Patch clamp studies on the kinetics and selectivity of N-methyl-D-aspartate receptor antagonism by memantine (1-amino-3,5-dimethyladamantan).
Memantine (1-amino-3,5-dimethyladamantan) was tested as an antagonist of N-methyl-D-aspartate (NMDA) receptors on cultured superior collicular and hippocampal neurones using the patch clamp technique and its actions were compared to those of Mg2+ ions, ketamine, dextrorphan, dextromethorphan, phencyclidine and dizocilpine (MK-801). Memantine (2-33 microM) concentration-dependently antagonized responses to NMDA 100 microM with an IC50 of 2.92 +/- 0.05 microM. In contrast, current responses to (S)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (L-AMPA 50-100 microM) and gamma-amino butyric acid (GABA 10 microM) were unaffected by Memantine 8 microM. Memantine 8 microM caused a non-parallel shift of the NMDA concentration-response curve to the right in a manner indicative of uncompetitive open channel block. The effects of memantine were similar to ketamine in that both antagonists were weakly use- and strongly voltage-dependent. In contrast, MK-801, phencyclidine and dextrorphan showed much slower kinetics that was reflected in their marked use- and weaker voltage-dependency. The antagonistic effects of memantine were not reversed by increasing concentrations of glycine (0.1-100 microM) ruling out the possibility of an interaction of memantine with the strychnine-insensitive glycine modulatory site associated with the NMDA receptor-channel complex. Memantine (1-100 microM) also selectively antagonized responses to NMDA (40 microM) in the cortical wedge preparation with IC50 of 12.9 +/- 1.5 microM.
Parsons
C G
CG
Department of Pharmacology, Merz + Co.GmbH&Co., Frankfurt am Main, Germany.
Gruner
R
R
Rozental
J
J
Millar
J
J
Lodge
D
D
D000818:Animals; D002478:Cells, Cultured; D003917:Dextrorphan / Q000494:pharmacology; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian; D005998:Glycine / Q000494:pharmacology; D006624:Hippocampus / Q000502:physiology*; D007649:Ketamine / Q000494:pharmacology; D007700:Kinetics; D008274:Magnesium / Q000494:pharmacology; D008559:Memantine / Q000494:pharmacology*; D008564:Membrane Potentials / Q000187:drug effects; D016202:N-Methylaspartate / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D010622:Phencyclidine / Q000494:pharmacology; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D013477:Superior Colliculi / Q000502:physiology*; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
D016194:Receptors, N-Methyl-D-Aspartate; D003917:Dextrorphan; D005680:gamma-Aminobutyric Acid; D016202:N-Methylaspartate; D007649:Ketamine; D016291:Dizocilpine Maleate; D008274:Magnesium; D010622:Phencyclidine; D005998:Glycine; D008559:Memantine