Melanocortin Receptor Selective Ligands

黑皮质素受体选择性配体

• 批准号: 10713372
• 负责人: Marc Giulianotti
• 金额: $ 9.23万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10713372
• 关键词: ART protein; Acute; Age; Agonist; Basic Science; Biological; Blood Pressure; Body mass index; Brain; Bypass; Central Nervous System; Collection; Complex; Country; Coupled; Data; Developed Countries; Diet; Disease; Eating; Energy Intake; Energy Metabolism; Exercise; Fatty acid glycerol esters; Feeding behaviors; Food Energy; Food Intake Regulation; GTP-Binding Proteins; Genes; Genetic; Goals; Heart Diseases; Homeostasis; Human; Hyperphagia; Hypertension; Hypothalamic structure; In Vitro; Knockout Mice; Lead; Ligands; Mediating; Melanocortin 3 Receptor; Melanocortin 4 Receptor; Metabolic; Modification; Molecular Probes; Morbidity - disease rate; Mus; Neurons; Neurosecretory Systems; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Obesity associated disease; Outcome; Pathway interactions; Peer Review; Peptides; Persons; Pharmaceutical Chemistry; Phenotype; Physiological; Physiology; Population; Pro-Opiomelanocortin; Publications; Receptor Activation; Regulation; Reporting; Research; Research Project Grants; Risk Factors; Role; Satiation; Stroke; Therapeutic; Therapeutic Agents; Transcript; United States; Validation; Weight; Wild Type Mouse; antagonist; antagonist G; blood glucose regulation; candidate selection; design; drug discovery; erection; experimental study; genetic manipulation; in vivo; in vivo evaluation; lead candidate; male; melanocortin receptor; metabolic phenotype; mouse genetics; obesity treatment; preprohormone; rational design; receptor; screening; side effect; small molecule; small molecule libraries; tool

Obesity (body mass index, BMI >30) 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, hypertension, and morbidity. The G-protein coupled melanocortin-3 receptor (MC3R) is expressed in the central nervous system (brain) and is part of the melanocortin pathway involved in the regulation of energy homeostasis. The specific role of the MC3R in the regulation of obesity has not been clearly defined due to a lack of receptor specific ligands and a complex metabolic phenotype of the MC3R knockout mouse. This project is focused upon the discovery of MC3R selective molecular probes (peptide and small molecules), in vitro lead candidate selection, and use of wild type and knockout mice for further molecule lead selection. The working hypothesis of this project is that the MC3R is directly involved in the regulation of food intake, satiety, and energy/metabolic homeostasis. It is anticipated that MC3R ligands have the potential to become therapeutic ligands for obesity related diseases that bypass the human melanocortin-4 receptor (MC4R) agonist associated side effects of male erectile activity and hypertension.

肥胖（身体质量指数，BMI >30）困扰着美国数百万人， 其他国家，是心脏病，II型糖尿病， 中风、高血压和发病率。G蛋白偶联黑皮质素-3受体 （MC 3R）在中枢神经系统（脑）中表达，是神经系统的一部分。 黑皮质素途径参与能量稳态的调节。的具体作用 MC 3R在肥胖调节中的作用还没有明确定义， 受体特异性配体和MC 3R敲除的复杂代谢表型 老鼠.本项目的重点是发现MC 3R选择性分子探针 （肽和小分子），体外先导候选物选择，以及野生型和 敲除小鼠用于进一步的分子先导选择。这个项目的工作假设 MC 3R直接参与调节食物摄入，饱腹感， 能量/代谢稳态。预计MC 3R配体具有潜在的 成为肥胖相关疾病的治疗配体， 黑素皮质素-4受体（MC 4 R）激动剂与男性勃起活动相关的副作用 和高血压。

项目成果

Discovery of Nanomolar Melanocortin-3 Receptor (MC3R)-Selective Small Molecule Pyrrolidine Bis-Cyclic Guanidine Agonist Compounds Via a High-Throughput "Unbiased" Screening Campaign.

• DOI: 10.1021/acs.jmedchem.0c02041
• 发表时间: 2021-05-13
• 期刊: Journal of medicinal chemistry
• 影响因子: 7.3
• 作者: Doering SR;Freeman K;Debevec G;Geer P;Santos RG;Lavoi TM;Giulianotti MA;Pinilla C;Appel JR;Houghten RA;Ericson MD;Haskell-Luevano C
• 通讯作者: Haskell-Luevano C

Functional Mixture-Based Positional Scan Identifies a Library of Antagonist Tetrapeptide Sequences (LAtTeS) with Nanomolar Potency for the Melanocortin-4 Receptor and Equipotent with the Endogenous AGRP(86-132) Antagonist.

• DOI: 10.1021/acs.jmedchem.1c01417
• 发表时间: 2021-10-14
• 期刊: Journal of medicinal chemistry
• 影响因子: 7.3
• 作者: Ericson MD;Doering SR;Larson CM;Freeman KT;LaVoi TM;Donow HM;Santos RG;Cho RH;Koerperich ZM;Giulianotti MA;Pinilla C;Houghten RA;Haskell-Luevano C
• 通讯作者: Haskell-Luevano C

The Parallel Structure-Activity Relationship Screening of Three Compounds Identifies the Common Agonist Pharmacophore of Pyrrolidine Bis-Cyclic Guanidine Melanocortin-3 Receptor (MC3R) Small-Molecule Ligands.

• DOI: 10.3390/ijms241210145
• 发表时间: 2023-06-14
• 期刊: International journal of molecular sciences
• 影响因子: 5.6

Incorporation of Indoylated Phenylalanine Yields a Sub-Micromolar Selective Melanocortin-4 Receptor Antagonist Tetrapeptide.

• DOI: 10.1021/acsomega.2c03307
• 发表时间: 2022-08-09
• 期刊: ACS OMEGA
• 影响因子: 4.1
• 作者: Ericson, Mark D.;Larson, Courtney M.;Freeman, Katie T.;Nicke, Lennart;Geyer, Armin;Haskell-Luevano, Carrie
• 通讯作者: Haskell-Luevano, Carrie