Department of Chemistry "G. Ciamician", University of Bologna, via Selmi 2, 40126 Bologna, Italy.
ChemMedChem. 2011 Sep 5;6(9):1640-53. doi: 10.1002/cmdc.201100169. Epub 2011 Jun 30.
Herein we propose the D-Trp-Phe sequence within an inverse type II β-turn as a new kind of pharmacophoric motif for μ-opioid receptor (MOR) cyclopeptide agonists. Initially, we observed that c[Tyr-D-Pro-D-Trp-Phe-Gly] (4), an analogue of endomorphin-1 (H-Tyr-Pro-Trp-Phe-NH₂) lacking the crucial protonatable amino group of Tyr 1, is a MOR agonist with 10⁻⁸ M affinity. Molecular docking analysis suggested that the relevant interactions with the receptor involve D-Trp-Phe. The bioactive conformation of this region was investigated by selected derivatives of 4 designed to adopt an inverse type II β-turn. These efforts led to c[Tyr-Gly-D-Trp-Phe-Gly] (14) and to the cyclotetrapeptide c[D-Asp-1-amide-β-Ala-D-Trp-Phe] (15), showing improved nanomolar affinity. Both 14 and 15 selectively bind MOR, as they have negligible affinity for the κ- and δ-opioid receptors. Both 14 and 15 behave as partial MOR agonists in functional assays. Conformational and docking analyses confirm the role of the inverse β-turn in binding. These results indicate that the D-Trp-Phe inverse β-turn structure can be used for designing non-endomorphin-like peptidomimetic opioid agonists in general, characterized by an atypical mechanism of interaction between ligand and receptor.
在这里，我们提出 D-Trp-Phe 序列在反向 II 型 β-转角内作为 μ 阿片受体 (MOR) 环肽激动剂的一种新的药效团特征。最初，我们观察到 c[Tyr-D-Pro-D-Trp-Phe-Gly]（4），一种缺少 Tyr1 关键可质子化氨基的内吗啡肽-1（H-Tyr-Pro-Trp-Phe-NH₂）类似物，是一种具有 10⁻⁸M 亲和力的 MOR 激动剂。分子对接分析表明，与受体的相关相互作用涉及 D-Trp-Phe。通过设计的 4 的一些衍生化合物来研究该区域的生物活性构象，这些衍生化合物旨在采用反向 II 型 β-转角。这些努力导致了 c[Tyr-Gly-D-Trp-Phe-Gly]（14）和环四肽 c[D-Asp-1-amide-β-Ala-D-Trp-Phe]（15）的产生，它们具有改善的纳摩尔亲和力。14 和 15 都选择性地结合 MOR，因为它们对 κ 和 δ 阿片受体几乎没有亲和力。14 和 15 在功能测定中均表现为部分 MOR 激动剂。构象和对接分析证实了反向 β-转角在结合中的作用。这些结果表明，D-Trp-Phe 反向 β-转角结构可用于设计非内吗啡肽样肽模拟阿片类激动剂，其特点是配体和受体之间的相互作用具有非典型机制。
