Distinct pharmacological properties of morphine metabolites at Gi-protein and β-arrestin signaling pathways activated by the human μ-opioid receptor
Distinct pharmacological properties of morphine metabolites at Gi-protein and β-arrestin signaling pathways activated by the human μ-opioid receptor
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DOI：
10.1016/j.bcp.2011.03.001
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发表时间：
2011-05-15
影响因子：
5.8
通讯作者：
Zenk, Meinhart H.
中科院分区：
文献类型：
--
作者：
Froelich, Nadine;Dees, Christian;Zenk, Meinhart H.
吗啡和其他几种阿片类药物是治疗急性和慢性疼痛的重要药物。阿片类药物诱导的镇痛作用主要由μ阿片受体（莫尔）介导。当施用于人类时，复杂的代谢途径导致产生许多代谢物，其中九种可被认为是主要代谢物。虽然两种主要化合物吗啡-6-葡糖苷酸和吗啡-3-葡糖苷酸的性质已得到充分描述，但其他吗啡代谢物的活性在很大程度上尚不清楚。在这里，我们通过比较吗啡及其九种主要代谢物对人类莫尔参与的两种主要信号通路的功效和效力进行了广泛的药理学表征，这两种信号通路分别通过G（i）-蛋白活化和β-抑制蛋白发生。我们使用放射性配体结合研究和基于FRET的方法来监测单个完整2931细胞中MOR介导的G（i）蛋白激活和β-抑制蛋白募集。这种方法确定了两个主要的吗啡代谢物，我们分为“强”和“弱”受体配体。强部分激动剂吗啡、吗啡-6-葡糖苷酸、去甲吗啡、吗啡-6-硫酸盐、6-乙酰吗啡和3-乙酰吗啡在纳摩尔范围内显示出效力，而弱代谢物吗啡-N-氧化物、吗啡-3-硫酸盐、吗啡-3-葡糖苷酸和假吗啡仅在微摩尔范围内激活莫尔途径。有趣的是，去甲吗啡、6-乙酰吗啡和吗啡-6-葡萄糖醛酸苷这三种代谢物对Gi-蛋白激活的效力较低，但对β-抑制蛋白募集的效力和功效高于吗啡本身，这表明它们偏向于β-抑制蛋白途径。(C)2011 Elsevier Inc. All rights reserved.
Morphine and several other opioids are important drugs for the treatment of acute and chronic pain. Opioid-induced analgesia is predominantly mediated by the mu-opioid receptor (MOR). When administered to humans, complex metabolic pathways lead to generation of many metabolites, nine of which may be considered major metabolites. While the properties of the two main compounds, morphine-6-glucuronide and morphine-3-glucuronide, are well described, the activity of other morphine metabolites is largely unknown. Here we performed an extensive pharmacological characterization by comparing efficacies and potencies of morphine and its nine major metabolites for the two main signaling pathways engaged by the human MOR, which occur via G(i)-protein activation and beta-arrestins, respectively. We used radioligand binding studies and FRET-based methods to monitor MOR-mediated G(i)-protein activation and beta-arrestin recruitment in single intact 2931 cells. This approach identified two major groups of morphine metabolites, which we classified into "strong" and "weak" receptor ligands. Strong partial agonists morphine, morphine-6-glucuronide, normorphine, morphine-6-sulfate, 6-acetylmorphine and 3-acetylmorphine showed efficacies in the nanomolar range, while the weak metabolites morphine-N-oxide, morphine-3-sulfate, morphine-3-glucuronide and pseudomorphine activated MOR pathways only in the micromolar range. Interestingly, three metabolites, normorphine, 6-acetylmorphine and morphine-6-glucuronide, had lower potencies for Gi-protein activation but higher potencies and efficacies for beta-arrestin recruitment than morphine itself, suggesting that they are biased towards beta-arrestin pathways. (C) 2011 Elsevier Inc. All rights reserved.