Clinically, amantadine and memantine are drugs whose therapeutic utility is linked to their ability to block N-methyl-D-aspartate receptors (NMDARs) in a voltage-dependent manner. Nevertheless many studies that have characterized the pharmacological actions of amantadine and memantine have done so in the absence of physiological levels of Mg2+ ions. This study quantifies the extent to which Mg2+ alters the potency of the block produced by both amantadine and memantine at human recombinant GluN1/GluN2A NMDARs. Human recombinant GluN1/GluN2A NMDARs were expressed in Xenopus laevis oocytes and two-electrode voltage-clamp recordings were made at -80, -60 and -40 mV to quantify amantadine and memantine block in the absence and presence of Mg2+. Amantadine and memantine blocked human GluN1/GluN2A NMDARs in a voltage-dependent manner with IC50 values (at 80 mV) of 49 +/- 6 mu M (n = 7) and 1.0 +/- 0.3 mu M (n = 7), respectively. In the presence of Mg2+ (1 mM) the equivalent IC50 values were 165 +/- 10 mu M (n = 6) and 6.6 +/- 0.3 mu M (n = 5). Similarly in the presence of amantadine or memantine the potency of Mg2+ in blocking GluN1/GluN2A NMDARs was reduced. The decrease in the potencies of both amantadine and memantine in the presence of physiological concentrations of Mg2+ indicates that other targets (e.g. alpha 7-nicotinic acetylcholine receptors and 5-HT3 receptors) in addition to NMDARs may well be sites of the therapeutic action of these channel blockers. (C) 2010 Elsevier Ltd. All rights reserved.