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 [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.