Novel non-peptide agonists of the melanocortin receptor

描述(摘自申请者摘要)：肥胖是最常见的 世界范围内疾病的促成因素，包括II型等疾病 糖尿病、冠心病和癌症。虽然分子基础是 肥胖仍然是未知的，最近的研究提供了证据表明 证明黑素皮质素在调节能量方面起着重要作用 平衡。来自小鼠遗传学实验的结果，在这些实验中，黑素皮质素-3 受体基因已经被打乱，提示这个受体可能发挥着独特的 在这些动物的整体能量代谢中起着调节作用。因此，我们建议 启动一系列研究来探索这种受体的药理作用 以及它在肥胖中的作用。最初，我们将使用一种MC3-R选择性多肽 调节剂，γ-黑素细胞刺激素，以测试其对能量的影响 肥胖小鼠的平衡。同时，我们还建议发起一项有重点的 高通量组合化学方法鉴定小分子有机物 旨在刺激MC3受体的分子，以及选择性 拮抗剂，以便提供更好的药理工具。如果我们的结果 确认MC3-R的激活不会影响食欲，而是 影响能量分配和代谢的小分子激动剂 在这项研究的第一阶段中确定的可能作为一种新的化学线索 一流的减肥治疗药物。 建议的商业应用： 我们建议开发一种黑素皮质素-3受体的小分子激动剂。这种受体已被证明在调节体内脂肪量和能量平衡方面起着关键作用。因此，MO受体激动剂可能是预防肥胖及其共病的一种新方法，并可能提供一类重要的新型人类治疗药物。

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.