STRUCTURE-ACTIVITY STUDIES OF NEUROPEPTIDE Y

神经肽 Y 的结构活性研究

• 批准号: 3306596
• 负责人: AMBIKAIPAKAN BALASUBRAMANIAM
• 金额: $ 21.23万
• 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 1997-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3306596
• 关键词: adenylate cyclase; anorexic agent; clone cells; drug design /synthesis /production; enzyme activity; laboratory rat; neuropeptide Y; neuropeptide receptor; neuropeptides; peptide analog; peptide chemical synthesis; protein sequence; protein structure function; synthetic peptide; 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），一种从猪中分离出的36个残留肽酰胺 大脑，是包括肽在内的同源激素家族的成员 YY和胰多肽。 NPY广泛分布在中央 和周围神经系统，并以较高的浓度发生 哺乳动物的大脑和心脏比迄今为止孤立的任何其他肽。 npy 与许多中央和外围调节有关 角色，现在被认为是最有效的搅拌机之一， 甲状腺素肽。 还显示它抑制冠状动脉流动， 孤立心脏的收缩和心率。 这些观察和 高血压的血浆中NPY水平升高的发现 大鼠，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 适应治疗用途。 调查表明，几乎 需要整个npy序列才能引起施加和甲基化的序列 响应，这些效果是由同一类介导的 受体（Y-1）。 此外，我们已经证明了NPY动作 心脏是由非典型受体介导的，NPY（18-36）是 竞争性心脏NPY受体拮抗剂。 因此提出了 综合NPY和NPY的类似物（18-36），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，一种用于介导NPY的Y-1受体的模型系统 对喂养和血压的影响以及大鼠心室 膜分别。 这些调查有望导致 具有选择性的激动剂和拮抗剂肽的发展 特定目标的属性。 这些类似物会很棒 基础研究和发展中的重要性 各种疾病的治疗药物 疾病和高血压。