Effects of the 1-amino-adamantanes at the MK-801-binding site of the NMDA-receptor-gated ion channel: a human postmortem brain study.
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 [3H]MK-801 binding in membrane homogenates of postmortem human frontal cortex. The most potent substance (1-amino-3,5-diethyl-adamantane) had a Ki-value of 0.19 +/- 0.06 microM while the weakest substance (1-N-methyl-amino-adamantane) had a Ki-value of 21.72 +/- 1.63 microM. The Ki-value of amantadine was 10.50 +/- 6.10 microM. In agreement with our earlier investigation, the Ki-value of memantine was 0.54 +/- 0.23 microM. 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 [3H]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.
Kornhuber
J
J
Department of Psychiatry, University of Würzburg, F.R.G.
Bormann
J
J
Hübers
M
M
Rusche
K
K
Riederer
P
P
D000218:Adamantane / Q000031:analogs & derivatives* / Q000494:pharmacology; D000547:Amantadine / Q000378:metabolism / Q000494:pharmacology; D001665:Binding Sites; D001921:Brain / Q000378:metabolism* / Q000648:ultrastructure; D016291:Dizocilpine Maleate / Q000378:metabolism*; D006801:Humans; D015640:Ion Channel Gating / Q000502:physiology; D007473:Ion Channels / Q000378:metabolism; D007700:Kinetics; D008559:Memantine / Q000378:metabolism / Q000494:pharmacology; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014316:Tritium
D007473:Ion Channels; D016194:Receptors, N-Methyl-D-Aspartate; D014316:Tritium; D016291:Dizocilpine Maleate; D000547:Amantadine; D000218:Adamantane; D008559:Memantine