Melanocortin Selective Ligands

描述（由申请人提供）：肥胖（体重指数，BMI >30）困扰着美国和其他国家的数百万人，并且是心脏病、II型糖尿病、中风、高血压和发病率的主要危险因素。G蛋白偶联黑皮质素-3受体（MC 3R）在中枢神经系统（脑）中表达，是参与能量稳态调节的黑皮质素途径的一部分。由于缺乏受体特异性配体和MC 3R敲除小鼠的复杂代谢表型，MC 3R在肥胖调节中的具体作用尚未明确定义。该项目的重点是MC 3R选择性分子（肽和小分子）的药物发现，体外先导候选物选择，以及使用野生型和敲除小鼠进行进一步的分子先导物选择，并探索MC 3R在MC 3R直接参与调节食物摄入和饱腹感的新假设中的作用。预期MC 3R配体具有成为肥胖症相关疾病的治疗配体的潜力，所述肥胖症相关疾病绕过与人类黑皮质素-4受体（MC 4 R）激动剂相关的男性勃起活动和高血压的副作用。

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.