Small molecule BDNF mimetics activate TrkB signaling and prevent neuronal degeneration in rodents

• Published in: The Journal of clinical investigation 2010-05, Vol.120 (5), p.1774-1785
• Main Authors: Massa, Stephen M, Yang, Tao, Xie, Youmei, Shi, Jian, Bilgen, Mehmet, Joyce, Jeffrey N, Nehama, Dean, Rajadas, Jayakumar, Longo, Frank M
• Format: Article
• Language: English
• Subjects: Alzheimer's disease; Animals; Biomedical research; Brain-derived neurotrophic factor; Brain-Derived Neurotrophic Factor - metabolism; Cellular signal transduction; Disease; Genetic aspects; Hippocampus - metabolism; Hydrogen bonds; Hypotheses; Kinases; Kinetics; Ligands; Male; Mice; Mice, Inbred C57BL; Models, Biological; Neurodegenerative Diseases - metabolism; Neurons; Neurons - metabolism; NIH 3T3 Cells; Peptides; Phosphorylation; Properties; Protein Binding; Rats; Rats, Sprague-Dawley; Receptor, trkB - metabolism; Signal Transduction; Technical Advance; Traumatic brain injury
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/jci41356

Brain-derived neurotrophic factor (BDNF) activates the receptor tropomyosin-related kinase B (TrkB) with high potency and specificity, promoting neuronal survival, differentiation, and synaptic function. Correlations between altered BDNF expression and/or function and mechanism(s) underlying numerous neurodegenerative conditions, including Alzheimer disease and traumatic brain injury, suggest that TrkB agonists might have therapeutic potential. Using in silico screening with a BDNF loop-domain pharmacophore, followed by low-throughput in vitro screening in mouse fetal hippocampal neurons, we have efficiently identified small molecules with nanomolar neurotrophic activity specific to TrkB versus other Trk family members. Neurotrophic activity was dependent on TrkB and its downstream targets, although compound-induced signaling activation kinetics differed from those triggered by BDNF. A selected prototype compound demonstrated binding specificity to the extracellular domain of TrkB. In in vitro models of neurodegenerative disease, it prevented neuronal degeneration with efficacy equal to that of BDNF, and when administered in vivo, it caused hippocampal and striatal TrkB activation in mice and improved motor learning after traumatic brain injury in rats. These studies demonstrate the utility of loop modeling in drug discovery and reveal what we believe to be the first reported small molecules derived from a targeted BDNF domain that specifically activate TrkB.We propose that these compounds constitute a novel group of tools for the study of TrkB signaling and may provide leads for developing new therapeutic agents for neurodegenerative diseases.