Layer R T, Skolnick P, Bertha C M, Bandarage U K, Kuehne M E, Popik P
Laboratory of Neuroscience, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892-0008, USA.
Eur J Pharmacol. 1996 Aug 8;309(2):159-65. doi: 10.1016/0014-2999(96)00304-4.
Based on both preclinical findings and anecdotal evidence in man, the psychoactive indole alkaloid ibogaine has been suggested to have anti-addictive properties. Previous studies indicate that blockade of NMDA receptors may mediate at least some of the putative anti-addictive actions of ibogaine. The potencies of a series of ibogaine analogs to inhibit (+)-[3-3H]5-methyl-10,11-dihydro-5H-dibenzo-[a,d]cyclohepten-5,10- imine ([3H]MK-801) binding to NMDA receptors were examined. This series of analogs included the putative ibogaine metabolite O-desmethylibogaine, its metabolism resistant analog O-t-butyl-O-desmethylibogaine, the iboga alkaloids (+/-)-ibogamine, (+/-)-coronaridine, tabernanthine, harmaline, and the indolotropanes endo-3-(1-methylindol-2-yl)-8-methyl-8-azabicyclo[3.2.1]loctane (RS 075194-190), exo-3-(1-methylindol-2-yl)-8-methyl-8-azabicyclo[3.2.1]octane (RS 075237-190), and endo-3-(indol-2-yl)-8-methyl-8-azabicyclo[3.2.1]octane (RS 025989-190). Among these compounds, ibogaine was the most potent inhibitor of [3H]MK-801 binding (Ki = approximately 1.2 microM), whilst the compounds with the greatest structural similarity to ibogaine, O-desmethylibogaine and O-t-butyl-O-desmethylibogaine were less potent (Ki = approximately 5.5 and 179.0 microL, respectively). In morphine-dependent mice, ibogaine, but not O-desmethylibogaine or O-t-butyl-O-desmethylibogaine, attenuated naloxone precipitated withdrawal jumping. These findings are consistent with the hypothesis that inhibition of the expression of morphine dependence by ibogaine is related to its NMDA receptor antagonist properties.
基于临床前研究结果和人体中的轶事证据，精神活性吲哚生物碱伊博格碱被认为具有抗成瘾特性。先前的研究表明，N-甲基-D-天冬氨酸（NMDA）受体的阻断可能介导了伊博格碱至少部分假定的抗成瘾作用。检测了一系列伊博格碱类似物抑制（+）-[3-³H]5-甲基-10,11-二氢-5H-二苯并[a,d]环庚烯-5,10-亚胺（[³H]MK-801）与NMDA受体结合的效力。这一系列类似物包括假定的伊博格碱代谢物O-去甲基伊博格碱、其抗代谢类似物O-叔丁基-O-去甲基伊博格碱、伊博格生物碱（±）-伊博加明、（±）-异胡豆碱、瑞枯灵、骆驼蓬碱，以及吲哚托烷类化合物内型-3-（1-甲基吲哚-2-基）-8-甲基-8-氮杂双环[3.2.1]辛烷（RS 075194-190）、外型-3-（1-甲基吲哚-2-基）-8-甲基-8-氮杂双环[3.2.1]辛烷（RS 075237-190）和内型-3-（吲哚-2-基）-8-甲基-8-氮杂双环[3.2.1]辛烷（RS 025989-190）。在这些化合物中，伊博格碱是[³H]MK-801结合的最有效抑制剂（Ki约为1.2微摩尔），而与伊博格碱结构最相似且抗代谢的化合物O-去甲基伊博格碱和O-叔丁基-O-去甲基伊博格碱效力较低（Ki分别约为5.5和179.0微升）。在吗啡依赖的小鼠中，伊博格碱可减轻纳洛酮诱发的戒断跳跃反应，而O-去甲基伊博格碱或O-叔丁基-O-去甲基伊博格碱则无此作用。这些发现与以下假设一致，即伊博格碱对吗啡依赖性表达的抑制作用与其NMDA受体拮抗剂特性有关。
