Weltrowska Grazyna, Nguyen Thi M-D, Chung Nga N, Wood JodiAnne, Ma Xiaoyu, Guo Jason, Wilkes Brian C, Ge Yang, Laferrière André, Coderre Terence J, Schiller Peter W
Laboratory of Chemical Biology and Peptide Research, Clinical Research Institute of Montreal , 110 Pine Avenue des Pins Ouest, Montreal, Quebec H2W 1R7, Canada.
Center for Drug Discovery, Northeastern University , 360 Huntington Avenue, Boston, Massachusetts 02115, United States.
J Med Chem. 2016 Oct 13;59(19):9243-9254. doi: 10.1021/acs.jmedchem.6b01200. Epub 2016 Oct 3.
Head-to-tail cyclization of the μ opioid receptor (MOR) agonist [Dmt]DALDA (H-Dmt-d-Arg-Phe-Lys-NH (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 Asp and Glu 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[CHNH]Dmt-] (8), with MOR agonist activity.
μ阿片受体（MOR）激动剂[Dmt]DALDA（H-Dmt-d-Arg-Phe-Lys-NH（9；Dmt = 2'，6'-二甲基酪氨酸）的首尾环化产生了一种高活性、选择性的MOR拮抗剂c[-d-Arg-Phe-Lys-Dmt-]（1）（“环达”），其结合亲和力为亚纳摩尔。使用非活性形式的MOR晶体结构对环达进行的对接研究显示了一种独特的结合模式，配体的两个碱性残基与受体的Asp和Glu残基形成盐桥。环达表现出高血浆稳定性，静脉注射时能够穿过血脑屏障，逆转吗啡诱导的中枢介导的镇痛作用。令人惊讶的是，环达的镜像异构体（旋光对映体）c[-Arg-d-Phe-d-Lys-d-Dmt-]（2）也被证明是一种具有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首个例子，其两个旋光对映体都具有高结合亲和力。环达中Lys-Dmt肽键的还原产生了一种具有MOR激动剂活性的类似物c[-d-Arg-Phe-LysΨ[CHNH]Dmt-]（8）。
