the effects on adenylate cyclase activity using the SK-N-MC cell line, a model system for Y-1 receptors mediating NPY effects on feeding and blood pressure, and rat cardiac ventricular membranes, respectively. These investigations are expected to result in the development of agonist and antagonist peptides with selective properties for specific targets. These analogs will have great significance both in fundamental studies as well as in the development of therapeutic drugs for a variety of conditions including feeding disorders and hypertension.

神经肽 Y(NPY)，一种从猪中分离出来的 36 残基肽酰胺 大脑，是同源激素家族的成员，包括肽 YY和胰多肽。 NPY广泛分布于中部地区 和周围神经系统，并以较高浓度出现 哺乳动物的大脑和心脏比迄今为止分离的任何其他肽都更有效。 NPY 涉及多项中央及外围监管 的作用，现在被认为是最有效的血管升压药之一 促食欲肽。 它还被证明可以抑制冠状动脉血流， 离体心脏的收缩力和心率。 这些观察和 研究发现高血压患者血浆中 NPY 水平升高 大鼠、患有充血性心力衰竭（CHF）和嗜铬细胞瘤的患者， 在肥胖大鼠的下丘脑中，NPY 序列可能是 调制用于治疗用途。 调查显示，几乎 需要 NPY 的整个序列来引发升压和食欲 反应，并且这些效应是由同一类物质介导的 受体（Y-1）。 此外，我们还表明 NPY 对 心脏由非典型受体介导，NPY (18-36) 是一种 竞争性心脏 NPY 受体拮抗剂。 因此建议 合成 NPY 和 NPY (18-36) 的类似物，并研究 受体亲和力以及对腺苷酸环化酶活性的影响 SK-N-MC 细胞系，Y-1 受体介导 NPY 的模型系统 对喂养、血压和大鼠心室的影响 膜，分别。 这些调查预计将导致 选择性激动剂和拮抗剂肽的开发 特定目标的属性。 这些类似物将有很大的作用 无论是在基础研究还是在发展方面都具有重要意义 适用于多种病症（包括喂养）的治疗药物 疾病和高血压。