Novel molecular targets of dezocine and their clinical implications.
Novel molecular targets of dezocine and their clinical implications.
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DOI：
10.1097/aln.0000000000000076
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发表时间：
2014-03
期刊：
影响因子：
8.8
通讯作者：
Roth BL
中科院分区：
文献类型：
--
作者：
Liu R;Huang XP;Yeliseev A;Xi J;Roth BL
虽然马洛辛是一种部分μ阿片受体激动剂，但它不是一种受控物质。因此，表征的分子靶点的西兰花碱是至关重要的科学和临床意义。本研究的目的是表征西洋参碱的分子靶点及其意义。对44种可用的受体和转运蛋白进行了马诺新的结合筛选。沿着计算进行新靶点的功能测定以定位结合位点。对人κ阿片受体进行了G蛋白活化研究，以确定马洛辛是否为κ拮抗剂。数据表示为平均值± SE。对于mu受体、δ受体和kappa受体，马诺辛的亲和力分别为3.7±0.7 nM、527±70 nM和31.9±1.9 nM。地佐辛不能诱导G蛋白与κ阿片受体的激活，并且浓度依赖性地抑制κ激动剂（salvinorin A和纳布啡）诱导的受体激活，表明地佐辛是κ拮抗剂。两个新的分子靶点（去甲肾上腺素转运蛋白，NET和血清素转运蛋白，SERT）被确定。地佐辛浓度依赖性地抑制去甲肾上腺素和5-羟色胺在体外的再摄取。NET和SERT的半数最大抑制浓度（以pIC 50表示）分别为5.68±0.11和5.86 ± 0.17。地佐辛占据已知NET和SERT抑制剂的结合位点。揭示了马洛辛作为部分μ受体激动剂、κ受体拮抗剂和去甲肾上腺素和5-羟色胺再摄取抑制剂（通过NET和SERT）的独特分子药理学特征。这些发现揭示了潜在的重要的新的临床意义和药物相互作用的西洋参碱。
While dezocine is a partial mu opioid receptor agonist, it is not a controlled substance. Thus, the characterization of the molecular targets of dezocine is critical for scientific and clinical implications. The goal of this study is to characterize molecular targets for dezocine and their implications. A binding screen for dezocine was performed on 44 available receptors and transporter proteins. Functional assays for the novel targets were performed along with computation calculations to locate the binding site. A G protein activation study was performed for the human kappa opioid receptor to determine whether dezocine is a kappa antagonist. Data are presented as mean ± SE. The affinities for dezocine were 3.7±0.7 nM for the mu receptor, 527±70 nM for the delta receptor, and 31.9±1.9 nM for the kappa receptor. Dezocine failed to induce G protein activation with kappa opioid receptor and concentration dependently inhibited kappa agonist (salvinorin A and nalbuphine) induced receptor activation, indicating that dezocine is a kappa antagonist. Two novel molecular targets (norepinephrine transporter, NET; and serotonin transporter, SERT) were identified. Dezocine concentration-dependently inhibited norepinephrine and serotonin reuptake in vitro. The half maximal inhibitory concentrations (expressed as pIC50) were 5.68±0.11 for NET and 5.86 ± 0.17 for SERT. Dezocine occupied the binding site for known NET and SERT inhibitors. The unique molecular pharmacological profile of dezocine as a partial mu receptor agonist, a kappa receptor antagonist and a norepinephrine and serotonin reuptake inhibitor (via NET and SERT) was revealed. These discoveries reveal potentially important novel clinical implications and drug interactions of dezocine.