Laboratory of Chemical Biology, Institute of Biochemistry, Biological Research Centre, Szeged, 62. Temesvári krt., H-6726 Szeged, Hungary.
Theoretical Medicine Doctoral School, Faculty of Medicine, University of Szeged, 97. Tisza L. krt., H-6722 Szeged, Hungary.
Molecules. 2020 Sep 17;25(18):4260. doi: 10.3390/molecules25184260.
The opioid receptors are members of the G-protein-coupled receptor (GPCR) family and are known to modulate a variety of biological functions, including pain perception. Despite considerable advances, the mechanisms by which opioid agonists and antagonists interact with their receptors and exert their effect are still not completely understood. In this report, six new hybrids of the Dmt-Tic pharmacophore and cyclic peptides, which were shown before to have a high affinity for the µ-opioid receptor (MOR) were synthesized and characterized pharmacologically in calcium mobilization functional assays. All obtained ligands turned out to be selective antagonists of the δ-opioid receptor (DOR) and did not activate or block the MOR. The three-dimensional structural determinants responsible for the DOR antagonist properties of these analogs were further investigated by docking studies. The results indicate that these compounds attach to the DOR in a slightly different orientation with respect to the Dmt-Tic pharmacophore than Dmt-TicΨ[CH-NH]Phe-Phe-NH (DIPP-NH[Ψ]), a prototypical DOR antagonist peptide. Key pharmacophoric contacts between the DOR and the ligands were maintained through an analogous spatial arrangement of pharmacophores, which could provide an explanation for the predicted high-affinity binding and the experimentally observed functional properties of the novel synthetic ligands.
阿片受体是 G 蛋白偶联受体 (GPCR) 家族的成员，已知其调节多种生物学功能，包括疼痛感知。尽管取得了相当大的进展，但阿片类激动剂和拮抗剂与其受体相互作用并发挥作用的机制仍不完全清楚。在本报告中，合成了六个新的 Dmt-Tic 药效团和环状肽的杂种，这些杂种以前显示出对μ-阿片受体 (MOR) 具有高亲和力，并在钙动员功能测定中进行了药理学表征。所有获得的配体均被证明是 δ-阿片受体 (DOR) 的选择性拮抗剂，既不激活也不阻断 MOR。通过对接研究进一步研究了这些类似物具有 DOR 拮抗剂特性的三维结构决定因素。结果表明，与 Dmt-TicΨ[CH-NH]Phe-Phe-NH(DIPP-NH[Ψ])相比，这些化合物以略微不同的方向与 DOR 结合，DIPP-NH[Ψ]是一种典型的 DOR 拮抗剂肽。DOR 和配体之间的关键药效团接触通过药效团的类似空间排列得以维持，这可以解释预测的高亲和力结合和新型合成配体的实验观察到的功能特性。
