Allosteric Modulators of MC4R Signaling

描述(申请人提供)：黑素皮质素-4受体(MC4R)是一种有效的药物靶点，用于开发治疗肥胖症和疾病恶病质的疗法。最近的研究表明，MC4R化合物在糖尿病和代谢综合征、抑郁症相关的厌食和快感障碍以及强迫症等方面具有潜在的应用前景。然而，使用MC4R的强效正构体激动剂治疗常见肥胖症的临床试验已经失败，这是由于不可接受的靶向介导的升压活性。然而，两项独立的研究已经确定了多肽MSH类似物可以在没有升压反应的情况下显著减轻体重。因此，我们假设，如果对MC4R信号在减肥和心血管调节中的作用方式(S)和作用部位(S)有更深入的了解，可以从药理学上区分MC4R的减肥和升压作用。在之前的资助期间，我们对MC4R的正变构调节剂进行了高通量筛选，鉴定了多种机制类别的165种受体特异性化合物，并展示了其中几种化合物的体内活性。MC4R的变构调节剂应该适用于通过恢复黑素皮质素受体单倍体功能不全的正常受体活性水平来治疗综合征性肥胖，这是一种导致高达5%的早发性肥胖的综合征，事实上，我们的化合物的子集目前正在葛兰素史克的药物开发管道中。然而，GPCRs的变构调节剂通常具有良好的受体亚型、配体和信号模式特异性，也是探测受体功能的优秀工具。我们还在体内鉴定MC4R信号的分化模式方面取得了重大进展。在之前的资助期间，我们发现了该受体的两种新的信号转导方式，即黑素皮质素受体相关蛋白2(MRAP2)介导的受体敏化，以及该受体与内向整流性K通道Kir7.1的偶联，Kir7.1是α-MSH对下丘脑MC4R神经元去极化所必需的。在这个应用中，我们建议使用上述独特的药理学工具，以及一组组织特异性的缺失MC4R神经元中GαS、Kir7.1、MRAP2和β-arrestin1信号的基因敲除小鼠来验证MC4RPAMS可以纠正黑素皮质素单倍体不足的假设，并确定MC4R在调节其众所周知的减肥、升压和心脏加速作用中的作用模式(S)和作用部位(S)。这一研究计划的结果将1)增进我们对MC4R独特药理学特性的理解，2)加强我们对能量平衡的中央控制的理解，3)为研究界提供一套独特的药理学和遗传学工具，以及4)提供有效利用MC4R作为药物靶点所需的基本知识。

DESCRIPTION (provided by applicant): The melanocortin-4 receptor (MC4R) is a well-validated drug target for the development of therapeutics for the treatment of obesity and disease cachexia. More recent studies suggest potential applications for MC4R compounds in diabetes and aspects of metabolic syndrome, depression related anorexia and anhedonia, and obsessive compulsive disorder. Clinical trials for treatment of common obesity using potent orthosteric agonists of the MC4R have failed, however, due to unacceptable target-mediated pressor activity. Two independent studies, however, have identified peptide MSH analogues that produce significant weight loss without a pressor response. Therefore, we hypothesize that the weight loss and pressor actions of MC4R can be discriminated pharmacologically, given a more thorough understanding of the mode(s) and site(s) of action of MC4R signaling in weight loss and cardiovascular regulation. During the previous funding period, we conducted a high throughput screen for positive allosteric modulators of the MC4R that identified a collection of 165 receptor-specific compounds in multiple mechanistic classes, and have demonstrated in vivo activity for several of these. Allosteric modulators of the MC4R should be applicable to treatment of syndromic obesity through restoration of normal levels of receptor activity in melanocortin receptor haploinsufficiency, a syndrome responsible for up to 5% of early onset obesity, and indeed a subset of our compounds are currently in the drug development pipeline at GSK. However, allosteric modulators of GPCRs, known to often exhibit excellent receptor subtype, ligand, and signaling mode specificity, are also outstanding tools for probing receptor function. We have also made significant progress in the identification of differentiated modes of MC4R signaling in vivo. During the previous funding period, we identified two novel signaling modalities of the receptor, melanocortin receptor associated protein 2 (MRAP2) mediated receptor-sensitization, and coupling of the receptor to an inwardly-rectifying K channel, Kir7.1 that is essential for depolarization of hypothalamic MC4R neurons by α-MSH. In this application, we propose to use the unique pharmacological tools described above, and a set of tissue-specific knockout mice that delete Gαs, Kir7.1, MRAP2, and β-arrestin1 signaling in MC4R neurons to test the hypothesis that MC4R PAMS can correct melanocortin haploinsufficiency, and to identify the mode(s) and site(s) of action of MC4R in mediating its well-characterized weight loss, pressor, and cardioacceleratory effects. The results of this research program should 1) advance our understanding of the unique pharmacological properties of the MC4R, 2) enhance our understanding of the central control of energy homeostasis, 3) provide a unique set of pharmacological and genetic tools for the research community, and 4) provide the basic knowledge necessary to effectively utilize the MC4R as a drug target.