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 K 1-value of 0.19 ± 0.06 μM while the weakest substance (1- N-methyl-amino-adamantane) had a K 1-value of 21.72 ± 1.63 μM. The K 1-value of amantadine was 10.50 ± 6.10 μM. In agreement with our earlier investigation, the K 1-value of memantine was 0.54 ± 0.23 μM. 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.