Subtype-Specific Agonists for NMDA Receptor Glycine Binding Sites

Maolanon, Alex; Risgaard, Rune; Wang, Shuangyan; Snoep, Yoran; Papangelis, Athanasios; Yi, Feng; Holley, David C.; Barslund, Anne F; Svenstrup, Niels; Hansen, Kasper B.; Clausen, Rasmus P.

doi:10.1021/acschemneuro.7b00117

Cited by 20 publications

(26 citation statements)

References 22 publications

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“…Other features of GluN2C-containing receptors appear unique, raising the question of whether NMDA-Rs that contain this subunit have distinct structural conformations for some domains that differ from GluN2A, GluN2B, and GluN2D. For example, the ability of several glycine site agonists (Sheinin et al, 2001;Dravid et al, 2010;Maolanon et al, 2017) to enhance activity to levels above those observed for saturating glycine is unique to the GluN2C subunit, and unrelated to the glycine pocket, which resides within the GluN1 subunit. Thus, GluN2C could be a unique pharmacological target for modulation of thalamic and cerebellar circuits, where it is abundantly expressed (Akazawa et al, 1994;Karavanova et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

The Bioactive Protein-Ligand Conformation of GluN2C-Selective Positive Allosteric Modulators Bound to the NMDA Receptor

et al. 2017

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-methyl-d-aspartate (NMDA) receptors are ligand-gated, cation-selective channels that mediate a slow component of excitatory synaptic transmission. Subunit-selective positive allosteric modulators of NMDA receptor function have therapeutically relevant effects on multiple processes in the brain. A series of pyrrolidinones, such as PYD-106, that selectively potentiate NMDA receptors that contain the GluN2C subunit have structural determinants of activity that reside between the GluN2C amino terminal domain and the GluN2C agonist binding domain, suggesting a unique site of action. Here we use molecular biology and homology modeling to identify residues that line a candidate binding pocket for GluN2C-selective pyrrolidinones. We also show that occupancy of only one site in diheteromeric receptors is required for potentiation. Both GluN2A and GluN2B can dominate the sensitivity of triheteromeric receptors to eliminate the actions of pyrrolidinones, thus rendering this series uniquely sensitive to subunit stoichiometry. We experimentally identified NMR-derived conformers in solution, which combined with molecular modeling allows the prediction of the bioactive binding pose for this series of GluN2C-selective positive allosteric modulators of NMDA receptors. These data advance our understanding of the site and nature of the ligand-protein interaction for GluN2C-selective positive allosteric modulators for NMDA receptors.

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Section: Discussionmentioning

confidence: 99%

The Bioactive Protein-Ligand Conformation of GluN2C-Selective Positive Allosteric Modulators Bound to the NMDA Receptor

et al. 2017

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“…Importantly, the enhancement of GluN2B subunits in CA1 could directly compensate for a lack of D-serine. GluN2A and GluN2B allosterically regulate co-agonist potency at the GluN1 glycine binding site (Priestley et al, 1995;Madry et al, 2007;Chen et al, 2008;Maolanon et al, 2017) with a two-to five-fold higher potency of co-agonists at GluN2B-containing NMDARs. Therefore, enhancement of GluN2B could compensate for a loss of D-serine given a smaller but stable pool of synaptic glycine.…”

Section: Regulation Of Ltp By Postsynaptic Serine Racemasementioning

confidence: 99%

Postsynaptic Serine Racemase Regulates NMDA Receptor Function

et al. 2020

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for their assistance in mouse breeding and genotyping. Human tissue was obtained from the NIH NeuroBioBank. Competing Interests: JTC reports consulting with Concert Pharm and holding a patent on D-serine for the treatment of serious mental illness, which is owned by Massachusetts General Hospital. DTB served as a consultant for LifeSci Capital and received research support from Takeda Pharmaceuticals. All other authors declare no competing financial interests.

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“…There are two feasible ways of stimulating the glycine-binding site of the NMDA receptor, i.e., by direct stimulation of the glycine-binding site and by elevating the synaptic glycine levels. Agonists of the glycine-binding site of the NMDA receptors include glycine, D-serine, D-cycloserine, GLYX-13, vinyl glycine and a series of 3-acylamino-2-aminopropionic acid derivatives [79,80,81].…”

Section: Role Of the Nmda Receptors In Social Interactionmentioning

confidence: 99%

The Role of the N-Methyl-D-Aspartate Receptors in Social Behavior in Rodents

Zoicas

Kornhuber

2019

IJMS

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The appropriate display of social behaviors is essential for the well-being, reproductive success and survival of an individual. Deficits in social behavior are associated with impaired N-methyl-D-aspartate (NMDA) receptor-mediated neurotransmission. In this review, we describe recent studies using genetically modified mice and pharmacological approaches which link the impaired functioning of the NMDA receptors, especially of the receptor subunits GluN1, GluN2A and GluN2B, to abnormal social behavior. This abnormal social behavior is expressed as impaired social interaction and communication, deficits in social memory, deficits in sexual and maternal behavior, as well as abnormal or heightened aggression. We also describe the positive effects of pharmacological stimulation of the NMDA receptors on these social deficits. Indeed, pharmacological stimulation of the glycine-binding site either by direct stimulation or by elevating the synaptic glycine levels represents a promising strategy for the normalization of genetically-induced, pharmacologically-induced or innate deficits in social behavior. We emphasize on the importance of future studies investigating the role of subunit-selective NMDA receptor ligands on different types of social behavior to provide a better understanding of the underlying mechanisms, which might support the development of selective tools for the optimized treatment of disorders associated with social deficits.

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Subtype-Specific Agonists for NMDA Receptor Glycine Binding Sites

Cited by 20 publications

References 22 publications

The Bioactive Protein-Ligand Conformation of GluN2C-Selective Positive Allosteric Modulators Bound to the NMDA Receptor

The Bioactive Protein-Ligand Conformation of GluN2C-Selective Positive Allosteric Modulators Bound to the NMDA Receptor

Postsynaptic Serine Racemase Regulates NMDA Receptor Function

The Role of the N-Methyl-D-Aspartate Receptors in Social Behavior in Rodents

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