salvindolin 可引发阿片系统介导的镇痛和抗抑郁样活性。
Salvindolin elicits opioid system-mediated antinociceptive and antidepressant-like activities.
机构信息
1 Department of BioMolecular Sciences, Division of Pharmacognosy, University of Mississippi, University, MS, USA.
2 Department of BioMolecular Sciences, Research Institute of Pharmaceutical Sciences, University of Mississippi, University, MS, USA.
出版信息
J Psychopharmacol. 2019 Jul;33(7):865-881. doi: 10.1177/0269881119849821. Epub 2019 Jun 13.
BACKGROUND
Salvinorin A is known as a highly selective kappa opioid receptor agonist with antinociceptive but mostly pro-depressive effects.
AIMS
In this article, we present its new semisynthetic analog with preferential mu opioid affinity, and promising antinociceptive, as well as antidepressant-like activities.
METHODS
Competitive binding studies were performed for salvindolin with kappa opioid and mu opioid. The mouse model of nociception (acetic-acid-induced writhing, formalin, and hot plate tests), depression (forced swim and tail suspension tests), and the open field test, were used to evaluate antinociceptive, antidepressant-like, and locomotion effects, respectively, of salvindolin. We built a 3-D molecular model of the kappa opioid receptor, using a mu opioid X-ray crystal structure as a template, and docked salvindolin into the two proteins.
RESULTS/OUTCOMES: Salvindolin showed affinity towards kappa opioid and mu opioid receptors but with 100-fold mu opioid preference. Tests of salvindolin in mice revealed good oral bioavailability, antinociceptive, and antidepressive-like effects, without locomotor incoordination. Docking of salvindolin showed strong interactions with the mu opioid receptor which matched well with experimental binding data. Salvindolin-induced behavioral changes in the hot plate and forced swim tests were attenuated by naloxone (nonselective opioid receptor antagonist) and/or naloxonazine (selective mu opioid receptor antagonist) but not by nor-binaltorphimine (selective kappa opioid receptor antagonist). In addition, WAY100635 (a selective serotonin 1A receptor antagonist) blocked the antidepressant-like effect of salvindolin.
CONCLUSIONS/INTERPRETATION: By simple chemical modification, we were able to modulate the pharmacological profile of salvinorin A, a highly selective kappa opioid receptor agonist, to salvindolin, a ligand with preferential mu opioid receptor affinity and activity on the serotonin 1A receptor. With its significant antinociceptive and antidepressive-like activities, salvindolin has the potential to be an analgesic and/or antidepressant drug candidate.
背景
沙蟾毒精 A 是一种高度选择性的κ阿片受体激动剂，具有镇痛作用，但主要表现为致抑郁作用。
目的
本文报道了其具有优先μ阿片亲和力、具有潜在镇痛和抗抑郁样活性的新型半合成类似物。
方法
采用竞争结合实验检测沙蟾毒精 A 与κ阿片和μ阿片受体的亲和力。采用醋酸诱导扭体、福尔马林和热板试验检测镇痛作用，采用强迫游泳和悬尾试验检测抗抑郁样作用，采用旷场试验检测运动行为，分别评价沙蟾毒精 A 的镇痛、抗抑郁样和运动行为效应。构建κ阿片受体的三维分子模型，以μ阿片 X 射线晶体结构为模板，将沙蟾毒精 A 对接至两种蛋白。
结果/结论：沙蟾毒精 A 对κ阿片和μ阿片受体具有亲和力，但对μ阿片受体的亲和力高 100 倍。沙蟾毒精 A 在小鼠中的试验显示其具有良好的口服生物利用度、镇痛和抗抑郁样作用，且无运动协调障碍。沙蟾毒精 A 与μ阿片受体的对接显示其具有较强的相互作用，与实验结合数据吻合良好。沙蟾毒精 A 引起的热板和强迫游泳试验中的行为变化可被纳洛酮（非选择性阿片受体拮抗剂）和/或纳洛酮嗪（选择性μ阿片受体拮抗剂）减弱，但不能被 nor-binaltorphimine（选择性 κ阿片受体拮抗剂）减弱。此外，WAY100635（选择性 5-羟色胺 1A 受体拮抗剂）阻断了沙蟾毒精 A 的抗抑郁样作用。
结论/解释：通过简单的化学修饰，我们能够调节沙蟾毒精 A 的药理学特性，将其从高度选择性的 κ阿片受体激动剂转变为对 5-羟色胺 1A 受体具有优先亲和力和活性的配体沙蟾毒精 A。沙蟾毒精 A 具有显著的镇痛和抗抑郁样活性，有可能成为一种镇痛和/或抗抑郁候选药物。
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