Novel non-peptide agonists of the melanocortin receptor

黑皮质素受体的新型非肽激动剂

• 批准号: 6444815
• 负责人: RICHARD SCOTT STRUTHERS
• 金额: $ 13.93万
• 依托单位: NEUROCRINE BIOSCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-02-01 至 2003-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6444815
• 关键词: adrenocorticotropic hormone; basal metabolism; bioenergetics; combinatorial chemistry; gastrointestinal pharmacology; hormone receptor; laboratory mouse; noninsulin dependent diabetes mellitus; obesity; receptor binding; receptor expression

DESCRIPTION (Scanned from the Applicant's Abstract): Obesity is the most common contributing factor to illness worldwide, including such diseases as Type II diabetes, coronary heart disease and cancer. Although the molecular basis for obesity is still unknown, recent research has provided evidence which demonstrated that melanocortins play a prominent role in regulating energy balance. Results from murine genetic experiments, in which the melanocortin-3 receptor gene has been disrupted, suggests that this receptor may play a unique regulatory role in overall energy metabolism of these animals. Thus, we propose to initiate a series of studies to explore the pharmacology of this receptor and its role in obesity. Initially, we will use a MC3-R selective peptide modulator, gamma-melanocyte stimulating hormone, to test its effect on energy balance in obese mice. In parallel, we also propose to initiate a focused high-throughput combinatorial chemistry approach to identify small organic molecules designed to stimulate the MC3 receptor, as well as selective antagonists, in order to provide better pharmacologic tools. If our results confirm that activation of MC3-R does not effect appetite, but rather influences energy partitioning and metabolism, the small molecule agonists identified in Phase I of this study could serve as chemical leads for a novel class of anti-obesity therapeutics. PROPOSED COMMERCIAL APPLICATION: We are proposing to develop a small molecule agonist of the melanocortin-3 receptor. This receptor has been shown to play a key role in regulating the amount of body fat and energy balance. Thus, an MO receptor agonist may be a novel approach toward preventing obesity and its co-morbidities, and could provide an important novel class of human therapeutic agents.

描述（从申请人的摘要中扫描）：肥胖是最常见的 导致全世界疾病的因素，包括 II 型疾病 糖尿病、冠心病和癌症。虽然分子基础 肥胖仍然是一个未知数，最近的研究提供了证据 证明黑皮质素在调节能量方面发挥着重要作用 平衡。小鼠基因实验的结果，其中 melanocortin-3 受体基因已被破坏，表明该受体可能发挥独特的作用 这些动物的整体能量代谢中的调节作用。因此，我们建议 启动一系列研究来探索该受体的药理学 及其在肥胖中的作用。最初，我们将使用 MC3-R 选择性肽 调节剂，γ-黑素细胞刺激激素，测试其对能量的影响 肥胖小鼠的平衡。与此同时，我们还建议启动一项有针对性的 高通量组合化学方法识别小有机物 旨在刺激 MC3 受体的分子，以及选择性 拮抗剂，以提供更好的药理工具。如果我们的结果 证实 MC3-R 的激活不会影响食欲，而是会影响 影响能量分配和新陈代谢，小分子激动剂 本研究第一阶段确定的可作为新型化学先导物 一类抗肥胖疗法。 拟议的商业应用： 我们提议开发一种黑皮质素-3 受体的小分子激动剂。该受体已被证明在调节体内脂肪量和能量平衡方面发挥着关键作用。因此，MO受体激动剂可能是预防肥胖及其并发症的新方法，并且可以提供一类重要的新型人类治疗剂。