N-methyl-D-aspartate receptors (NMDARs) display differences in their sensitivity to the channel-blockers Mg²⁺ and memantine that are dependent on the identity of the NR2 subunit present in the receptor-channel complex. This study, using two-electrode voltage-clamp recordings from Xenopus laevis oocytes expressing recombinant NMDARs, investigates the actions of Mg²⁺ and memantine at the two NMDARs displaying the largest differences in sensitivity to these blockers, namely NR1/NR2A and NR1/NR2D NMDARs. In addition, NR2A/2D chimeric subunits have been employed to examine the effects of pore-forming elements and ligand-binding domains (LBD) on the potency of the block produced by each of these inhibitors. Our results show that, as previously documented, NR2D-containing NMDARs are less sensitive to voltage-dependent Mg²⁺-block than their NR2A-containing counterparts. The reduced sensitivity is determined by the M1M2M3 membrane-associated regions as replacing these regions in NR2A subunits with those found in NR2D subunits results in a ~10-fold reduction in Mg²⁺ potency. Intriguingly replacing the NR2A LBD with that from NR2D subunits results in a ~2-fold increase in Mg²⁺ potency. Moreover, when responses mediated by NR1/NR2A NMDARs are evoked by the partial agonist, homoquinolinate, rather than glutamate, Mg²⁺ also displays an increased potency. Memantine-block of glutamate-evoked currents is most potent at NR1/NR2D NMDARs, however, no differences are observed in its ability to inhibit NR2A-containing or NR2A/2D chimaeric NMDARs. We suggest that structural elements, in addition to the pore-forming regions, in particular the LBD and its ability to transduce conformational changes following agonist binding to channel-gating influences the potency of block of NMDARs by Mg²⁺.