N末端脂肪酰化His-dPhe-Arg-Trp-NH（2）四肽：脂肪酸链长对小鼠黑皮质素受体和人类黑素细胞的效能和选择性的影响。,Journal of Medicinal Chemistry

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N末端脂肪酰化His-dPhe-Arg-Trp-NH（2）四肽：脂肪酸链长对小鼠黑皮质素受体和人类黑素细胞的效能和选择性的影响。
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2005 May 5 , DOI: 10.1021/jm0490843
Aleksandar Todorovic ₁ , Jerry Ryan Holder ₁ , Rayna M. Bauzo ₁ , Joseph Walker Scott ₁ , Renny Kavanagh ₁ , Zalfa Abdel-Malek ₁ , Carrie Haskell-Luevano ₁

Affiliation

黑皮质素系统参与多种重要生理途径的调节，包括色素沉着，进食行为，体重和能量稳态，炎症和性功能。所有内源性黑皮质素激动剂配体均具有保守的His-Phe-Arg-Trp四肽序列，该序列被认为对黑皮质素受体分子的识别和刺激很重要。我们实验室的先前研究导致发现，His-dPhe-Arg-Trp-NH（2）四肽N端“加帽”区域的烷基链长度增加，导致黑皮质素受体激动剂效力增加100倍。进行这项研究来系统地评估增加CH（3）（CH（2））（n）CO-His-dPhe-Arg-Trp-NH（2）的N封端烷基链长度的药理作用（n = 6-16）四肽模板。合成了十二个类似物，并在小鼠黑皮质素受体MC1R和MC3R-MC5R以及已知表达MC1R的人黑素细胞上进行了药理学表征。这些肽表现出与先前公开的四肽不同的黑皮质素受体选择性。在MC1R上观察到了最显着的增强配体效价（20到200倍）和受体选择性的结果。就刺激人黑素细胞酪氨酸酶活性而言，具有九个以上烷基的四肽优于α-MSH。此外，从人黑素细胞培养基中除去该肽后，该正十五烷酰基衍生物对酪氨酸酶活性具有残留作用，该作用至少存在4天。这些数据证明了通过添加N-末端脂肪酸部分，黑皮质素四肽的效用，效力和残留作用。

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N-terminal fatty acylated His-dPhe-Arg-Trp-NH(2) tetrapeptides: influence of fatty acid chain length on potency and selectivity at the mouse melanocortin receptors and human melanocytes.

The melanocortin system is involved in the regulation of a diverse number of physiologically important pathways including pigmentation, feeding behavior, weight and energy homeostasis, inflammation, and sexual function. All the endogenous melanocortin agonist ligands possess the conserved His-Phe-Arg-Trp tetrapeptide sequence that is postulated to be important for melanocortin receptor molecular recognition and stimulation. Previous studies by our laboratory resulted in the discovery that increasing alkyl chain length at the N-terminal "capping" region of the His-dPhe-Arg-Trp-NH(2) tetrapeptide resulted in a 100-fold increased melanocortin receptor agonist potency. This study was undertaken to systematically evaluate the pharmacological effects of increasing N-capping alkyl chain length of the CH(3)(CH(2))(n)CO-His-dPhe-Arg-Trp-NH(2) (n = 6-16) tetrapeptide template. Twelve analogues were synthesized and pharmacologically characterized at the mouse melanocortin receptors MC1R and MC3R-MC5R and human melanocytes known to express the MC1R. These peptides demonstrated melanocortin receptor selectivity profiles different from those of previously published tetrapeptides. The most notable results of enhanced ligand potency (20- to 200-fold) and receptor selectivity were observed at the MC1R. Tetrapeptides that possessed greater than nine alkyl groups were superior to alpha-MSH in terms of the stimulation of human melanocyte tyrosinase activity. Additionally, the n-pentadecanoyl derivative had a residual effect on tyrosinase activity that existed for at least 4 days after the peptide was removed from the human melanocyte culture medium. These data demonstrate the utility, potency, and residual effect of melanocortin tetrapeptides by adding N-terminal fatty acid moieties.

更新日期：2017-01-31

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