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.