The N-methyl-D-aspartate receptor (NMDAR) is a member of the ionotropic glutamate receptor
(iGluR) family that plays a crucial role in brain signalling and development. NMDARs are nonselective
cation channels that are involved with the propagation of excitatory neurotransmission signals
with important effects on synaptic plasticity. NMDARs are functionally and structurally complex receptors,
they exist as a family of subtypes each with its own unique pharmacological properties. Their implication
in a variety of neurological and psychiatric conditions means they have been a focus of research
for many decades. Disruption of NMDAR-related signalling is known to adversely affect higherorder
cognitive functions (e.g. learning and memory) and the search for molecules that can recover (or
even enhance) receptor output is a current strategy for CNS drug discovery. A number of positive allosteric
modulators (PAMs) that specifically attempt to overcome NMDAR hypofunction have been discovered.
They include various chemotypes that have been found to bind to several different binding sites
within the receptor. The heterogeneity of chemotype, binding site and NMDAR subtype provide a broad
landscape of ongoing opportunities to uncover new features of NMDAR pharmacology. Research on
NMDARs continues to provide novel mechanistic insights into receptor activation and this review will
provide a high-level overview of the research area and discuss the various chemical classes of PAMs
discovered so far.
Positive Allosteric Modulators of the D
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Dopamine Receptor Act at Diverse Binding Sites
