The amino acid L-glutamate is the most important fast excitatory neurotransmitter in neuronal circuits in the mammalian central nervous system (CNS).lp2 Almost all CNS neurons can be excited by L-glutamate, acting on a variety of different ligandgated ion channel cell surface receptors. These are classified into two main categories, those for which the synthetic glutamate analogue N-methyl-D-aspartate is a potent excitant (NMDA receptors) and those on which NMDA is not active (non-NMDA). The unique glycine modulatory site on the NMDA receptor represents a novel target for medicinal chemistry which has attracted considerable interest since its discovery in 1987.3~4 In both NMDA and non-NMDA classes of receptors, glutamate opens an ion channel which leads to a rapid influx of cations and a resulting discharge of the normally negative intracellular membrane potential. A third family of glutamate receptors, the "metabotropic glutamate receptors," are G-protein-coupled and represent targets of so far less well understood modulatory actions of glutamate in the CNS2 NMDA receptors are widely distributed in brain and spinal cord, with the highest densities in cerebral cortex and hippocampus. The receptor when activated controls the opening of an ion channel which permits the entry of monovalent (mainly Na+) and divalent (mainly Ca2+) cations into target cells. An unusual feature of the NMDA receptor is that it is inoperative when target cells are in a resting state, as under such conditions of negative intracellular membrane potential the ion channel associated with the NMDA receptor is fully blocked by Mg2+ ions. This block is voltage dependent, however,and is removed if the target cell is partially depolarized by activation of non-NMDA receptors or other excitatory inputs. Thus, the NMDA receptor mechanism has a "conditional" feature, making it potentially an important "logic gate" in CNS circuits, especially relevant in processes of learning and memorya5 The NMDA receptor has another unusual feature, as excessive activation of the receptor can lead to over-excitation of the target neurons to the point of cell death, probably caused by an excess accumulation of intracellular Ca2+. Much research has focused on the role of NMDA receptors in such "excitotoxic" cell death in recent years, as it seems likely that this mechanism contributes importantly to the permanent damage to the CNS that occurs when there is excessive release of L-glutamate following traumatic head or spinal cord injury, stroke, perinatal ischemia, or in hypoglycemic conditions. The discovery of potent NMDA receptor antagonists has shown that such drugs have the potential to protect the CNS from excitotoxic damage in these conditions, and several compounds of this type are currently undergoing clinical trials to assess their efficacy in the acute treatment of stroke and head inj~ry.~,~