ArticleNeuropsychopharmacology : official publication of the American College of Neuropsychopharmacology2021
Positive modulation of NMDA receptors by AGN-241751 exerts rapid antidepressant-like effects via excitatory neurons.
Article in Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers, 2 of them syntheses that pooled it.
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Who cites it
15 citing papers in PubMed, 2 syntheses or guidelines pooled it, 32 citations in OpenAlex.
- Phytochemicals in the treatment of patients with depression: a systemic review.Frontiers in psychiatry · 2024Pooled it
- Investigational Drugs for the Treatment of Depression (Part 2): Glutamatergic, Cholinergic, Sestrin Modulators, and Other Agents.Frontiers in pharmacology · 2022Pooled it
- GluN2B-specific NMDAR positive allosteric modulation reverses cognitive and behavioral abnormalities inScience advances · 2026Article
- Demystifying the Antidepressant Mechanism of Action of Stinels, a Novel Class of Neuroplastogens: Positive Allosteric Modulators of the NMDA Receptor.Pharmaceuticals (Basel, Switzerland) · 2025Review
- Research Progress on NMDA Receptor Enhancement Drugs for the Treatment of Depressive Disorder.CNS drugs · 2024Review
- Review
- The Complex World of Kynurenic Acid: Reflections on Biological Issues and Therapeutic Strategy.International journal of molecular sciences · 2024Review
- Targeting metaplasticity mechanisms to promote sustained antidepressant actions.Molecular psychiatry · 2024Review
- Central regulation of stress-evoked peripheral immune responses.Nature reviews. Neuroscience · 2023Review
- GluN2B-containing NMDARs in the mammalian brain: pharmacology, physiology, and pathology.Frontiers in molecular neuroscience · 2023Review
- Zelquistinel Is an Orally Bioavailable Novel NMDA Receptor Allosteric Modulator That Exhibits Rapid and Sustained Antidepressant-Like Effects.The international journal of neuropsychopharmacology · 2022Article
- Region-Specific Enhancement of c-fos Expression by Combined Treatment With NMDA Receptor Agonists and Antagonists With Antidepressant Potential.The international journal of neuropsychopharmacology · 2022Article
- The trilateral interactions between mammalian target of rapamycin (mTOR) signaling, the circadian clock, and psychiatric disorders: an emerging model.Translational psychiatry · 2022Review
- Mechanisms of ketamine and its metabolites as antidepressants.Biochemical pharmacology · 2022Review
- Novel Pharmacological Approaches to the Treatment of Depression.Life (Basel, Switzerland) · 2022Review
Corrections and comments
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Authors and funding
7 authors at 2 institutions in 1 country.
Funding
Abstract
Dysregulation of the glutamatergic system and its receptors in medial prefrontal cortex (mPFC) has been implicated in major depressive disorder. Recent preclinical studies have shown that enhancing NMDA receptor (NMDAR) activity can exert rapid antidepressant-like effects. AGN-241751, an NMDAR positive allosteric modulator (PAM), is currently being tested as an antidepressant in clinical trials, but the mechanism and NMDAR subunit(s) mediating its antidepressant-like effects are unknown. We therefore used molecular, biochemical, and electrophysiological approaches to examine the cell-type-specific role of GluN2B-containing NMDAR in mediating antidepressant-like behavioral effects of AGN-241751. We demonstrate that AGN-241751 exerts antidepressant-like effects and reverses behavioral deficits induced by chronic unpredictable stress in mice. AGN-241751 treatment enhances NMDAR activity of excitatory and parvalbumin-inhibitory neurons in mPFC, activates Akt/mTOR signaling, and increases levels of synaptic proteins crucial for synaptic plasticity in the prefrontal cortex. Furthermore, cell-type-specific knockdown of GluN2B-containing NMDARs in mPFC demonstrates that GluN2B subunits on excitatory, but not inhibitory, neurons are necessary for antidepressant-like effects of AGN-241751. Together, these results demonstrate antidepressant-like actions of the NMDAR PAM AGN-241751 and identify GluN2B on excitatory neurons of mPFC as initial cellular trigger underlying these behavioral effects.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.