Noribogaine (12-hydroxyibogamine): A biologically active metabolite of the antiaddictive drug ibogaine
Noribogaine (12-hydroxyibogamine): A biologically active metabolite of the antiaddictive drug ibogaine
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DOI：
10.1111/j.1749-6632.2000.tb05210.x
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发表时间：
2000-01-01
期刊：
影响因子：
--
通讯作者：
Mash, DC
中科院分区：
文献类型：
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作者：
Baumann, MH;Pablo, JP;Mash, DC
伊博加因 (IBO) 是一种植物来源的生物碱，目前正在评估其是否可能作为治疗物质使用障碍的药物。当对猴子和人类进行外周给药时，IBO 会迅速转化为邻位去甲基化代谢物 12-羟基波甘胺 (NORIBO)。我们在大鼠中发现 NORIBO 的血液峰值水平可以超过母体化合物，并且 NORIBO 在血液中持续存在至少 24 小时。令人惊讶的是，很少有研究检查 NORIBO 的体内生物活性。在本系列实验中，我们比较了静脉注射 IBO 和 NORIBO（1 和 10 mg/kg）对雄性大鼠伏核中无条件行为、循环应激激素以及多巴胺 (DA) 和血清素 (5-HT) 细胞外水平的影响。 IBO 会引起与剂量相关的震颤和前爪踩踏的增加，而 NORIBO 则不会。 IBO 和 NORIBO 均使血浆皮质酮和催乳素显着升高，但 IBO 作为皮质酮分泌的刺激剂更有效。两种药物均不影响伏隔核中的细胞外 DA 水平。然而，IBO 和 NORIBO 都增加了细胞外 5-HT 水平，并且 NORIBO 在这方面更有效。目前的数据表明 NORIBO 具有生物活性，并且无疑有助于 IBO 在大鼠体内的药理学特征。最重要的是，NORIBO 似乎不太可能产生与 IBO 相关的不良反应（即震颤和应激轴激活），这表明该代谢物可能是药物开发的更安全替代品。
lbogaine (IBO) is a plant-derived alkaloid that is being evaluated as a possible medication for substance use disorders. When administered peripherally to monkeys and humans, IBO is rapidly converted to an o-demethylated metabolite, 12-hydroxyibogamine (NORIBO). We have found in rats that peak blood levels of NORIBO can exceed those of the parent compound, and NORIBO persists in the bloodstream for at least 24 h. Surprisingly few studies have examined the in vivo biological activity of NORIBO. In the present series of experiments, we compared the effects of intravenous (iv) administration of IBO and NORIBO (1 and 10 mg/kg) on unconditioned behaviors, circulating stress hormones, and extracellular levels of dopamine (DA) and serotonin (5-HT) in the nucleus accumbens of male rats. IBO caused dose-related increases in tremors and forepaw treading, whereas NORIBO did not. Both IBO and NORIBO produced significant elevations in plasma corticosterone and prolactin, but IBO was more potent as a stimulator of corticosterone secretion. Neither drug affected extracellular DA levels in the nucleus accumbens. However, both IBO and NORIBO increased extracellular 5-HT levels, and NORIBO was more potent in this regard. The present data demonstrate that NORIBO is biologically active and undoubtedly contributes to the in vivo pharmacological profile of IBO in rats. Most importantly, NORIBO appears less likely to produce the adverse effects associated with IBO (i.e., tremors and stress-axis activation), suggesting that the metabolite may be a safer alternative for medication development.