NMDA receptors: the first decade

A little over ten years ago, three events occurred which began the story of the N-methyl-D-aspartate (NMDA) receptor, as far as drug discovery was concerned. In a series of publications, Watkins and co-workers marshalled sufficient evidence about the ability of certain antagonists to block the excitatory action of NMDA. This evidence served to convince a majority of scientists that NMDA receptors did indeed exist. The mechanism of action of MK-801 was discovered to be the blockade of ion channels associated with NMDA receptors. Finally, the first competitive NMDA antagonists to be developed for therapeutic purposes, CPP and CGS19755, were discovered. It was the honeymoon for the NMDA receptor, with expected side effects exceeded only by predicted therapeutic applications. Now there has been sufficient time to test many of the original concepts surrounding the NMDA receptor and its antagonists, and to test the first generation of NMDA antagonists in man. At the same time, many other classes of compounds acting at different sites of the NMDA receptor have appeared, with potential clinical applications. This review will cover the clinical testing of these concepts and compounds, followed by a review of key recent developments in basic and preclinical research for the next generation of ligands acting at the NMDA receptor.