Allosteric modulators of NMDA receptors: multiple sites and mechanisms

•NMDA receptors form massive multi-domain multi-subunit molecular complexes.•NMDA receptors harbor a multiplicity of binding sites for allosteric modulators.•N-terminal, agonist-binding and transmembrane regions all contain allosteric sites.•Interfaces between subunits are key loci for allosteric modulation.•The rich pharmacology of NMDARs bears strong therapeutic potential.

N-methyl-d-aspartate receptors (NMDARs) are glutamate-gated ion channels that are essential mediators of excitatory neurotransmission and synaptic plasticity. NMDARs are also implicated in a plethora of neuropathological conditions thus receiving strong interest as potential therapeutic targets. Recent years have witnessed major progress in our understanding of the structure and pharmacology of NMDARs with the decoding of the first full-length receptor crystal structures and the discovery of allosteric modulators acting at novel binding sites and with unique patterns of subunit selectivity. Here we review the properties and structural mechanisms of various allosteric modulators that target NMDARs, emphasizing the newly identified compounds. The expanding pharmacology of NMDARs should help delineate the roles of various NMDAR subtypes in brain function, with potential for drug development.