在小鼠黑皮质素-3受体上具有最小激动剂活性的黑皮质素拮抗剂四肽。
Melanocortin antagonist tetrapeptides with minimal agonist activity at the mouse melanocortin-3 receptor.
作者信息
Doering Skye R, Todorovic Aleksandar, Haskell-Luevano Carrie
机构信息
Department of Medicinal Chemistry, University of Minnesota , Twin Cities, Minnesota 55455, United States.
Department of Medicinal Chemistry, University of Florida , Gainesville, Florida 32610, United States.
出版信息
ACS Med Chem Lett. 2014 Dec 29;6(2):123-7. doi: 10.1021/ml500340z. eCollection 2015 Feb 12.
Abstract
The melanocortin system regulates many important functions in the body. There are five melanocortin G protein-coupled receptor subtypes known to date. Herein, we report a structure-activity relationship (SAR) study of a tetrapeptide lead discovered through a double substitution strategy at the melanocortin core His-Phe-Arg-Trp sequence. Several compounds were identified with micromolar agonist activity at the mouse melanocortin-1 (mMC1R) and mouse melanocortin-5 receptor (mMC5R) subtypes, weak antagonist activity at the mouse melanocortin-3 receptor (mMC3R), and potent antagonist activity at the mouse melanocortin-4 receptor (mMC4R). Two compounds (2 and 3) were nanomolar mMC4R antagonists with no mMC3R antagonist activity observed. Additionally, we identified three tetrapeptide MC3R antagonists (1, 6, and 7) that possess minimal mMC3R agonist activity only at 100 μM, not commonly observed for mMC3R/mMC4R antagonists. These novel molecular templates have the potential as molecular probes to better differentiate the roles of the centrally expressed MC3 and MC4 receptors.
摘要
黑皮质素系统调节身体许多重要功能。迄今已知有五种黑皮质素G蛋白偶联受体亚型。在此，我们报告了通过对黑皮质素核心His-Phe-Arg-Trp序列进行双取代策略发现的一种四肽先导物的构效关系（SAR）研究。鉴定出了几种化合物，它们对小鼠黑皮质素-1（mMC1R）和小鼠黑皮质素-5受体（mMC5R）亚型具有微摩尔级激动剂活性，对小鼠黑皮质素-3受体（mMC3R）具有弱拮抗剂活性，对小鼠黑皮质素-4受体（mMC4R）具有强效拮抗剂活性。两种化合物（2和3）是纳摩尔级mMC4R拮抗剂，未观察到mMC3R拮抗剂活性。此外，我们鉴定出三种四肽MC3R拮抗剂（1、6和7），它们仅在100μM时具有最小的mMC3R激动剂活性，这在mMC3R/mMC4R拮抗剂中并不常见。这些新型分子模板有潜力作为分子探针，以更好地区分中枢表达的MC3和MC4受体的作用。
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Structure-activity relationships of the melanocortin tetrapeptide Ac-His-D-Phe-Arg-Trp-NH2 at the mouse melanocortin receptors. 4. Modifications at the Trp position.小鼠黑皮质素受体处黑皮质素四肽Ac-His-D-Phe-Arg-Trp-NH2的构效关系。4.色氨酸位置的修饰。
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