Discovery of Rapid-Acting, Orally Available Antidepressants by Activating TrkB Signaling.
Xu Cheng, Fan Jiang, Lixin Liu, Yuanqiang Wang, Shuang Chen, Wei Cui
Journal of Medicinal Chemistry July 29, 2025 DOI: 10.1021/acs.jmedchem.5c01750 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical study Peer reviewed |
|---|---|
| Intervention | B11 |
| Topics | Neuroplasticity |
| Keywords | Depression treatment Mental health therapy Mood disorder treatment Psychiatric medication Rapid-acting drugs Fast-acting therapy Quick-onset medication Novel antidepressants Breakthrough treatment Brain pathways Brain adaptation Neurological research Cns Drug discovery New compound Pharmaceutical research Preclinical studies Therapeutic development Novel therapies |
| Citations | 1 |
| Key points | B11 is a rapid-acting antidepressant that activates the TrkB-CREB signaling axis with minimal interference with targets associated with psychotic side effects in preclinical models. |
Abstract
Major depressive disorder (MDD) remains a significant global health burden, and its current treatments are limited by the delayed onset of efficacy weeks after dosing. While esketamine and psychedelics were clinically successful as rapid-acting antidepressants in recent years, these molecules are heavily associated with psychotic side effects and the risks of substance abuse. In this study, we identified a rapid-acting antidepressant B11 through phenotypic screening and pharmacophore-oriented lead optimization. Unlike the existing fast-onset antidepressants, B11 showed minimal interference with targets associated with psychotic side effects while demonstrating potent antidepressant effects through activation of the TrkB-CREB signaling axis in preclinical models. Besides, B11 readily penetrates the blood-brain barrier and possesses a favorable pharmacokinetic profile that enables oral administration. Our findings highlight the potential of optimized fast-onset therapeutics for addressing unmet clinical needs in depression treatment and underscore the importance of neuroplasticity modulation in drug discovery efforts for MDD.
Comparable studies
Other preclinical and animal studies on neuroplasticity, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors In vitro and in vivo (rodent) models | 2023 | Experimental study | |
| Psychedelics promote plasticity by directly binding to BDNF receptor TrkB Mice | 2023 | Experimental study | |
| Effects of psilocybin on hippocampal neurogenesis and extinction of trace fear conditioning Mice | 2013 | Experimental study | |
| The alkaloids of Banisteriopsis caapi, the plant source of the Amazonian hallucinogen Ayahuasca, stimulate adult neurogenesis in vitro Progenitor cells from subventricular and subgranular zones of adult mice brains | 2017 | In vitro experimental study | |
| N,N-dimethyltryptamine compound found in the hallucinogenic tea ayahuasca, regulates adult neurogenesis in vitro and in vivo Mice | 2020 | In vitro and in vivo experimental study |
Citations in the library
Cites 12
- Psychedelics Promote Structural and Functional Neural Plasticity Cell Reports June 1, 2018
- Single-Dose Psilocybin for a Treatment-Resistant Episode of Major Depression. New England Journal of Medicine November 3, 2022
- Single-Dose Psilocybin Treatment for Major Depressive Disorder JAMA August 31, 2023
- Psychedelics promote plasticity by directly binding to BDNF receptor TrkB Nature Neuroscience June 1, 2023
- Harnessing psilocybin: antidepressant-like behavioral and synaptic actions of psilocybin are independent of 5-HT2R activation in mice Proceedings of the National Academy of Sciences April 13, 2021
and 7 more in the library