EFFECTS OF THE 1-AMINO-ADAMANTANES AT THE MK-801-BINDING SITE OF THE NMDA-RECEPTOR-GATED ION CHANNEL - A HUMAN POSTMORTEM BRAIN STUDY
EFFECTS OF THE 1-AMINO-ADAMANTANES AT THE MK-801-BINDING SITE OF THE NMDA-RECEPTOR-GATED ION CHANNEL - A HUMAN POSTMORTEM BRAIN STUDY
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DOI：
10.1016/0922-4106(91)90113-v
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发表时间：
1991-04-25
期刊：
影响因子：
--
通讯作者：
RIEDERER, P
中科院分区：
文献类型：
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作者：
KORNHUBER, J;BORMANN, J;RIEDERER, P
我们实验室最近的研究提供了证据，证明1-氨基-金刚烷衍生物美金刚（1-氨基-3，5-二甲基-金刚烷）与N-甲基-D-天冬氨酸（NMDA）受体门控离子通道的MK-801结合位点结合。该作用被认为是药物抗帕金森病和解痉挛活性的原因。在目前的调查中，我们已经扩展了我们的工作，通过测试一系列的1-氨基金刚烷，包括金刚烷胺（1-氨基金刚烷）和美金刚胺，他们的能力，竞争与[H-3]MK-801结合在膜匀浆的死后人额叶皮层。效力最强的物质（1-氨基-3，5-二乙基-金刚烷）的K（i）值为0.19 +/- 0.06 μ M，而效力最弱的物质（1-N-甲基-氨基-金刚烷）的K（i）值为21.72 +/- 1.63 μ M。金刚烷胺的K（i）值为10.50 +/- 6.10 μ M。与我们先前的研究一致，美金刚胺的K（i）值为0.54 +/- 0.23 μ-M。结果表明，1-氨基金刚烷，一般来说，可能会产生其药理作用，通过与NMDA受体门控离子通道的相互作用。因此，[H-3]MK-801结合的置换可能为预测新型取代的1-氨基金刚烷和可能的其他药物的抗帕金森病和解痉活性提供基础。
Recent studies from our laboratory have provided evidence that the 1-amino-adamantane derivative memantine (1-amino-3,5-dimethyl-adamantane) binds to the MK-801-binding site of the N-methyl-D-aspartate (NMDA)-receptor-gated ion channel. This action has been suggested to account for the antiparkinsonian and antispastic activity of the drug. In the present investigation we have extended our work by testing a series of 1-amino-adamantanes, including amantadine (1-amino-adamantane) and memantine, for their ability to compete with [H-3]MK-801 binding in membrane homogenates of postmortem human frontal cortex. The most potent substance (1-amino-3,5-diethyl-adamantane) had a K(i)-value of 0.19 +/- 0.06-mu-M while the weakest substance (1-N-methyl-amino-adamantane) had a K(i)-value of 21.72 +/- 1.63-mu-M. The K(i)-value of amantadine was 10.50 +/- 6.10-mu-M. In agreement with our earlier investigation, the K(i)-value of memantine was 0.54 +/- 0.23-mu-M. The results indicate that 1-amino-adamantanes, in general, may produce their pharmacological effects through an interaction with the NMDA-receptor-gated ion channel. The displacement of [H-3]MK-801 binding thus may provide the basis to predict the antiparkinsonian and antispastic activity of novel substituted 1-amino-adamantanes and possibly of other drugs.