Head‐to‐tail cyclized analogs of the µ opioid receptor (MOR) agonist tetrapeptides DALDA (H‐Tyr‐D‐Arg‐Phe‐Lys‐NH₂ and [Dmt¹]DALDA (H‐Dmt‐D‐Arg‐Phe‐Lys‐NH₂; Dmt = 2′,6′‐dimethyltyrosine) and their enantiomers (mirror‐image isomers) were synthesized and pharmacologically characterized in vitro. Three pairs of enantiomeric cyclic peptides with both mirror‐image isomers having equipotent MOR binding affinities but different binding affinities at the δ and κ opioid receptors were identified. The cyclic peptide enantiomers c[‐D‐Arg‐Phe‐Lys‐Tyr‐] (1) and c[‐Arg‐D‐Phe‐D‐Lys‐D‐Tyr‐] (2) showed nearly identical MOR binding affinity (1‐2 nM) and equipotent MOR antagonist activity. The results of a MOR docking study indicated a very similar binding mode of the two enantiomers with nearly complete spatial overlap of the peptide ring structures and side chain interactions with the same MOR residues. Compounds 1 and 2 represent the first pair of enantiomeric G‐protein‐coupled receptor (GPCR) ligands having multiple chiral centers, with both optical antipodes showing equal, low nanomolar receptor binding affinity.

中文翻译：

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μ阿片受体上环状阿片肽的等价对映体。

μ阿片受体激动剂四肽的头尾环化类似物DALDA（H‐Tyr‐D‐Arg‐Phe‐Lys‐NH ₂和[Dmt ¹ ] DALDA（H‐Dmt‐D‐Arg‐Phe‐合成了Lys‐NH ₂ ; Dmt = 2'，6'-二甲基酪氨酸及其对映异构体（镜像异构体），并在体外进行了药理学表征，三对对映体环状肽均具有相同的MOR结合亲和力，但镜像镜像异构体在δ和κ阿片受体上有不同的结合亲和力，环肽对映体c [-D-Arg-Phe-Lys-Tyr-]（1）和c [-Arg-D-Phe-Dy-Lys-D- Tyr‐]（2）显示出几乎相同的MOR结合亲和力（1-2 nM）和相等的MOR拮抗剂活性。MOR对接研究的结果表明，两种对映异构体的结合模式非常相似，肽环结构的空间重叠几乎完全，并且具有相同MOR残基的侧链相互作用。化合物1和2代表第一对具有多个手性中心的对映体G蛋白偶联受体（GPCR）配体，两个光学对映体均显示出相同的低纳摩尔受体结合亲和力。