Therapeutic N-methyl-D-aspartate receptor antagonists: will reality meet expectation?

The initial promise of the N-methyl-D-aspartate (NMDA) receptor antagonists gave hope for the therapeutic treatment of neurological disorders, which ultimately was unfulfilled. In many cases, their adverse psychotomimetic effects were too severe for them to be used therapeutically in the way that most had envisaged. The last decade has seen significant progress in our understanding of the NMDA receptor complex and the site(s) of action of various uncompetitive antagonists. In particular, this has led to the development of a family of low-affinity, uncompetitive, cation channel antagonists that seem to offer many of the benefits of the older channel blockers but with a more acceptable side effect profile. Drugs such as memantine have demonstrated beneficial effects in clinical trials for Alzheimer's disease and ischemia, with few adverse side effects. Likewise, the NMDA receptor NR2B subunit antagonists derived from drugs such as ifenprodil, have proven beneficial in the treatment of neuropathic pain, and are also associated with few adverse side effects. These, and other new experimental agents, are demonstrating that it may yet be possible to tap the enormous potential of NMDA receptor antagonists as therapeutic drugs, without necessarily incurring the adverse side effects associated with the first generation compounds.