Demystifying the Antidepressant Mechanism of Action of Stinels, a Novel Class of Neuroplastogens: Positive Allosteric Modulators of the NMDA Receptor.
John E Donello, Roger S McIntyre, Donald B Pickel, Stephen M Stahl
Pharmaceuticals January 24, 2025 DOI: 10.3390/ph18020157 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Review Peer reviewed |
|---|---|
| Topics | Ketamine Neuroplasticity |
| Keywords | N-methyl-d-aspartate receptor Mechanism Neuroplastogens Positive allosteric modulator Depression treatment Antidepressants ssris Snris Maois Tricyclics Neuroplasticity brain plasticity |
| Citations | 14 |
| Key findings | Stinels are defined as positive allosteric modulators of NMDAR activity with a novel regulatory binding site, not glycine-like partial agonists as previously described. |
Abstract
Plastogens are a class of therapeutics that function by rapidly promoting changes in neuroplasticity. A notable example, ketamine, is receiving great attention due to its combined rapid and long-term antidepressant effects. Ketamine is an N-methyl-D-aspartate receptor (NMDAR) antagonist, and, in addition to its therapeutic activity, it is associated with psychotomimetic and dissociative side effects. Stinels-rapastinel, apimostinel, and zelquistinel-are also plastogens not only with rapid and long-term antidepressant effects but also with improved safety and tolerability profiles compared to ketamine. Previous descriptions of the mechanism by which stinels modulate NMDAR activity have been inconsistent and, at times, contradictory. The purpose of this review is to clarify the mechanism of action and contextualize stinels within a broader class of NMDAR-targeting therapeutics. In this review, we present the rationale behind targeting NMDARs for treatment-resistant depression and other psychiatric conditions, describe the various mechanisms by which NMDAR activity is regulated by different classes of therapeutics, and present evidence for the stinel mechanism. In contrast with previous descriptions of glycine-like NMDAR partial agonists, we define stinels as positive allosteric modulators of NMDAR activity with a novel regulatory binding site.
Comparable studies
Other narrative reviews on neuroplasticity, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| A neurotrophic hypothesis of depression: role of synaptogenesis in the actions of NMDA receptor antagonists | 2012 | Review | |
| Towards an understanding of psychedelic-induced neuroplasticity. Review of preclinical and clinical studies | 2023 | Review | |
| Buddha's Brain: Neuroplasticity and Meditation [In the Spotlight] | 2008 | Review | |
| Neuroplasticity as a convergent mechanism of ketamine and classical psychedelics | 2021 | Review | |
| Psychedelics in Psychiatry: Neuroplastic, Immunomodulatory, and Neurotransmitter Mechanisms | 2020 | Review |
Citations in the library
Cited by 9
- The therapeutic potential of psilocybin beyond psychedelia through shared mechanisms with ketamine. Molecular Psychiatry July 7, 2025
- Synaptic priming: A framework for pharmacotherapy in depression. Neuron November 19, 2025
- Correlation analysis between clinical effective emotional treatment and plasma N-methyl-D-aspartate receptor function-related indexes. Frontiers in Neuroscience 2025
- Modulating tonic NMDA receptor currents: mechanistic insights into ketamine, esketamine, and dextromethorphan for major depressive disorder and implications for the discovery and development of investigational agents. Expert Opinion on Therapeutic Targets January 28, 2026
- New Antidepressant Development in the Treatment of Depression. Advances in experimental medicine and biology 2026
and 4 more in the library
Cites 22
- mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Science August 19, 2010
- NMDAR inhibition-independent antidepressant actions of ketamine metabolites Nature April 24, 2016
- Ketamine and Ketamine Metabolite Pharmacology: Insights into Therapeutic Mechanisms Pharmacological Reviews June 26, 2018
- Psychedelics Promote Structural and Functional Neural Plasticity Cell Reports June 1, 2018
- Mechanisms of Ketamine Action as an Antidepressant Molecular Psychiatry March 13, 2018
and 17 more in the library