NMDA receptor subunits: function and pharmacology

N-methyl-D-aspartate receptors (NMDARs) are glutamate-gated ion channels widely expressed in the central nervous system that play key roles in excitatory synaptic transmission. Because of their involvement in numerous neurological disorders, NMDARs are also targets of therapeutic interest. NMDARs occur as multiple subtypes which differ in their subunit composition and in their biophysical and pharmacological properties. In particular, NMDARs contain a diversity of sites at which endogenous ligands or pharmacological agents can act to modulate receptor activity in a subunit-selective manner, and recent structural and functional data have started to reveal the molecular determinants for this subunit selectivity. These include the binding sites for glutamate, the ion-channel pore and the recently identified allosteric sites on the N-terminal domain. Other potential sites yet unexplored by medicinal chemistry programs are also considered, in particular at the interface between subunits. Given the growing body of evidence that diverse brain disorders implicate different NMDAR subtypes, such as NR2B in pain or NR3A in white matter injury, there is a growing interest in exploiting the pharmacological heterogeneity of NMDARs for the development of novel NMDAR subtype-selective compounds.