Alzheimer's therapeutics: neurotrophin small molecule mimetics

A substantial portion of neuronal populations undergoing degeneration in Alzheimer's and other neurodegenerative disorders express neurotrophin receptors. Neurotrophin small molecule mimetics constitute candidate compounds that might be useful in preventing or delaying loss of neuronal function, neural networks or neuronal death in neurodegenerative states. We are testing the hypothesis that pharmacophores based on a combination of the crystal structures of neurotrophins and structure-activity relationships of active neurotrophin peptidomimetics can be used to screen small molecule libraries to identify non-peptide small molecules with neurotrophin agonist or antagonist activity. In preliminary screens using pharmacophores based on two nerve growth factor (NGF) loop domains, a number of small molecules have been identified that display neurotrophic activity using in vitro bioassays. Current studies are focused on determining whether these small molecules function via neurotrophin receptors and whether they activate neurotrophin signaling cascades. Assessment of structure-activity relationships between active and inactive small molecules will allow modification of pharmacophores and provide a basis for the iterative process if identifying compounds with increased potency and efficacy. A collection of such compounds will provide a basis for synthesis of compounds with targeted pharmacological properties.