The open-channel structure of the N-methyl-D-aspartate (NMDA) receptor was investigated to explain apparently conflicting interpretations about ionic interactions within the pore. Patch-clamp techniques were applied to tissue-cultured rat hippocampal neurons from the CA1 region. A wide range of ammonium derivatives was studied to learn about the structure of the pore from permeability and open-channel blocking characteristics. We conclude that the pore is asymmetric, having high-affinity binding for organic cations from the outside and having a larger external entrance. The minimum cross-sectional area of the pore is rectangular (approximately 0.45 x 0.57 nm) and is the single-occupancy binding site(s) for small permeant cations. The narrow region extending from this minimum cross section is short, and its shape underlies the voltage dependencies of blocking cations. While occupying the blocking site, some open-channel blockers can interact with permeant cations at their binding site in the minimum cross section. A structurally based hypothesis is presented, explaining that the electrostatic interactions between the blocking site and permeant-ion site produce a high voltage dependence for blockade by some cations.