A Cyclic Tetrapeptide (“Cyclodal”) and Its Mirror-Image Isomer Are Both High-Affinity μ Opioid Receptor Antagonists,Journal of Medicinal Chemistry

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A Cyclic Tetrapeptide (“Cyclodal”) and Its Mirror-Image Isomer Are Both High-Affinity μ Opioid Receptor Antagonists
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2016-10-03 00:00:00 , DOI: 10.1021/acs.jmedchem.6b01200
Grazyna Weltrowska ₁ , Thi M.-D. Nguyen ₁ , Nga N. Chung ₁ , JodiAnne Wood ₂ , Xiaoyu Ma ₂ , Jason Guo ₂ , Brian C. Wilkes ₁ , Yang Ge ₃ , André Laferrière ₃ , Terence J. Coderre ₃ , Peter W. Schiller _{1,

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Affiliation

Head-to-tail cyclization of the μ opioid receptor (MOR) agonist [Dmt¹]DALDA (H-Dmt-d-Arg-Phe-Lys-NH₂ (9; Dmt = 2′,6′-dimethyltyrosine) resulted in a highly active, selective MOR antagonist, c[-d-Arg-Phe-Lys-Dmt-] (1) (“cyclodal”), with subnanomolar binding affinity. A docking study of cyclodal using the crystal structure of MOR in the inactive form showed a unique binding mode with the two basic residues of the ligand forming salt bridges with the Asp¹²⁷ and Glu²²⁹ receptor residues. Cyclodal showed high plasma stability and was able to cross the blood–brain barrier to reverse morphine-induced, centrally mediated analgesia when given intravenously. Surprisingly, the mirror-image isomer (optical antipode) of cyclodal, c[-Arg-d-Phe-d-Lys-d-Dmt-] (2), also turned out to be a selective MOR antagonist with 1 nM binding affinity, and thus, these two compounds represent the first example of mirror image opioid receptor ligands with both optical antipodes having high binding affinity. Reduction of the Lys-Dmt peptide bond in cyclodal resulted in an analogue, c[-d-Arg-Phe-LysΨ[CH₂NH]Dmt-] (8), with MOR agonist activity.

中文翻译：

环状四肽（“ Cyclodal”）及其镜像异构体均为高亲和力μ阿片受体拮抗剂

μ阿片受体激动剂[Dmt ¹ ] DALDA（H-Dmt- d -Arg-Phe-Lys-NH ₂（9 ; Dmt = 2'，6'-二甲基酪氨酸）从头到尾环化导致一种具有高活性的选择性MOR拮抗剂c [ -d -Arg-Phe-Lys-Dmt-]（1）（“环糊精”），具有亚纳摩尔结合亲和力。形式显示出独特的结合模式，配体的两个基本残基与Asp ¹²⁷和Glu ²²⁹形成盐桥受体残基。静脉注射时，摆线针显示出较高的血浆稳定性，并能够穿过血脑屏障以逆转吗啡诱导的中央介导的镇痛作用。出乎意料的是，环化的c [-Arg- d -Phe- d -Lys- d -Dmt-]（2）的镜像异构体（光学对映体）也被证明是具有1 nM结合亲和力的选择性MOR拮抗剂。因此，这两种化合物代表了镜像阿片受体配体的第一个实例，其两个光学对映体均具有高结合亲和力。灭环蛋白中Lys-Dmt肽键的还原产生了具有MOR激动剂活性的类似物c [ -d -Arg-Phe-LysD [CH ₂ NH] Dmt-]（8）。

更新日期：2016-10-03

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