Joseph Christine G, Wang Xiang S, Scott Joseph W, Bauzo Rayna M, Xiang Zhimin, Richards Nigel G, Haskell-Luevano Carrie
Department of Medicinal Chemistry, University of Florida, Gainesville, FL 32610, USA.
J Med Chem. 2004 Dec 30;47(27):6702-10. doi: 10.1021/jm0492756.
The agouti-related protein (AGRP) is an endogenous antagonist of the centrally expressed melanocortin receptors. The melanocortin-4 receptor (MC4R) is involved in energy homeostasis, food intake, sexual function, and obesity. The endogenous hAGRP protein is 132 amino acids in length, possesses five disulfide bridges at the C-terminus of the molecule, and is expressed in the hypothalamus of the brain. We have previously reported that a monocyclic hAGRP(103-122) peptide is an antagonist at the melanocortin receptors expressed in the brain. Stereochemical inversion from the endogenous l- to d-isomers of single or multiple amino acid modifications in this monocyclic truncated hAGRP sequence resulted in molecules that are converted from melanocortin receptor antagonists into melanocortin receptor agonists. The Asp-Pro-Ala-Ala-Thr-Ala-Tyr-cyclo[Cys-Arg-DPhe-DPhe-Asn-Ala-Phe-Cys]-Tyr-Ala-Arg-Lys-Leu peptide resulted in a 60 nM melanocortin-1 receptor agonist that is 100-fold selective versus the mMC4R, 1000-fold selective versus the mMC3R, and ca. 180-fold selective versus the mMC5R. In attempts to identify putative ligand-receptor interactions that may be participating in the agonist induced stimulation of the MC4R, selected ligands were docked into a homology molecular model of the mMC4R. These modeling studies have putatively identified hAGRP ligand DArg111-mMC4RAsn115 (TM3) and the hAGRP DPhe113-mMC4RPhe176 (TM4) interactions as important for agonist activity.
刺鼠相关蛋白（AGRP）是中枢表达的黑皮质素受体的内源性拮抗剂。黑皮质素-4受体（MC4R）参与能量平衡、食物摄入、性功能和肥胖。内源性hAGRP蛋白长度为132个氨基酸，在分子的C末端具有五个二硫键，并在大脑的下丘脑表达。我们之前报道过，单环hAGRP(103 - 122)肽是大脑中表达的黑皮质素受体的拮抗剂。在这个单环截短的hAGRP序列中，单个或多个氨基酸修饰从内源性L-异构体立体化学转化为D-异构体，导致分子从黑皮质素受体拮抗剂转变为黑皮质素受体激动剂。天冬氨酸-脯氨酸-丙氨酸-丙氨酸-苏氨酸-丙氨酸-酪氨酸-环[半胱氨酸-精氨酸-D-苯丙氨酸-D-苯丙氨酸-天冬酰胺-丙氨酸-苯丙氨酸-半胱氨酸]-酪氨酸-丙氨酸-精氨酸-赖氨酸-亮氨酸肽产生了一种60 nM的黑皮质素-1受体激动剂，对mMC4R的选择性为100倍，对mMC3R的选择性为1000倍，对mMC5R的选择性约为180倍。为了确定可能参与激动剂诱导的MC4R刺激的假定配体-受体相互作用，将选定的配体对接至mMC4R的同源分子模型中。这些建模研究推测确定hAGRP配体DArg111-mMC4RAsn115（跨膜区3）和hAGRP DPhe113-mMC4RPhe176（跨膜区4）相互作用对激动剂活性很重要。
