Willemse Tom, Eiselt Emilie, Hollanders Karlijn, Schepens Wim, van Vlijmen Herman W T, Chung Nga N, Blais Véronique, Holleran Brain, Longpré Jean-Michel, Schiller Peter W, Maes Bert U W, Sarret Philippe, Gendron Louis, Ballet Steven
Research Group of Organic Chemistry, Departments of Bioengineering Sciences and Chemistry, Vrije Universiteit Brussel, Pleinlaan 2, 1050 Brussels, Belgium; Organic Synthesis Division, University of Antwerp, Groenenborgerlaan 171, 2020 Antwerp, Belgium.
Department of Pharmacology-Physiology, Faculty of Medicine and Health Sciences, Institut de Pharmacologie de Sherbrooke, Centre de Recherche du CHUS, Université de Sherbrooke, 3001 12(e)Avenue Nord, Sherbrooke, Quebec J1H 5N4, Canada.
Bioorg Med Chem Lett. 2018 Jul 15;28(13):2320-2323. doi: 10.1016/j.bmcl.2018.05.015. Epub 2018 May 12.
In this study, affinities and activities of derivatized analogues of Dmt-dermorphin[1-4] (i.e. Dmt-d-Ala-Phe-GlyNH, Dmt = 2',6'-dimethyl-(S)-tyrosine) for the µ opioid receptor (MOP) and δ opioid receptor (DOP) were evaluated using radioligand binding studies, functional cell-based assays and isolated organ bath experiments. By means of solid-phase or solution-phase Suzuki-Miyaura cross-couplings, various substituted regioisomers of the phenylalanine moiety in position 3 of the sequence were prepared. An 18-membered library of opioid tetrapeptides was generated via screening of the chemical space around the Phe side chain. These substitutions modulated bioactivity, receptor subtype selectivity and highly effective ligands with subnanomolar binding affinities, contributed to higher functional activities and potent analgesic actions. In search of selective peptidic ligands, we show here that the Suzuki-Miyaura reaction is a versatile and robust tool which could also be deployed elsewhere.
在本研究中，使用放射性配体结合研究、基于细胞的功能测定和离体器官浴实验，评估了Dmt-德莫啡肽[1-4]（即Dmt-d-Ala-Phe-GlyNH，Dmt = 2',6'-二甲基-(S)-酪氨酸）的衍生类似物对μ阿片受体（MOP）和δ阿片受体（DOP）的亲和力和活性。通过固相或溶液相铃木-宫浦交叉偶联反应，制备了序列中第3位苯丙氨酸部分的各种取代区域异构体。通过筛选苯丙氨酸侧链周围的化学空间，生成了一个包含18种阿片类四肽的文库。这些取代作用调节了生物活性、受体亚型选择性以及具有亚纳摩尔结合亲和力的高效配体，有助于提高功能活性和强效镇痛作用。为了寻找选择性肽类配体，我们在此表明铃木-宫浦反应是一种通用且强大的工具，也可应用于其他领域。
