Recent Advances in the Development of NR2B Subtype-Selective NMDA Receptor Antagonists

Layton, M. E.; Kelly, Michael J.; Rodzinak, Kevin J.

doi:10.2174/156802606776894447

Cited by 60 publications

(36 citation statements)

References 76 publications

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“…Memantine demonstrates that clinical success can be achieved with NMDA antagonists of unique pharmacological characteristics. Another class of compounds that has gained attention as having such potential is the GluN2B subunit-selective NMDA receptor antagonists (Chazot, 2004;Gogas, 2006;Mony et al, 2009), for which a rich pharmacology exists (Chenard and Menniti, 1999;Nikam and Meltzer, 2002;McCauley, 2005;Layton et al, 2006). By blocking only one NMDA receptor subtype, these compounds could have therapeutic benefits but minimize on-target side effects.…”

Section: The Next Generation N-methyl-d-aspartate Receptor Antagonmentioning

confidence: 99%

Glutamate Receptor Ion Channels: Structure, Regulation, and Function

et al. 2010

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Section: The Next Generation N-methyl-d-aspartate Receptor Antagonmentioning

confidence: 99%

Glutamate Receptor Ion Channels: Structure, Regulation, and Function

et al. 2010

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“…The broad SAR governing these compound classes has typically involved two aromatic rings separated by a carbon linker that often contains nitrogen (Chenard and Menniti, 1999;Tamiz et al, 1999;Nikam and Meltzer, 2002;Borza and Domá ny, 2006;Layton et al, 2006). A variety of chemically distinct linkers and substituted aryl compounds retain activity, leading to considerable diversity in ligand structure.…”

Section: The Glun2b Amino-terminal Domain Harbors a Binding Site For mentioning

confidence: 99%

Control of Assembly and Function of Glutamate Receptors by the Amino-Terminal Domain

Hansen¹,

Furukawa²,

Traynelis³

2010

Mol Pharmacol

103

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The extracellular amino-terminal domains (ATDs) of the ionotropic glutamate receptor subunits form a semiautonomous component of all glutamate receptors that resides distal to the membrane and controls a surprisingly diverse set of receptor functions. These functions include subunit assembly, receptor trafficking, channel gating, agonist potency, and allosteric modulation. The many divergent features of the different ionotropic glutamate receptor classes and different subunits within a class may stem from differential regulation by the amino-terminal domains. The emerging knowledge of the structure and function of the amino-terminal domains reviewed here may enable targeting of this region for the therapeutic modulation of glutamatergic signaling. Toward this end, NMDA receptor antagonists that interact with the GluN2B ATD show promise in animal models of ischemia, neuropathic pain, and Parkinson's disease.

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“…This heterogeneity among NMDA receptor subunits creates an opportunity to identify subunit selective agonists, partial agonists, antagonists, and modulators. Among these, most success has been achieved with the development of NR2B selective antagonists, which have received significant attention as potential therapeutic candidates (Chazot, 2004;Borza and Domany, 2006;Layton et al, 2006).…”

Section: Nr2d-containing Receptors (46-fold) Analysis Of Chimericmentioning

confidence: 99%

Subunit-Specific Agonist Activity at NR2A-, NR2B-, NR2C-, and NR2D-ContainingN-Methyl-d-aspartate Glutamate Receptors

et al. 2007

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The four N-methyl-D-aspartate (NMDA) receptor NR2 subunits (NR2A-D) have different developmental, anatomical, and functional profiles that allow them to serve different roles in normal and neuropathological situations. Identification of subunit-selective NMDA receptor agonists, antagonists, or modulators could prove to be both valuable pharmacological tools as well as potential new therapeutic agents. We evaluated the potency and efficacy of a wide range of glutamate-like compounds at NR1/NR2A, NR1/NR2B, NR1/NR2C, and NR1/NR2D receptors. Twenty-five of 53 compounds examined exhibited agonist activity at the glutamate binding site of NMDA receptors. Concentration-response relationships were determined for these agonists at each NR2 subunit. We find consistently higher potency at the NR2D subunit for a wide range of dissimilar structures, with (2S,4R)-4-methylglutamate (SYM2081) showing the greatest differential potency between NR2A-and NR2D-containing receptors (46-fold). Analysis of chimeric NR2A/D receptors suggests that enhanced agonist potency for NR2D is controlled by residues in both of the domains (Domain1 and Domain2) that compose the bilobed agonist binding domain. Molecular dynamics (MD) simulations comparing a crystallography-based hydrated NR1/NR2A model with a homology-based NR1/NR2D hydrated model of the agonist binding domains suggest that glutamate exhibits a different binding mode in NR2D compared with NR2A that accommodates a 4-methyl substitution in SYM2081. Mutagenesis of functionally divergent residues supports the conclusions drawn based on the modeling studies. Despite high homology and conserved atomic contact residues within the agonist binding pocket of NR2A and NR2D, glutamate adopts a different binding orientation that could be exploited for the development of subunit selective agonists and competitive antagonists.NMDA receptors are ligand-gated ion channels that mediate a component of excitatory synaptic transmission that can trigger changes in synaptic strength (Malenka and Nicoll, 1993). NMDA receptors have also been implicated in the pathophysiology of stroke and brain injury (Wang and Shuaib, 2005), epilepsy (Mares et al., 2004), as well as a range of psychiatric disorders (Heresco-Levy and Javitt, 1998;MacDonald and Chafee, 2006). NMDA receptors are tetrameric protein complexes composed of a combination of glycine-binding NR1 subunits and glutamate-binding NR2 subunits (Dingledine et al., 1999;Chen and Wyllie, 2006).

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Recent Advances in the Development of NR2B Subtype-Selective NMDA Receptor Antagonists

Cited by 60 publications

References 76 publications

Glutamate Receptor Ion Channels: Structure, Regulation, and Function

Glutamate Receptor Ion Channels: Structure, Regulation, and Function

Control of Assembly and Function of Glutamate Receptors by the Amino-Terminal Domain

Subunit-Specific Agonist Activity at NR2A-, NR2B-, NR2C-, and NR2D-ContainingN-Methyl-d-aspartate Glutamate Receptors

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