Mash D C, Staley J K, Pablo J P, Holohean A M, Hackman J C, Davidoff R A
Department of Neurology, University of Miami School of Medicine, FL 33101, USA.
Neurosci Lett. 1995 Jun 2;192(1):53-6. doi: 10.1016/0304-3940(95)11608-y.
The putative anti-addiction alkaloid ibogaine and its principal metabolite 12-hydroxyibogamine appear to act at the (+)-5 methyl-10,11,dihydro-5H- dibenzo[a,d]cycloheten-5-10-imine maleate (MK-801) binding site in the N-methyl-D-aspartate (NMDA)-receptor cation channel. This conclusion is based on findings that both compounds competitively displaced specific [3H]MK-801 binding to membranes from postmortem human caudate and cerebellum and from frog spinal cord. Ibogaine was 4-6-fold more potent than its metabolite and both compounds were less potent (50-1000-fold) than MK-801 binding to the NMDA receptor. In addition, ibogaine (100 microM) and 12-hydroxyibogamine (1 mM) blocked (85-90% of control) the ability of NMDA (100 microM, 5 s) to depolarize frog motoneurons in the isolated frog spinal cord. The prevention of NMDA-depolarizations in frog motoneurons showed use-dependency and was very similar to the block produced by MK-801. In view of the abilities of MK-801 to affect the responses to addictive substances in pre-clinical investigations, our results are compatible with the idea that the ability of ibogaine and 12-hydroxyibogamine to interrupt drug-seeking behavior may, in part, result from their actions at the MK-801 binding site.
假定的抗成瘾生物碱伊博格碱及其主要代谢产物12-羟基伊博格胺似乎作用于N-甲基-D-天冬氨酸（NMDA）受体阳离子通道中的（+）-5-甲基-10,11-二氢-5H-二苯并[a,d]环庚烯-5,10-亚胺马来酸盐（MK-801）结合位点。这一结论基于以下发现：这两种化合物都能竞争性地取代特异性[3H]MK-801与死后人类尾状核和小脑以及青蛙脊髓膜的结合。伊博格碱的效力比其代谢产物强4至6倍，且这两种化合物与MK-801结合到NMDA受体的效力相比都较弱（50至1000倍）。此外，伊博格碱（100微摩尔）和12-羟基伊博格胺（1毫摩尔）可阻断（对照的85%至90%）NMDA（100微摩尔，5秒）使分离的青蛙脊髓中的青蛙运动神经元去极化的能力。对青蛙运动神经元中NMDA去极化的预防显示出使用依赖性，并且与MK-801产生的阻断非常相似。鉴于在临床前研究中MK-801能够影响对成瘾物质的反应，我们的结果与以下观点一致，即伊博格碱和12-羟基伊博格胺中断觅药行为的能力可能部分源于它们在MK-801结合位点的作用。
