Weirath Nicholas A, Zajac Jonathan W P, Donow Haley M, Lavoi Travis M, Pinilla Clemencia, Santos Radleigh G, Prajapati Ritu, Speth Robert, Ericson Mark D, Sarupria Sapna, Giulianotti Marcello A, Haskell-Luevano Carrie
Department of Medicinal Chemistry and the Institute for Translational Neuroscience, University of Minnesota, Minneapolis, Minnesota 55455, United States.
Department of Chemistry and Chemical Theory Center, University of Minnesota, Minneapolis, Minnesota 55455, United States.
J Med Chem. 2025 Feb 13;68(3):2504-2527. doi: 10.1021/acs.jmedchem.4c01556. Epub 2025 Jan 20.
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.
黑皮质素受体是一类在中枢和外周表达的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，可作为肥胖和恶病质等疾病的潜在治疗靶点。实施了一项基于混合物的无偏向高通量文库筛选，以鉴定新型配体，重点是鉴定小鼠黑皮质素-3受体的纳摩尔级强效激动剂。该筛选发现了一种N-支链三环胍支架（TPI2408），其中包含三种纳摩尔级强效mMC3R激动剂以及对mMC4R具有拮抗作用的其他化合物。通过后续的位置扫描拮抗剂筛选证实了该支架文库在mMC4R上的拮抗剂特性。此外，本文的分子动力学模拟为黑皮质素受体的多药理学特性提供了机制性见解。所公开的材料有可能作为研究黑皮质素受体功能的重要工具和构效关系支架。
