Berríos-Cárcamo Pablo, Quintanilla María E, Herrera-Marschitz Mario, Vasiliou Vasilis, Zapata-Torres Gerald, Rivera-Meza Mario
Program of Molecular and Clinical Pharmacology, Faculty of Medicine, Institute of Biomedical Sciences, University of ChileSantiago, Chile; Department of Environmental Health Sciences, Yale School of Public HealthNew Haven, CT, USA.
Program of Molecular and Clinical Pharmacology, Faculty of Medicine, Institute of Biomedical Sciences, University of Chile Santiago, Chile.
Front Behav Neurosci. 2017 Jan 23;10:253. doi: 10.3389/fnbeh.2016.00253. eCollection 2016.
: Several studies have shown that the ethanol-derived metabolite salsolinol (SAL) can activate the mesolimbic system, suggesting that SAL is the active molecule mediating the rewarding effects of ethanol. and studies suggest that SAL exerts its action on neuron excitability through a mechanism involving opioid neurotransmission. However, there is no direct pharmacologic evidence showing that SAL activates opioid receptors. : The ability of racemic (R/S)-SAL, and its stereoisomers (R)-SAL and (S)-SAL, to activate the μ-opioid receptor was tested in cell-based (light-emitting) receptor assays. To further characterizing the interaction of SAL stereoisomers with the μ-opioid receptor, a molecular docking study was performed using the crystal structure of the μ-opioid receptor. : This study shows that SAL activates the μ-opioid receptor by the classical G protein-adenylate cyclase pathway with an half-maximal effective concentration (EC) of 2 × 10 M. The agonist action of SAL was fully blocked by the μ-opioid antagonist naltrexone. The EC for the purified stereoisomers (R)-SAL and (S)-SAL were 6 × 10 M and 9 × 10 M respectively. It was found that the action of racemic SAL on the μ-opioid receptor did not promote the recruitment of β-arrestin. Molecular docking studies showed that the interaction of (R)- and (S)-SAL with the μ-opioid receptor is similar to that predicted for the agonist morphine. : It is shown that (R)-SAL and (S)-SAL are agonists of the μ-opioid receptor. (S)-SAL is a more potent agonist than the (R)-SAL stereoisomer. analysis predicts a morphine-like interaction between (R)- and (S)-SAL with the μ-opioid receptor. These results suggest that an opioid action of SAL or its enantiomers is involved in the rewarding effects of ethanol.
多项研究表明，乙醇衍生代谢物salsolinol（SAL）可激活中脑边缘系统，这表明SAL是介导乙醇奖赏效应的活性分子。并且研究表明，SAL通过涉及阿片类神经传递的机制对神经元兴奋性发挥作用。然而，尚无直接药理学证据表明SAL能激活阿片受体。：在基于细胞的（发光）受体测定中测试了消旋（R/S）-SAL及其立体异构体（R）-SAL和（S）-SAL激活μ-阿片受体的能力。为了进一步表征SAL立体异构体与μ-阿片受体的相互作用，利用μ-阿片受体的晶体结构进行了分子对接研究。：本研究表明，SAL通过经典的G蛋白-腺苷酸环化酶途径激活μ-阿片受体，半数有效浓度（EC）为2×10⁻⁶M。SAL的激动剂作用被μ-阿片拮抗剂纳曲酮完全阻断。纯化的立体异构体（R）-SAL和（S）-SAL的EC分别为6×10⁻⁶M和9×10⁻⁶M。发现消旋SAL对μ-阿片受体的作用不会促进β-抑制蛋白的募集。分子对接研究表明，（R）-和（S）-SAL与μ-阿片受体的相互作用类似于激动剂吗啡的预测情况。：结果表明，（R）-SAL和（S）-SAL是μ-阿片受体的激动剂。（S）-SAL是比（R）-SAL立体异构体更强效的激动剂。分析预测（R）-和（S）-SAL与μ-阿片受体之间存在类似吗啡的相互作用。这些结果表明，SAL或其对映体的阿片样作用参与了乙醇的奖赏效应。
