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J Clin Invest. 2011 May;121(5):1846-57. doi: 10.1172/JCI43992. Epub 2011 Apr 18.

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

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  • 1Neurobiology and Molecular Pharmacology, Centre de Psychiatrie et Neurosciences, UMR-894 INSERM/Université Paris Descartes, Paris, France. mc3195@columbia.edu

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.

Comment in

PMID:
21505263
[PubMed - indexed for MEDLINE]
PMCID:
PMC3083767
Free PMC Article

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