Potency, voltage-dependency, agonist concentration-dependency, blocking kinetics and partial untrapping of the uncompetitive N-methyl-d-aspartate (NMDA) channel blocker memantine at human NMDA (GluN1/GluN2A) receptors

Both the clinical tolerability and the symptomatic effects of memantine in the treatment of Alzheimer's disease have been attributed to its moderate affinity (IC50 around 1 μM at −70 mV) for NMDA receptor channels and associated fast, double exponential blocking/unblocking kinetics and strong voltage-dependency. Most of these biophysical data have been obtained from rodent receptors. Some substances show large species-specific differences, so using human rather than rodent receptors and tissue may highlight important differences in the effects of drugs. In the present study we compared the potency of memantine, ketamine and (+)MK-801 in binding to NMDA receptors in post-mortem human cortical tissue and to antagonize intracellular Ca2+ responses of human GluN1/GluN2A receptors expressed in HEK-293 cells. In addition, the biophysical properties of memantine and ketamine were compared using patch clamp recordings from these cells.Memantine was confirmed to be a moderate affinity (IC50 at −70 mV of 0.79 ± 0.02 μM, Hill = 0.92 ± 0.02), strongly voltage-dependent (δ = 0.90 ± 0.09) uncompetitive antagonist of human GluN1/GluN2A receptors. Moreover, the rapid double exponential blocking kinetics (e.g. at 10 μM – onset τfast = 273 ± 25 ms (weight 69%), onset τslow = 2756 ± 296 ms, offset τfast = 415 ± 82 ms (weight 38%) offset τslow = 5107 ± 1204 ms) and partial untrapping (around 20%) previously reported for memantine on rodent receptors were confirmed for human receptors. Ketamine showed similar potency (IC50 at −70 mV of 0.71 ± 0.03 μM, Hill = 0.84 ± 0.02) but somewhat less pronounced voltage-dependency (δ = 0.79 ± 0.04), slower, single exponential kinetics (ketamine: kon = 0.15 ± 0.05 × 106 M−1 s−1, koff = 0.22 ± 0.05 s−1 c.f. memantine following normalization kon = 0.32 ± 0.11 × 106  M−1 s−1, koff = 0.53 ± 0.10 s−1) and was fully trapped.The present data closely match previously reported data from studies in rodent receptors and suggest that the proposed mechanism of action of memantine in Alzheimer's disease as a fast, voltage-dependent open-channel blocker of NMDA receptors can be confirmed for human NMDA receptors.