Pharmacological screen for activities of 12-hydroxyibogamine: a primary metabolite of the indole alkaloid ibogaine.
Pharmacological screen for activities of 12-hydroxyibogamine: a primary metabolite of the indole alkaloid ibogaine.
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12-羟基波加明活性的药理学筛选：吲哚生物碱伊博加因的主要代谢物。
DOI：
10.1007/bf02805969
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发表时间：
1996
影响因子：
3.4
通讯作者：
Mash,DC
中科院分区：
文献类型：
--
作者：
Staley,JK;Ouyang,Q;Pablo,J;Hearn,WL;Flynn,DD;Rothman,RB;Rice,KC;Mash,DC
伊波鲁肽治疗药物依赖的据称疗效可能部分归因于活性代谢物。伊波替尼经历首过代谢并异O-去甲基化为12-羟基伊波胺（12-OH伊波胺）。进行放射性配体结合测定以鉴定伊波替康和12-OH伊波加明的效力和选择性概况。12-OH ibogamine与先前确定的iboglitazone的主要分子靶点的比较表明，代谢产物具有与母体药物相似但不相同的结合特征。伊博格碱和12-OH伊博格胺在5-HT转运蛋白上的可卡因识别位点均表现出最高效力值。对于5-HT转运蛋白上的[3 H]帕罗西汀结合位点，观察到相同的等级顺序（12-OH ibogamine > iboclavine），但效力较低。伊波替尼和12-OH伊波加明在囊泡单胺和多巴胺转运蛋白上是等效的。与母体药物相比，代谢产物对kappa-1受体的亲和力较高，对NMDA受体复合物的亲和力较低。伊博替林和12-OH伊博加明的局部脑水平的定量证明了大鼠脑中母体药物和代谢产物的微摩尔浓度。药物依赖是由不同但相互关联的神经化学适应引起的，这些适应是耐受性、敏感性和戒断的基础。伊波替尼改变药物寻求行为的能力可能是由于母体药物和代谢物在调节药物奖赏回路活性的关键药理学靶点上的联合作用。
The purported efficacy of ibogaine for the treatment of drug dependence may be due in part to an active metabolite. Ibogaine undergoes first pass metabolism and isO-demethylated to 12-hydroxyibogamine (12-OH ibogamine). Radioligand binding assays were conducted to identify the potency and selectivity profiles for ibogaine and 12-OH ibogamine. A comparison of 12-OH ibogamine to the primary molecular targets identified previously for ibogaine demonstrates that the metabolite has a binding profile that is similar, but not identical to the parent drug. Both ibogaine and 12-OH ibogamine demonstrated the highest potency values at the cocaine recognition site on the 5-HT transporter. The same rank order (12-OH ibogamine > ibogaine), but lower potencies were observed for the [3H]paroxetine binding sites on the 5-HT transporter. Ibogaine and 12-OH ibogamine were equipotent at vesicular monoamine and dopamine transporters. The metabolite demonstrated higher affinity at the kappa-1 receptor and lower affinity at the NMDA receptor complex compared to the parent drug. Quantitation of the regional brain levels of ibogaine and 12-OH ibogamine demonstrated micromolar concentrations of both the parent drug and metabolite in rat brain. Drug dependence results from distinct, but inter-related neurochemical adaptations, which underlie tolerance, sensitization and withdrawal. Ibogaine’s ability to alter drug-seeking behavior may be due to combined actions of the parent drug and metabolite at key pharmacological targets that modulate the activity of drug reward circuits.