The success of the low affinity use-dependent NMDA receptor antagonists to reach clinical trials can be readily attributed to their wider margins of safety and lack of neurotoxicity at higher doses. Several mechanistic differences distinguish the low affinity from the high affinity use-dependent antagonists: 1) Differential regional affinities for the various NMDA receptor subtypes; 2) The static receptor blockade due to the faster on/off rate receptor kinetics which limit, but do not totally prevent the amount of Ca+2 entry into the cell during glutamate-induced depolarization; and 3) Rapid egress of the compounds from the ion channel during recovery resulting in less membrane trapping between transmission pulses. Advanced clinical trials are in progress for the following indications: epilepsy, stroke, head trauma, tardive dyskinesia, pain plus Parkinson's, Huntington's and Alzheimer's diseases.