基于促黑素皮质素激动剂Ac-His-dPhe-Arg-Trp-NH2序列的α/β(3)-肽的合成与药理学
Synthesis and Pharmacology of α/β(3)-Peptides Based on the Melanocortin Agonist Ac-His-dPhe-Arg-Trp-NH2 Sequence.
作者信息
Singh Anamika, Tala Srinivasa R, Flores Viktor, Freeman Katie, Haskell-Luevano Carrie
机构信息
Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota , Minneapolis, Minnesota 55455, United States ; Department of Pharmacodynamics, College of Pharmacy, University of Florida , Gainesville, Florida 32610, United States.
Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota , Minneapolis, Minnesota 55455, United States.
出版信息
ACS Med Chem Lett. 2015 Apr 8;6(5):568-72. doi: 10.1021/acsmedchemlett.5b00053. eCollection 2015 May 14.
Abstract
The melanocortin-3 and -4 receptors are expressed in the brain and play key roles in regulating feeding behavior, metabolism, and energy homeostasis. In the present study, incorporation of β(3)-amino acids into a melanocortin tetrapeptide template was investigated. Four linear α/β(3)-hybrid tetrapeptides were designed with the modifications at the Phe, Arg, and Trp residues in the agonist sequence Ac-His-dPhe-Arg-Trp-NH2. The most potent mouse melanocortin-4 receptor (mMC4R) agonist, Ac-His-dPhe-Arg-β(3)hTrp-NH2 (8) showed 35-fold selectivity versus the mMC3R. The study presented here has identified a new template with heterogeneous backbone for designing potent and selective melanocortin receptor ligands.
摘要
黑皮质素-3和-4受体在大脑中表达，并在调节进食行为、新陈代谢和能量平衡方面发挥关键作用。在本研究中，对将β(3)-氨基酸掺入黑皮质素四肽模板进行了研究。设计了四种线性α/β(3)-杂合四肽，对激动剂序列Ac-His-dPhe-Arg-Trp-NH2中的苯丙氨酸、精氨酸和色氨酸残基进行了修饰。最有效的小鼠黑皮质素-4受体（mMC4R）激动剂Ac-His-dPhe-Arg-β(3)hTrp-NH2（8）对mMC3R的选择性为35倍。此处介绍的研究确定了一种具有异质主链的新模板，用于设计强效和选择性的黑皮质素受体配体。
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