Department of Biomolecular Chemistry, Faculty of Medicine, Medical University of Lodz, Lodz, Poland.
Department of Medical Sciences, Section of Pharmacology and Italian Institute of Neuroscience, University of Ferrara, 44121 Ferrara, Italy.
Peptides. 2018 Mar;101:227-233. doi: 10.1016/j.peptides.2017.11.020. Epub 2017 Nov 28.
Opioid peptides and alkaloid drugs such as morphine, mediate their analgesic effects, but also undesired side effects, mostly through activation of the mu opioid receptor which belongs to the G protein-coupled receptor (GPCR) family. A new important pharmacological concept in the field of GPCRs is biased agonism. Two mu receptor ligands, Dmt-c[D-Lys-Phe-Phe-Asp]NH (C-36) and Dmt-c[D-Lys-Phe-p-CF-Phe-Asp]NH (F-81), were evaluated in terms of their ability to promote or block mu receptor/G protein and mu receptor/β-arrestin interactions. Using the bioluminescence resonance energy transfer (BRET) assay it was shown that C-36 activated both, G protein and β-arrestin pathways. Incorporation of trifluoromethyl group into the aromatic ring of phenylalanine in the sequence of F-81 led to activation of G-protein pathway rather than β-arrestin recruitment. Opioid cyclopeptide F-81 turned out to be a biased G protein mu receptor agonist. Such biased ligands are able to separate the biological actions of an activated receptor and have the potential to become more effective drug candidates with fewer side effects.
阿片肽和生物碱类药物（如吗啡）通过激活属于 G 蛋白偶联受体（GPCR）家族的μ阿片受体发挥其镇痛作用，但也会产生不良的副作用。在 GPCR 领域，一个新的重要药理学概念是偏向激动作用。两种μ受体配体，Dmt-c[D-Lys-Phe-Phe-Asp]NH（C-36）和 Dmt-c[D-Lys-Phe-p-CF-Phe-Asp]NH（F-81），在促进或阻断μ受体/G 蛋白和 μ受体/β-arrestin 相互作用的能力方面进行了评估。使用生物发光共振能量转移（BRET）测定法表明，C-36 激活了 G 蛋白和β-arrestin 途径。在 F-81 的序列中，苯丙氨酸的芳环上引入三氟甲基导致 G 蛋白途径的激活，而不是β-arrestin 的募集。阿片环肽 F-81 是一种偏向 G 蛋白μ受体激动剂。这种偏向配体能够分离激活受体的生物学作用，并有潜力成为更有效的候选药物，副作用更少。
