title: Identification of a low-molecular weight TrkB antagonist with anxiolytic and antidepressant activity in mice.
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.affiliation: Neurobiology and Molecular Pharmacology, Centre de Psychiatrie et Neurosciences, UMR-894 INSERM/Université Paris Descartes, Paris, France. mc3195@columbia.edu
authors.forename: Maxime
authors.initials: M
authors.lastname: Cazorla
authors.forename: Joël
authors.initials: J
authors.lastname: Prémont
authors.forename: Andre
authors.initials: A
authors.lastname: Mann
authors.forename: Nicolas
authors.initials: N
authors.lastname: Girard
authors.forename: Christoph
authors.initials: C
authors.lastname: Kellendonk
authors.forename: Didier
authors.initials: D
authors.lastname: Rognan
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D000928:Antidepressive Agents / Q000494:pharmacology*; D001007:Anxiety / Q000378:metabolism; D001381:Azepines / Q000737:chemistry / Q000494:pharmacology*; D001522:Behavior, Animal; D001549:Benzamides / Q000737:chemistry / Q000494:pharmacology*; D001921:Brain / Q000378:metabolism; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D002626:Chemistry, Pharmaceutical / Q000379:methods; D003863:Depression / Q000378:metabolism; D015195:Drug Design; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D006801:Humans; D008024:Ligands; D051379:Mice; D008970:Molecular Weight; D019964:Mood Disorders / Q000188:drug therapy; D009474:Neurons / Q000378:metabolism; D020917:Receptor, trkA / Q000378:metabolism; D020813:Receptor, trkB / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: C559317:ANA 12 compound; D014151:Anti-Anxiety Agents; D000928:Antidepressive Agents; D001381:Azepines; D001549:Benzamides; D019208:Brain-Derived Neurotrophic Factor; D008024:Ligands; D020917:Receptor, trkA; D020813:Receptor, trkB