Abstract

A series of 10 cyclic, biaryl analogs of enkephalin, with Tyr or Phe residues at positions 1 and 4, were synthesized according to the Miyaura borylation and Suzuki coupling methodology. Biaryl bridges formed by side chains of the two aromatic amino acid residues are of the meta–meta, meta–para, para–meta, and para–para configuration. Conformational properties of the peptides were studied by CD and NMR. CD studies allowed only to compare conformations of individual peptides while NMR investigations followed by XPLOR calculations provided detailed information on their conformation. Reliability of the XPLOR calculations was confirmed by quantum chemical ones performed for one of the analogs. No intramolecular hydrogen bonds were found in all the peptides. They are folded and adopt the type IV β-turn conformation. Due to a large steric strain, the aromatic carbon atoms forming the biaryl bond are distinctly pyramidalized. Seven of the peptides were tested in vitro for their affinity for the µ-opioid receptor.

中文翻译：

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联芳基环化在合成具有高度受限灵活性的环状脑啡肽类似物中的应用

摘要

根据 Miyaura 硼酸化和 Suzuki 偶联方法合成了一系列 10 个环状联芳基脑啡肽类似物，在 1 和 4 位具有 Tyr 或 Phe 残基。由两个芳香族氨基酸残基的侧链形成的联芳桥具有间-间、间-对、对-间和对-对构型。通过 CD 和 NMR 研究了肽的构象特性。CD 研究只能比较单个肽的构象，而 NMR 研究和 XPLOR 计算提供了有关其构象的详细信息。XPLOR 计算的可靠性通过对其中一种类似物进行的量子化学计算得到了证实。所有肽均未发现分子内氢键。它们折叠并采用 IV 型 β 转角构象。由于大的空间应变，形成联芳键的芳香族碳原子明显金字塔化。在体外测试了其中七种肽对μ-阿片受体的亲和力。