Ca2+ inhibits the association of memantine with N-methyl-D-aspartate (NMDA) receptor-gated ion channels

We examined the effect of 1-amino-3,5-dimethyladamantane (memantine) and (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine (MK-801) on the inhibition of [H-3]MK-801 binding to crude synaptic membranes of rat forebrains in the absence or presence of Ca2+. Ca2+ decreased the potency of memantine to inhibit [H-3]MK-801 binding. The effect of Ca2+ was apparently competitive with memantine and was not annulled by the addition of Mg2+. Ca2+ slightly enhanced [H-3]MK-801 binding, but showed no effect on the displacement of [H-3]MK-801 binding by MK-801. The Ca2+-sensitive interaction of memantine with N-methyl-D-aspartate (NMDA) receptor-gated ion channels may provide a clue to understanding its voltage-dependent and clinically tolerated character.