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Identification of a low–molecular weight TrkB antagonist with anxiolytic and antidepressant activity in mice
Open accessAbstract
The neurotrophin brain-derived neurotrophic factor (BDNF) and its receptor tropomyosin-related kinase B (TrkB) have emerged as key mediators in the pathophysiology of several mood disorders, including anxiety and depression. However, therapeutic compounds that interact with TrkB receptors have been difficult to develop. Using a combination of structure-based in silico screening and high-capacity functional assays in recombinant and neuronal cells, we identified a low-molecular weight TrkB ligand (ANA-12) that prevented activation of the receptor by BDNF with a high potency. ANA-12 showed direct and selective binding to TrkB and inhibited processes downstream of TrkB without altering TrkA and TrkC functions. KIRA-ELISA analysis demonstrated that systemic administration of ANA-12 to adult mice decreased TrkB activity in the brain without affecting neuronal survival. Mice administered ANA-12 demonstrated reduced anxiety- and depression-related behaviors on a variety of tests predictive of anxiolytic and antidepressant properties in humans. This study demonstrates that structure-based virtual screening strategy can be an efficient method for discovering potent TrkB-selective ligands that are active in vivo. We further propose that ANA-12 may be a valuable tool for studying BDNF/TrkB signaling and may constitute a lead compound for developing the next generation of therapeutic agents for the treatment of mood disorders.
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“ANA-12 is a selective partial agonist that was first developed by Carzola et al. in 2011 using a structure-based in silico screening (Cazorla et al. 2011).”
From Neurotrophic factors and neuroplasticity pathways in the pathophysiology and treatment of depression (2018) · cites this paper as Cazorla et al. 2011
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“Indeed, when PC12 cells transfected with TrkB were stimulated with BDNF for 48 h, neurite outgrowth was increased compared to the non-treated cells (Cazorla et al. 2011).”
From Neurotrophic factors and neuroplasticity pathways in the pathophysiology and treatment of depression (2018) · cites this paper as Cazorla et al. 2011
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“In their study, the authors identified a low-molecular weight antagonist of TrkB that could induce anxiolytic and antidepressant properties.”
From Neurotrophic factors and neuroplasticity pathways in the pathophysiology and treatment of depression (2018) · cites this paper as Cazorla et al. 2011
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“In spite of these interesting results, antagonists could also induce cell death, an issue that should be addressed when considering using these agents in chronic treatment regimens (Cazorla et al. 2011; Takemoto et al. 2015).”
From Neurotrophic factors and neuroplasticity pathways in the pathophysiology and treatment of depression (2018) · cites this paper as Cazorla et al. 2011
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Metadata
- Authors
- Cazorla, M., Prémont, J., Mann, A., Girard, N., Kellendonk, C., & Rognan, D.
- Affiliations
- Inserm (FR)
- Laboratoire d'Innovation Thérapeutique (FR)
- Columbia University Irving Medical Center (US)
- Venue
- Journal of Clinical Investigation
- Published
- 2011-05-02
- Volume
- 121
- Issue
- 5
- Pages
- 1846-1857
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC3083767
- OpenAlex
- W2087102666
- Cited by
- 392
- References
- 50
- Citations by year
- 2026: 32 · 2025: 23 · 2024: 21 · 2023: 21 · 2022: 22 · 2021: 21 · 2020: 39 · 2019: 29 · 2018: 47 · 2017: 22 · 2016: 29 · 2015: 32 · 2014: 19 · 2013: 16 · 2012: 13
- FWCI
- 12.65
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Funders
- Université de Strasbourg
- Centre National de la Recherche Scientifique
- Topics
- Health Sciences › Medicine › Pharmacology (medical) › Treatment of Major Depression
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nerve injury and regeneration
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Drug Discovery › Computational Drug Discovery Methods
- Keywords
- TrkB receptor, brain-derived neurotrophic factor, ANA-12, anxiolytic effects, antidepressant effects, mood disorders, anxiety, depression, structure-based virtual screening, BDNF/TrkB signaling
- MeSH terms
- Animals, Antidepressive Agents, Anxiety, Azepines, Behavior, Animal, Benzamides, Brain, Chemistry, Pharmaceutical, Depression, Enzyme-Linked Immunosorbent Assay, Humans, Ligands, Molecular Weight, Neurons, Anti-Anxiety Agents, Drug Design, Signal Transduction, Brain-Derived Neurotrophic Factor, Mood Disorders, Receptor, trkB, Receptor, trkA, Mice
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