The discovery of NMDA receptors (NMDARs) was made possible by the synthesis and study of NMDA (Figure 12.1) and various NMDAR antagonists by Jeff Watkins and colleagues [1]. These compounds, most notably (R)-α-aminoadipate ((R)-α-AA) and (R)-2-amino-5-phosphonopentanoate (Figure 12.2), were shown to block neuronal responses to applied NMDA, but not to block responses to kainate or quisqualate [2,3]. As a result, NMDARs were shown to represent a distinct subpopulation of excitatory amino acid receptors.

Over the next several years, these and other NMDAR antagonists led to the discovery that NMDARs play key roles in synaptic transmission, synaptic plasticity, learning and memory, neuronal development, excitotoxicity, stroke, seizures, and many other physiological and pathological processes. These studies generated great excitement about the potential use of NMDAR antagonists to treat neuropathological and neurodegenerative diseases. However, with the exception of the use of memantine for Alzheimer’s disease, the development of NMDAR-targeted therapeutics has been disappointing. Several agents failed in clinical trials due to adverse effects and/or a lack of clinical efficacy. Despite this disappointment, NMDAR therapeutics continue to exhibit significant potential. Of the multiple drug binding sites on the various NMDAR subunits, many potential types of NMDAR antagonists exist, and some of these reveal distinct patterns of selectivity. This chapter will summarize the current understanding of the various sites of drug action on the NMDAR complex.