Endogenous G-Protein Coupled Receptor Antagonists

描述（由申请人提供）：agouti相关蛋白（AGRP）和agouti （ASP）是迄今为止发现的仅有的两种天然存在的g蛋白偶联受体（gpcr）拮抗剂，当在小鼠中过度表达时，会导致肥胖表型。肥胖（身体质量指数bbbb25）折磨着美国和其他国家数百万人，是心脏病、二型糖尿病、中风和高血压的主要危险因素。在工业化国家，肥胖问题因暴饮暴食、高脂肪饮食和缺乏锻炼而更加严重。在过去的几年里，已经发现了30多种参与和调节摄食行为和能量稳态的途径。黑素皮质素通路包括黑素皮质素激动剂，源自激素前原原原黑素皮质素（POMC）基因转录物，迄今已鉴定的五种黑素皮质素受体（MC1R-MC5R），以及仅有的两种天然存在的gpcr拮抗剂，针刺子（ASP）和针刺子相关蛋白（AGRP）。在神经元中表达的四种黑素皮质素遗传因子（POMC、AGRP、MC3R和MC4R）已被确定参与能量稳态。AGRP是MC3R和MC4R的竞争性拮抗剂，也是MC4R的逆激动剂。在被诊断为神经性厌食症的人类中发现了AGRP多态性，将AGRP与人类生理疾病状态联系起来。这些数据支持了AGRP参与调节黑素皮质素受体介导的神经药理学的假设。当前应用的目的是：a)设计和合成具有更高受体亚型效力和/或选择性的配体；b)确定可能的配体-受体相互作用，以合理设计潜在的治疗分子；c)在小鼠中研究选定的分子。为了实现这些目标，我们将使用肽设计、组合文库和GPCR诱变策略。此外，还将使用生物物理技术[2D 1H NMR和计算机辅助分子建模（CAMM）]，并将选定的化合物给予野生型和MC4R敲除小鼠的大脑和外周，以研究生理变化。公共卫生相关性：肥胖是一种复杂的疾病，是其他几种相关疾病的危险因素。黑素皮质素通路已经在老鼠和人类身上被发现，以调节肥胖。本研究项目旨在为分子的合理设计提供知识，作为潜在的治疗剂，以预防或治疗与饮食过量或饮食不足相关的疾病。

DESCRIPTION (provided by applicant): Agouti-related protein (AGRP) and agouti (ASP) are the only two naturally occurring antagonists of G-protein coupled receptors (GPCRs) identified to date, and when over expressed in mice, result in an obese phenotype. Obesity (body mass index >25) 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 and hypertension. In industrialized countries, the problem of obesity is compounded by overeating, a high fat content diet, and a lack of exercise. The last few years have seen the characterization of over 30 pathways that have been identified to participate in and regulate feeding behavior and energy homeostasis. The melanocortin pathway includes the melanocortin agonists, derived from the preprohormone proopiomelanocortin (POMC) gene transcript, the five melanocortin receptors identified to date (MC1R-MC5R), and the only 2 naturally occurring antagonists of GPCRs, agouti (ASP) and agouti-related protein (AGRP). Four melanocortin genetic factors expressed in neurons (POMC, AGRP, MC3R, and MC4R) have been identified as being involved in energy homeostasis. AGRP is a competitive antagonist at the MC3R and MC4R as well as an inverse agonist at the MC4R. An AGRP polymorphism has been identified in humans diagnosed with anorexia nervosa, linking AGRP with a human physiological disease state. These data support the hypothesis that AGRP is involved in the regulation of melanocortin receptor mediated neuropharmacology. The aims of the current application are to a) design and synthesize ligands with increased receptor subtype potency and/or selectivity, b) identify putative ligand-receptor interactions for the rational design of potential therapeutic molecules, and c) study selected molecules in mice. To achieve these objectives, we will use peptide design, combinatorial libraries, and GPCR mutagenesis strategies. Additionally, biophysical techniques [2D 1H NMR and computer assisted molecular modeling (CAMM)] will also be used and selected compounds will be administered into the brain and periphery of wild type and MC4R knock out mice to study physiological changes. PUBLIC HEALTH RELEVANCE: Obesity is a complex disease and is a risk factor for several other associated diseases. The melanocortin pathway has been identified in mice and humans, to regulate obesity. This research project proposes to generate knowledge for the rational design of molecules as potential therapeutic agents to prevent or treat the diseases associated with over or under eating.