ALLOSTERIC MODULATORS OF MC4R SIGNALING

MC4R 信号传导的变构调节剂

• 批准号: 9463221
• 负责人: Roger D. Cone
• 金额: $ 51.84万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9463221
• 关键词: Affinity; Agonist; Anhedonia; Animals; Anorexia; Arrestins; Biological Assay; Body Weight; Body Weight decreased; Brain region; Cachexia; Cardiovascular Physiology; Cardiovascular system; Cell Nucleus; Clinical Trials; Collection; Communities; Coupling; Data; Development; Diabetes Mellitus; Disease; Drug Targeting; Exhibits; FOS gene; Funding; GTP-Binding Protein alpha Subunits, Gs; Genetic; Homeostasis; Hypothalamic structure; Knockout Mice; Knowledge; Laboratories; Learning; Ligands; LoxP-flanked allele; Mediating; Melanocortin 4 Receptor; Mental Depression; Metabolic; Metabolic syndrome; Modality; Mus; Neurons; Obesity; Obsessive-Compulsive Disorder; Peptides; Pharmacology; Phenotype; Physiological; Property; Proteins; Receptor Signaling; Regulation; Research; Rodent; Role; Signal Transduction; Site; Specificity; Structure-Activity Relationship; Syndrome; Testing; Tissues; Variant; Zebrafish; alpha-Melanocyte stimulating hormone; analog; base; common treatment; drug development; early onset; genetic analysis; high throughput screening; improved; in vivo; inward rectifier potassium channel; killer inhibitory receptor; melanocortin receptor; novel; obesity treatment; peptide analog; positive allosteric modulator; programs; public health relevance; receptor; receptor coupling; receptor function; response; restoration; small molecule; targeted treatment; therapeutic development; therapy development; tool

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 �-MSH. In this application, we propose to use the unique pharmacological tools described above, and a set of tissue-specific knockout mice that delete G�s, Kir7.1, MRAP2, and �-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.

描述（由申请人提供）：黑皮质素-4 受体 (MC4R) 是经过充分验证的药物靶点，可用于开发治疗肥胖和恶病质的疗法。最近的研究表明 MC4R 化合物在糖尿病和代谢综合征、抑郁症相关的厌食症和快感缺乏以及强迫症方面的潜在应用。然而，由于靶标介导的升压活性不可接受，使用 MC4R 的有效正位激动剂治疗普通肥胖症的临床试验失败了。然而，两项独立研究已经确定了肽 MSH 类似物可以在没有升压反应的情况下产生显着的体重减轻。因此，我们假设，如果更全面地了解 MC4R 信号在减肥和心血管调节中的作用模式和作用位点，可以从药理学上区分 MC4R 的减肥和升压作用。在上一个资助期间，我们对 MC4R 的正变构调节剂进行了高通量筛选，确定了多个机制类别的 165 种受体特异性化合物的集合，并证明了其中几种的体内活性。 MC4R 的变构调节剂应该适用于通过恢复黑皮质素受体单倍体不足中受体活性的正常水平来治疗综合征性肥胖，黑皮质素受体单倍体不足是一种导致高达 5% 早发性肥胖的综合征，事实上，我们的化合物的一部分目前正在葛兰素史克的药物开发管道中。然而，GPCR 的变构调节剂通常表现出优异的受体亚型、配体和信号传导模式特异性，也是探测受体功能的出色工具。我们在体内 MC4R 信号传导分化模式的鉴定方面也取得了重大进展。在之前的资助期间，我们确定了受体的两种新的信号传导模式，即黑皮质素受体相关蛋白 2 (MRAP2) 介导的受体敏化，以及受体与内向整流 K 通道 Kir7.1 的偶联，Kir7.1 对于 β-MSH 下丘脑 MC4R 神经元去极化至关重要。在本申请中，我们建议使用上述独特的药理学工具，以及一组删除 MC4R 神经元中 G’s、Kir7.1、MRAP2 和 β-arrestin1 信号传导的组织特异性敲除小鼠，以测试 MC4R PAMS 可以纠正黑皮质素单倍体不足的假设，并确定 MC4R 在介导其作用的模式和位点。 具有明显的减肥、升压和心脏加速作用。该研究计划的结果应：1) 增进我们对 MC4R 独特药理学特性的理解，2) 增强我们对能量稳态中央控制的理解，3) 为研究界提供一套独特的药理学和遗传工具，4) 提供有效利用 MC4R 作为药物靶点所需的基础知识。

项目成果

Cardiac Phenotype and Tissue Sodium Content in Adolescents With Defects in the Melanocortin System.

黑皮质素系统缺陷青少年的心脏表型和组织钠含量。

• DOI: 10.1210/clinem/dgab368
• 发表时间: 2021
• 期刊: The Journal of clinical endocrinology and metabolism
• 作者: Puder,Lia;Roth,Sophie;Krabusch,Philipp;Wiegand,Susanna;Opitz,Robert;Bald,Martin;Flück,Christa;Schulz,Esther;Voss,Egbert;Markó,Lajos;Linz,Peter;Berger,Felix;Müller,DominikN;Kuehne,Titus;Litt,MichaelJ;Cone,RogerD;Kühnen,P
• 通讯作者: Kühnen,P

Leptin grows up and gets a neural network.

• DOI: 10.1016/j.neuron.2011.06.033
• 发表时间: 2011-07-14
• 期刊: Neuron
• 影响因子: 16.2
• 作者: Cone RD;Simerly RB
• 通讯作者: Simerly RB

Body weight homeostat that regulates fat mass independently of leptin in rats and mice.

体重体重稳态，可独立于大鼠和小鼠的瘦素来调节脂肪质量。

• DOI: 10.1073/pnas.1715687114
• 发表时间: 2018-01-09
• 期刊: Proceedings of the National Academy of Sciences of the United States of America
• 影响因子: 11.1
• 作者: Jansson JO;Palsdottir V;Hägg DA;Schéle E;Dickson SL;Anesten F;Bake T;Montelius M;Bellman J;Johansson ME;Cone RD;Drucker DJ;Wu J;Aleksic B;Törnqvist AE;Sjögren K;Gustafsson JÅ;Windahl SH;Ohlsson C
• 通讯作者: Ohlsson C

Regulation of energy rheostasis by the melanocortin-3 receptor.

• DOI: 10.1126/sciadv.aat0866
• 发表时间: 2018-08
• 期刊: Science advances
• 影响因子: 13.6
• 作者: Ghamari-Langroudi M;Cakir I;Lippert RN;Sweeney P;Litt MJ;Ellacott KLJ;Cone RD
• 通讯作者: Cone RD

Development of a high throughput screen for allosteric modulators of melanocortin-4 receptor signaling using a real time cAMP assay.

• DOI: 10.1016/j.ejphar.2011.01.031
• 发表时间: 2011-06-11
• 期刊: EUROPEAN JOURNAL OF PHARMACOLOGY
• 影响因子: 5
• 作者: Pantel, Jacques;Williams, Savannah Y.;Mi, Dehui;Sebag, Julien;Corbin, Jackie D.;Weaver, C. David;Cone, Roger D.
• 通讯作者: Cone, Roger D.