Evaluation of allosteric NMDA receptor modulation by GluN2A-selective antagonists using pharmacological equilibrium modeling DOI Open Access
James S. Lotti,

J. V. JONES,

Jill Farnsworth

и другие.

Molecular Pharmacology, Год журнала: 2024, Номер 107(1), С. 100004 - 100004

Опубликована: Ноя. 5, 2024

NMDA-type ionotropic glutamate receptors are critically involved in excitatory neurotransmission and their dysfunction is implicated many brain disorders. Allosteric modulators with selectivity for specific NMDA receptor subtypes therefore attractive as therapeutic agents, sustained drug discovery efforts have resulted a wide range of new allosteric modulators. However, evaluation limited by the lack operational ligand-receptor models to describe modulator binding dissociation constants (KB) effects on agonist affinity (α) efficacy (β). Here, we pharmacological equilibrium model that encapsulates activation modulation receptors, apply this afford deeper understanding GluN2A-selective negative (NAMs), TCN-201, MPX-004, MPX-007. We exploit slow NAM unbinding examine at hemi-equilibrium when fully occupied agonists demonstrate TCN-201 display weaker glycine (KB = 42 nM, α 0.0032) compared MPX-004 9.3 0.0018) MPX-007 1.1 0.00053). increases (β 1.19), whereas 0.76) 0.82) reduce efficacy. These values describing diheteromeric GluN1/2A two sites unchanged triheteromeric GluN1/2A/2B single site. This reveals differences between ligand analogs shape utility tool compounds facilitates design potential. Significance Statement Detailed requires methods quantify strengths generic use characterization NAMs. The enables quantitative broad provides opportunities optimize these embellishing interpretation structure-activity relationships.

Язык: Английский

Assembly and architecture of endogenous NMDA receptors in adult cerebral cortex and hippocampus DOI Creative Commons
Ming Zhang,

Juan Feng,

Chun Xie

и другие.

Cell, Год журнала: 2025, Номер unknown

Опубликована: Янв. 1, 2025

The cerebral cortex and hippocampus are crucial brain regions for learning memory, which depend on activity-induced synaptic plasticity involving N-methyl-ᴅ-aspartate receptors (NMDARs). However, subunit assembly molecular architecture of endogenous NMDARs (eNMDARs) in the remain elusive. Using conformation- subunit-dependent antibodies, we purified eNMDARs from adult rat hippocampus. Three major subtypes GluN1-N2A-N2B, GluN1-N2B, GluN1-N2A were resolved by cryoelectron microscopy (cryo-EM) at resolution up to 4.2 Å. particle ratio these three was 9:7:4, indicating that about half GluN2A GluN2B subunits incorporated into tri-heterotetramers. Structural analysis revealed asymmetric GluN1-N2A-N2B receptor throughout extracellular transmembrane layers. Moreover, conformational variations between GluN1-N2B distinct biophysical properties across different eNMDAR subtypes. Our findings imply structural functional complexity shed light structure-based therapeutic design targeting vivo.

Язык: Английский

Процитировано

4
Molecular mechanism of ligand gating and opening of NMDA receptor DOI
Tsung‐Han Chou, Max Epstein, Russell G. Fritzemeier

и другие.

Nature, Год журнала: 2024, Номер 632(8023), С. 209 - 217

Опубликована: Июль 31, 2024

Язык: Английский

Процитировано

15
Structural and functional mechanisms of anti-NMDAR autoimmune encephalitis DOI

Kevin Michalski,

Taha Abdulla,

S. N. Kleeman

и другие.

Nature Structural & Molecular Biology, Год журнала: 2024, Номер unknown

Опубликована: Сен. 3, 2024

Язык: Английский

Процитировано

4
Green procedures for synthesizing potential hNMDA receptor allosteric modulators through reduction and one-pot reductive acetylation of nitro(hetero)arenes using a superparamagnetic Fe3O4@APTMS@Cp2ZrClx (x = 0, 1, 2) nanocatalyst DOI Creative Commons
Hossein Mousavi, Behzad Zeynizadeh,

Farhad Sepehraddin

и другие.

Nanoscale Advances, Год журнала: 2025, Номер unknown

Опубликована: Янв. 1, 2025

In this research, we have developed diverse strategies for synthesizing potential h NMDA receptor allosteric modulators through reduction and one-pot reductive acetylation of nitro(hetero)arenes using a mesoporous zirconocene-containing nanocatalyst.

Язык: Английский

Процитировано

0
The GluN3-containing NMDA receptors DOI Creative Commons

Kunlong Xiong,

Shulei Lou,

Lian Zhou

и другие.

Channels, Год журнала: 2025, Номер 19(1)

Опубликована: Апрель 16, 2025

N-methyl-D-aspartate receptors (NMDARs) are heterotetrameric ion channels that play crucial roles in brain function. Among all the NMDAR subtypes, GluN1-N3 exhibit unique agonist binding and gating properties. Unlike "conventional" GluN1-N2 receptors, which require both glycine glutamate for activation, activated solely by glycine. Furthermore, display faster desensitization, reduced Ca2+ permeability, lower sensitivity to Mg2+ blockage compared receptors. Due these characteristics, thought critical eliminating redundant synapses pruning spines early stages of development. Recent studies have advanced pharmacological tools specifically targeting provided direct evidence glycine-activated excitatory native tissue. The structural basis has also been elucidated through cryo-EM artificial intelligence. These findings highlight not only involved essential functions but present potential targets drug

Язык: Английский

Процитировано

0
Significance of NMDA receptor-targeting compounds in neuropsychological disorders: An In-depth Review DOI Creative Commons

Fatemeh Forouzanfar,

Amir Mahmoud Ahmadzadeh, Ali Mohammad Pourbagher‐Shahri

и другие.

European Journal of Pharmacology, Год журнала: 2025, Номер unknown, С. 177690 - 177690

Опубликована: Апрель 1, 2025

Язык: Английский

Процитировано

0
Adrenergic pathways in glycine-mediated feeding behavior: Evidence from layer chickens DOI Creative Commons
Hamed Zarei,

Fatemeh Kashefi,

Keyvan Hasani

и другие.

Poultry Science, Год журнала: 2025, Номер 104(8), С. 105338 - 105338

Опубликована: Май 26, 2025

Язык: Английский

Процитировано

0
Hydrogen sulfide and its donors for the treatment of traumatic brain injury: A comprehensive review DOI
Xianzhe Li,

Yumei An,

Mingyuan Xu

и другие.

International Journal of Pharmaceutics, Год журнала: 2025, Номер unknown, С. 125792 - 125792

Опубликована: Май 1, 2025

Язык: Английский

Процитировано

0
Structural prediction of GluN3 NMDA receptors DOI Creative Commons

Yunsheng Liu,

Da Shao,

Shulei Lou

и другие.

Frontiers in Physiology, Год журнала: 2024, Номер 15

Опубликована: Авг. 20, 2024

N -methyl- D -aspartate (NMDA) receptors are heterotetrametric ion channels composed of two obligatory GluN1 subunits and alternative GluN2 or GluN3 subunits, forming GluN1-N2, GluN1-N3, GluN1-N2-N3 type NMDA receptors. Extensive research has focused on the functional structural properties conventional GluN1–GluN2 due to their early discovery high expression levels. However, knowledge unconventional GluN1-N3 remains limited. In this study, we modeled GluN1-N3A, GluN1-N3B, GluN1-N3A-N3B using deep-learned protein-language predication algorithms AlphaFold RoseTTAFold All-Atom. We then compared these structures with GluN1-N2 GluN1-N3A receptor cryo-EM found that have distinct in subunit arrangement, domain swap, interaction. Furthermore, predicted agonist- antagonist-bound structures, highlighting key molecular–residue interactions. Our findings shed new light diversity provide a direction for drug development. This study uses advanced AI model receptors, revealing unique interactions By predicting ligand-bound our enhances understanding offers insights targeted

Язык: Английский

Процитировано

2
Evaluation of allosteric NMDA receptor modulation by GluN2A-selective antagonists using pharmacological equilibrium modeling DOI Open Access
James S. Lotti,

J. V. JONES,

Jill Farnsworth

и другие.

Molecular Pharmacology, Год журнала: 2024, Номер 107(1), С. 100004 - 100004

Опубликована: Ноя. 5, 2024

NMDA-type ionotropic glutamate receptors are critically involved in excitatory neurotransmission and their dysfunction is implicated many brain disorders. Allosteric modulators with selectivity for specific NMDA receptor subtypes therefore attractive as therapeutic agents, sustained drug discovery efforts have resulted a wide range of new allosteric modulators. However, evaluation limited by the lack operational ligand-receptor models to describe modulator binding dissociation constants (KB) effects on agonist affinity (α) efficacy (β). Here, we pharmacological equilibrium model that encapsulates activation modulation receptors, apply this afford deeper understanding GluN2A-selective negative (NAMs), TCN-201, MPX-004, MPX-007. We exploit slow NAM unbinding examine at hemi-equilibrium when fully occupied agonists demonstrate TCN-201 display weaker glycine (KB = 42 nM, α 0.0032) compared MPX-004 9.3 0.0018) MPX-007 1.1 0.00053). increases (β 1.19), whereas 0.76) 0.82) reduce efficacy. These values describing diheteromeric GluN1/2A two sites unchanged triheteromeric GluN1/2A/2B single site. This reveals differences between ligand analogs shape utility tool compounds facilitates design potential. Significance Statement Detailed requires methods quantify strengths generic use characterization NAMs. The enables quantitative broad provides opportunities optimize these embellishing interpretation structure-activity relationships.

Язык: Английский

Процитировано

0