N-Branched Tricyclic Guanidines as Novel Melanocortin-3 Receptor Agonists and Melanocortin-4 Receptor Antagonists

IF 6.8 1区 医学 Q1 CHEMISTRY, MEDICINAL
Nicholas A. Weirath, Jonathan W. P. Zajac, Haley M. Donow, Travis M. Lavoi, Clemencia Pinilla, Radleigh G. Santos, Ritu Prajapati, Robert Speth, Mark D. Ericson, Sapna Sarupria, Marcello A. Giulianotti and Carrie Haskell-Luevano*, 
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引用次数: 0

Abstract

The melanocortin receptors are a class of centrally and peripherally expressed G protein-coupled receptors, of which the MC3R and MC4R subtypes are implicated in the regulation of appetite and energy homeostasis and can serve as potential therapeutic targets for disorders such as obesity and cachexia. An unbiased high-throughput mixture-based library screen was implemented to identify novel ligands with an emphasis on the identification of nanomolar-potent agonists of the mouse melanocortin-3 receptor. This screen yielded the discovery of an N-branched tricyclic guanidine scaffold (TPI2408) that contained three nanomolar potent mMC3R agonists and additional compounds that possessed antagonism for the mMC4R. The antagonist character of this scaffold library at the mMC4R was confirmed by a follow-up positional scanning antagonist screen. Additionally, molecular dynamics simulations herein provide mechanistic insight into the polypharmacological characteristics of melanocortin receptors. The disclosed materials have the potential to serve as important tools and SAR scaffolds in the study of melanocortin receptor function.

Abstract Image

n支三环胍作为新型黑素皮质素-3受体激动剂和黑素皮质素-4受体拮抗剂
黑素皮质素受体是一类中枢和外周表达的G蛋白偶联受体,其中MC3R和MC4R亚型参与食欲和能量稳态的调节,可以作为肥胖和恶病质等疾病的潜在治疗靶点。一个无偏倚的高通量基于混合物的文库筛选,以确定新的配体,重点是鉴定小鼠黑素皮质素-3受体的纳米分子强效激动剂。该筛选结果发现了一种n支三环胍支架(TPI2408),其中含有三种纳摩尔强效mMC3R激动剂和其他具有mMC4R拮抗作用的化合物。该支架库在mMC4R处的拮抗剂特性通过后续的位置扫描拮抗剂筛选得到证实。此外,本文的分子动力学模拟为黑素皮质素受体的多药理特性提供了机制上的见解。公开的材料具有作为研究黑素皮质素受体功能的重要工具和SAR支架的潜力。
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来源期刊
Journal of Medicinal Chemistry
Journal of Medicinal Chemistry 医学-医药化学
CiteScore
4.00
自引率
11.00%
发文量
804
审稿时长
1.9 months
期刊介绍: The Journal of Medicinal Chemistry is a prestigious biweekly peer-reviewed publication that focuses on the multifaceted field of medicinal chemistry. Since its inception in 1959 as the Journal of Medicinal and Pharmaceutical Chemistry, it has evolved to become a cornerstone in the dissemination of research findings related to the design, synthesis, and development of therapeutic agents. The Journal of Medicinal Chemistry is recognized for its significant impact in the scientific community, as evidenced by its 2022 impact factor of 7.3. This metric reflects the journal's influence and the importance of its content in shaping the future of drug discovery and development. The journal serves as a vital resource for chemists, pharmacologists, and other researchers interested in the molecular mechanisms of drug action and the optimization of therapeutic compounds.
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