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 mo...

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Bibliographic Details
Published in:Current opinion in pharmacology Vol. 20; pp. 14 - 23
Main Authors: Zhu, Shujia, Paoletti, Pierre
Format: Journal Article
Language:English
Published: England Elsevier Ltd 01.02.2015
Subjects:
Allosteric Regulation - drug effects
Binding Sites
Brain - physiology
Brain - physiopathology
Drug Design
Humans
Internal Medicine
Medical Education
Molecular Targeted Therapy
Nervous System Diseases - drug therapy
Nervous System Diseases - physiopathology
Neuronal Plasticity - physiology
Receptors, N-Methyl-D-Aspartate - chemistry
Receptors, N-Methyl-D-Aspartate - drug effects
Receptors, N-Methyl-D-Aspartate - metabolism
ISSN:1471-4892, 1471-4973, 1471-4973
Online Access:Get full text
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Summary:•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.
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ISSN:1471-4892
1471-4973
1471-4973
DOI:10.1016/j.coph.2014.10.009