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Identification of a low–molecular weight TrkB antagonist with anxiolytic and antidepressant activity in mice
Maxime Cazorla, … , Christoph Kellendonk, Didier Rognan
Maxime Cazorla, … , Christoph Kellendonk, Didier Rognan
Published April 18, 2011
Citation Information: J Clin Invest. 2011;121(5):1846-1857. https://doi.org/10.1172/JCI43992.
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Research Article Neuroscience Article has an altmetric score of 26

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

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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.

Authors

Maxime Cazorla, Joël Prémont, Andre Mann, Nicolas Girard, Christoph Kellendonk, Didier Rognan

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Figure 1

Computational modeling of the specificity patch.

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Computational modeling of the specificity patch.
The structure-based vir...
The structure-based virtual screening was performed by targeting the specificity interaction patch between the N-terminal segment of BDNF (N-TERM, red/orange) and the d5 subdomain of TrkB (TrkB-d5, green). An alignment of the N-terminal amino acid sequence of rodent BDNF, NT-4/5, NT-3, and NGF is shown in the upper panel (the specific region is boxed; dashes represent gaps). The 3D model of the complex between the TrkB-d5 domain (green solid surface) and the BDNF N-terminal part (H1SDPAR6, orange sticks) is illustrated in the lower panel.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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