Melanocortin Ligands in Disease Cachexia

恶病质中的黑皮质素配体

基本信息

批准号：
7918646
负责人：
Kenneth Allen Gruber
金额：
$ 19.93万
依托单位：
TENSIVE CONTROLS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-06-15 至 2012-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7918646
关键词：
Achievement Acute Adipose tissue Adverse effects Affect Agonist Amides Amino Acid Sequence Amino Acids Anorexia Appetite Regulation Biological Assay Body Weight decreased C-terminal Cachexia Cardiovascular system Chemical Structure Chronic Clinical Communicable Diseases Complication Data Desire for food Digestion Disease Dissociation Dose Eating Energy Metabolism Family Fatal Outcome Fatty acid glycerol esters Food Intake Regulation Genome Goals Homeostasis Inflammatory Left Ligands Maintenance Malignant Neoplasms Megestrol Acetate Metabolic Metabolism Neuraxis Obesity Outcome Peptides Pharmaceutical Preparations Pharmacotherapy Phase Phenotype Play RFamide peptide Radiation Radiation therapy Regulation Rheumatoid Arthritis Role Series Structure Syndrome System Therapeutic Therapeutic Agents Therapeutic Index Virus Diseases Water arginylphenylalaninamide cytokine design drug candidate effective therapy improved in vivo indexing meetings melanocortin receptor mimetics pharmacophore phenylalanylarginine phenylalanyltryptophan preclinical study public health relevance receptor research study small molecule tryptophyltyrosine

项目摘要

DESCRIPTION (provided by applicant): This project has the long-term goal of developing melanocortin receptor (MCR) antagonists as therapeutic drugs for cachexia. Cachexia, characterized by a lack of appetite and a loss of lean body mass, is a frequent complication of malignancy, infectious diseases, and chronic inflammatory states. The melanocortin system appears to play a crucial role in the regulation of food intake and energy homeostasis. There is clear experimental evidence supporting the utility of MCR antagonists in the treatment of cachexia produced by malignancies, infectious diseases, and radiation. However, there is also experimental and clinical evidence that MCR ligands have unacceptable cardiovascular effects. However, we have data that most, if not all, of the cardiovascular effects of MCR ligands are not due to interactions with known MCRs. Using structure-activity-analysis of MCR ligands with in vivo assays, we demonstrate the dissociation of melanocortin from cardiovascular activity. Our "concept" is that appropriate derivatives of MC ligands can suppress cardiovascular side- effects, while leaving desired therapeutic actions intact. The Specific Aims and Milestones of our Phase I project are; 1. Design derivatives of MCR antagonists that suppress acute and chronic cardiovascular side- effects. Successful derivatives achieve Milestone #1. 2. Demonstrate that MCR antagonist derivatives with suppressed cardiovascular side-effects maintain anti-cachectic activity. Successful derivatives achieve Milestone #2. Achieving our Phase 1 milestones will demonstrate that we can increase the therapeutic index of MCR ligands, providing "proof of concept." Phase II of the project will involve the design and synthesis of centrally acting MCR antagonists to alleviate the metabolic sequelae of cachexia-inducing diseases. PUBLIC HEALTH RELEVANCE: Melanocortins (MCs) are naturally substances that have potential use as therapeutic agents in cachexia, a condition of reduced appetite with enhanced metabolic rate. However, MCs have unacceptable cardiovascular effects. We propose to develop MC drugs with reduced side-effects.

描述（由申请人提供）：该项目的长期目标是将黑色素皮质受体（MCR）拮抗剂作为恶病质药物。病虫气的特征是缺乏食欲和瘦体重的损失，是恶性肿瘤，传染病和慢性炎症状态的常见并发症。黑色皮质素系统似乎在食物摄入和能量稳态的调节中起着至关重要的作用。有明确的实验证据支持MCR拮抗剂在治疗恶性肿瘤，传染病和放射线产生的恶病质中的效用。但是，也有实验和临床证据表明MCR配体具有不可接受的心血管效应。但是，我们的数据表明，MCR配体的大多数（如果不是全部）的心血管效应并不是由于与已知MCR的相互作用所致。使用体内测定的MCR配体的结构 - 活性分析，我们证明了黑色皮质素与心血管活性的解离。我们的“概念”是，MC配体的适当衍生物可以抑制心血管副作用，同时保持所需的治疗作用完整。我们I阶段项目的具体目标和里程碑是： 1。抑制急性和慢性心血管副作用的MCR拮抗剂的设计衍生物。成功的衍生品获得了里程碑＃1。 2。证明具有抑制心血管副作用的MCR拮抗剂衍生物维持抗激活活性。成功的衍生产品实现了2号里程碑。实现我们的1阶段里程碑将表明我们可以增加MCR配体的治疗指数，从而提供“概念证明”。该项目的第二阶段将涉及中央作用MCR拮抗剂的设计和合成，以减轻诱导卡希克西氏症疾病的代谢后遗症。公共卫生相关性：黑色素皮质素（MC）是天然物质，在恶病质中可能用作治疗剂，这是食欲降低，代谢率提高。但是，MC具有不可接受的心血管效应。我们建议开发副作用降低的MC药物。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Safety of TCMCB07, a melanocortin-4 antagonist peptide, in dogs with naturally occurring cachexia.

DOI：
10.1111/jvim.16915
发表时间：
2023-11
期刊：
JOURNAL OF VETERINARY INTERNAL MEDICINE
影响因子：
2.6
作者：
Axiak-Bechtel, Sandra M.;Leach, Stacey B.;Newton-Northup, Jessica R.;Milner, Rowan J.;Fox-Alvarez, Stacey A.;Fagman, Lana I.;Young, Kaylee A.;Tate, Deborah J.;Wright, Zachary M.;Chretin, John D.;Allen, Justin W.;Yoshimoto, Sean K.;Selting, Kimberly A.;Flesner, Brian K.;White, Carrie R.;Mills, Tracy;Aherne, Michael;Bergman, Philip J.;Qi, LeAnn;Gruber, Kenneth A.;Callahan, Michael F.
通讯作者：
Callahan, Michael F.

Pharmacokinetics and safety of TCMCB07, a melanocortin-4 antagonist peptide in dogs.

DOI：
10.1002/prp2.777
发表时间：
2021-05
期刊：
Pharmacology research & perspectives
影响因子：
2.6
作者：
Axiak-Bechtel SM;Leach SB;Scholten DG;Newton-Northup JR;Johnson BJ;Durham HE;Gruber KA;Callahan MF
通讯作者：
Callahan MF

Intranasal application of vasopressin fails to elicit changes in brain immediate early gene expression, neural activity and behavioural performance of rats.