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（由适用提供）：黑色素皮质素-4受体（MC4R）是用于开发肥胖症和疾病缓存治疗治疗疗法的验证良好的药物靶标。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抗衰变的方面的潜在应用以及强迫症。然而，由于目标介导的压力活性，使用MC4R潜在的正常型激动剂治疗普通肥胖症的临床试验失败了。然而，两项独立的研究已经鉴定出肽MSH类似物，这些类似物会产生显着的体重减轻而没有压力反应。因此，我们假设MC4R的体重减轻和施加动作可以被歧视药物，鉴于对MC4R信号在体重减轻和心血管调节中的模式和部位有更透彻的了解。在上一个资金期间，我们对MC4R的阳性变构调节剂进行了高吞吐量筛选，该筛选确定了多种机械类别中165个受体特异性化合物的集合，并在其中几种中证明了体内活性。 MC4R的变构调节剂应适用于通过恢复黑色皮质素受体受体单倍症的正常受体活性来治疗综合征肥胖，这是一种综合征，综合征最多可占早期发作肥胖症的5％，而实际上我们的化合物的子集目前是GSK的药物发育渠道中的一个子集。然而，GPCR的变构调节剂（已知经常表现出出色的受体亚型，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。我们还在体内MC4R信号传导的分化模式的鉴定方面取得了重大进展。在上一个资金期间，我们确定了受体的两种新型信号传导方式，黑色素性受体相关的蛋白2（MRAP2）介导的受体敏化以及受体偶联的偶联是通过下丘脑MC4R神经元去极化的KIR7.1，这对于通过下丘脑的MC4R神经元去极至关重要。在此应用中，我们建议使用上述独特的药物工具，以及一组删除MC4R神经元中G的GIR7.1，MRAP2和�-arrestin1信号传导的组织特异性敲除小鼠，以测试MC4R PAMS可以纠正MECORACORTIN HAPLOISITION和SIDER（S）的MC4R PAM和S）的假设（S）特征良好的减肥，压力和有心脏的效果。该研究计划的结果应为1）提高我们对MC4R独特的药物特性的理解，2）增强我们对能量稳态的中心控制的理解，3）为研究社区提供了一套独特的药物和遗传工具，4）提供了有效利用MC4R作为药物目标的基本知识。

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

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.

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

• 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