Melanocortin Selective Ligands

描述(申请人提供)：肥胖(身体质量指数，BMI&GT；30)困扰着美国和其他国家的数百万人，是心脏病、II型糖尿病、中风、高血压和发病率的主要风险因素。G蛋白偶联黑素皮质素-3受体(MC3R)在中枢神经系统(脑)中表达，是黑素皮质素途径的一部分，参与能量稳态的调节。由于缺乏受体特异性配体和MC3R基因敲除小鼠复杂的代谢表型，MC3R在肥胖调控中的具体作用尚不清楚。本项目致力于MC3R选择性分子(多肽和小分子)的药物发现，体外铅候选选择，以及利用野生型和基因敲除小鼠进行进一步的分子铅选择，并探索MC3R在MC3R直接参与食物摄取和饱腹感调节这一新假说中的作用。预计MC3R配体有可能成为肥胖相关疾病的治疗配体，绕过与男性勃起活动和高血压相关的人类黑素皮质素-4受体(MC4R)激动剂的副作用。

DESCRIPTION (provided by applicant): Obesity (body mass index, BMI >30) afflicts millions of people in the United States and other countries, and is a major risk factor for heart disease, type II diabetes mellitus, stroke, hypertension, and morbidity. The G-protein coupled melanocortin-3 receptor (MC3R) is expressed in the central nervous system (brain) and is part of the melanocortin pathway involved in the regulation of energy homeostasis. The specific role of the MC3R in the regulation of obesity has not been clearly defined due to a lack of receptor specific ligands and a complex metabolic phenotype of the MC3R knockout mouse. This project is focused upon the drug discovery of MC3R selective molecules (peptide and small molecules), in vitro lead candidate selection, and use of wild type and knockout mice for further molecule lead selection and to probe the role of the MC3R in the novel hypothesis of the MC3R directly involved in the regulation of food intake and satiety. It is anticipated that MC3R ligands have the potential to become therapeutic ligands for obesity related diseases that bypass the human melanocortin-4 receptor (MC4R) agonist associated side effects of male erectile activity and hypertension.