Cited by 394Treatment of Major DepressionNerve injury and regenerationComputational Drug Discovery Methods

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Identification of a low–molecular weight TrkB antagonist with anxiolytic and antidepressant activity in mice

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Cazorla, Maxime, Prémont, Joël, Mann, Andre, Girard, Nicolas, Kellendonk, Christoph, Rognan, Didier·2011·Journal of Clinical Investigation

DOI 10.1172/jci43992PMC PMC3083767

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Abstract

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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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)
ORCID: Cazorla, Maxime
Girard, Nicolas
Kellendonk, Christoph
Rognan, Didier
Venue: Journal of Clinical Investigation
Publisher: American Society for Clinical Investigation
Published: 2011-05-02
Volume: 121
Issue: 5
Pages: 1846-1857
ISSN: 0021-9738 (ISSN-L)
DOI: 10.1172/jci43992
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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Identification of a low–molecular weight TrkB antagonist with anxiolytic and antidepressant activity in mice

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