Identification of novel allosteric modulator binding sites in NMDA receptors: A molecular modeling study

Kane, L.; Costa, Blaise M.

doi:10.1016/j.jmgm.2015.06.007

Cited by 5 publications

(2 citation statements)

References 51 publications

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“…In this study, through ongoing computational and experimental screening efforts, 31 , 32 , 33 , 34 , 35 we have identified a compound from the NIH PubChem database (CID# 3794169) that contains 111 million unique chemical structures. Previously known biological effects of this compound can be obtained from PubChem .…”

Section: Introductionmentioning

confidence: 99%

A glutamate concentration‐biased allosteric modulator potentiates NMDA‐induced ion influx in neurons

Costa

Kwapisz

Mehrkens

et al. 2021

Pharmacology Res & Perspec

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Precisely controlled synaptic glutamate concentration is essential for the normal function of the N‐methyl D‐aspartate (NMDA) receptors. Atypical fluctuations in synaptic glutamate homeostasis lead to aberrant NMDA receptor activity that results in the pathogenesis of neurological and psychiatric disorders. Therefore, glutamate concentration‐dependent NMDA receptor modulators would be clinically useful agents with fewer on‐target adverse effects. In the present study, we have characterized a novel compound (CNS4) that potentiates NMDA receptor currents based on glutamate concentration. This compound alters glutamate potency and exhibits no voltage‐dependent effect. Patch‐clamp electrophysiology recordings confirmed agonist concentration‐dependent changes in maximum inducible currents. Dynamic Ca 2+ and Na + imaging assays using rat brain cortical, striatal and cerebellar neurons revealed CNS4 potentiated ion influx through native NMDA receptor activity. Overall, CNS4 is novel in chemical structure, mechanism of action and agonist concentration‐biased allosteric modulatory effect. This compound or its future analogs will serve as useful candidates to develop drug‐like compounds for the treatment of treatment‐resistant schizophrenia and major depression disorders associated with hypoglutamatergic neurotransmission.

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Section: Introductionmentioning

confidence: 99%

A glutamate concentration‐biased allosteric modulator potentiates NMDA‐induced ion influx in neurons

Costa

Kwapisz

Mehrkens

et al. 2021

Pharmacology Res & Perspec

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“…Discovery of a novel family of GluN2 specific compounds and their binding sites revealed the existence of a potential modulator-binding site at the GluN1/2 LBD dimer interface (Costa et al, 2010). Furthermore, the LBD dimer interface was predicted by molecular modeling as the primary binding site for a GluN1/2A selective potentiator (Kane and Costa, 2015). Recently, a number of high affinity compounds have been developed to positively modulate GluN1/2A receptor function, and some of these compounds have been already co-crystallized with GluN1/2A LBD constructs and were found to bind in the dimer interface (Hackos et al, 2016; Volgraf et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Positive Modulatory Interactions of NMDA Receptor GluN1/2B Ligand Binding Domains Attenuate Antagonists Activity

Bledsoe¹,

Tamer²,

Mesic³

et al. 2017

Front. Pharmacol.

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N-methyl D-aspartate receptors (NMDAR) play crucial role in normal brain function and pathogenesis of neurodegenerative and psychiatric disorders. Functional tetra-heteromeric NMDAR contains two obligatory GluN1 subunits and two identical or different non-GluN1 subunits that include six different gene products; four GluN2 (A–D) and two GluN3 (A–B) subunits. The heterogeneity of subunit combination facilities the distinct function of NMDARs. All GluN subunits contain an extracellular N-terminal Domain (NTD) and ligand binding domain (LBD), transmembrane domain (TMD) and an intracellular C-terminal domain (CTD). Interaction between the GluN1 and co-assembling GluN2/3 subunits through the LBD has been proven crucial for defining receptor deactivation mechanisms that are unique for each combination of NMDAR. Modulating the LBD interactions has great therapeutic potential. In the present work, by amino acid point mutations and electrophysiology techniques, we have studied the role of LBD interactions in determining the effect of well-characterized pharmacological agents including agonists, competitive antagonists, and allosteric modulators. The results reveal that agonists (glycine and glutamate) potency was altered based on mutant amino acid sidechain chemistry and/or mutation site. Most antagonists inhibited mutant receptors with higher potency; interestingly, clinically used NMDAR channel blocker memantine was about three-fold more potent on mutated receptors (N521A, N521D, and K531A) than wild type receptors. These results provide novel insights on the clinical pharmacology of memantine, which is used for the treatment of mild to moderate Alzheimer's disease. In addition, these findings demonstrate the central role of LBD interactions that can be exploited to develop novel NMDAR based therapeutics.

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Ligand binding domain interface: A tipping point for pharmacological agents binding with GluN1/2A subunit containing NMDA receptors

Bledsoe

Vacca

Laube

et al. 2019

European Journal of Pharmacology

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Identification of novel allosteric modulator binding sites in NMDA receptors: A molecular modeling study

Cited by 5 publications

References 51 publications

A glutamate concentration‐biased allosteric modulator potentiates NMDA‐induced ion influx in neurons

A glutamate concentration‐biased allosteric modulator potentiates NMDA‐induced ion influx in neurons

Positive Modulatory Interactions of NMDA Receptor GluN1/2B Ligand Binding Domains Attenuate Antagonists Activity

Ligand binding domain interface: A tipping point for pharmacological agents binding with GluN1/2A subunit containing NMDA receptors

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