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- Title
Identification of a low-molecular weight TrkB antagonist with anxiolytic and antidepressant activity in mice.
- Authors
Cazorla, Maxime; Prémont, Joël; Mann, Andre; Girard, Nicolas; Kellendonk, Christoph; Rognan, Didier; Prémont, Joël
- 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.
- Subjects
NEUROPHYSIOLOGY; AFFECTIVE disorders; TRANQUILIZING drugs; ANTIDEPRESSANTS; PATHOLOGICAL physiology; ENZYME-linked immunosorbent assay; MOLECULAR weights
- Publication
Journal of Clinical Investigation, 2011, Vol 121, Issue 5, p1846
- ISSN
0021-9738
- Publication type
journal article
- DOI
10.1172/JCI43992