CNS Transporters have crucial roles on neurophysiology and etiology. Inhibition of these critical transporters can have therapeutic benefits or cause serious side effects in the CNS. Development of an assay platform and a comprehensive profile of drugs'inhibitory effects on important CNS transporters can have enormous impact on drug discovery and development, such as elucidating drugs'potential side effects in the CNS, and advancing development of new drugs to treat various CNS diseases, such as Alzheimer's disease, Parkinson's diseases, epilepsy etc., The overall goal of this project is to develop a comprehensive assay platform for evaluating drugs'inhibitory effects on key CNS transporters, and then to establish the industry's largest database on inhibitory effects of over 1000 prescription CNS and peripherally acting drugs on these transporters. The initial Phase I work will start with developing assays for 10 crucial CNS transporters, which are known as therapeutic targets or to play critical roles on CNS physiology. A small library of marketed CNS drugs will then be profiled for their inhibitory effects on these transporters, with aims to reveal possible interactions of the drugs with these transporters that are previously unknown to the research community. Future study would extend the scope to developing assays for more than 30 major CNS transporters, and scale up inhibitory profiling efforts for more than 1000 marketed drugs, with aims to explain causes of certain CNS side effects, to reveal potential new therapeutic indications of existing drugs, and to discover potential therapeutic benefits of inhibiting certain key CNS transporters in treating various CNS diseases.
Public Health Relevance: Success of this project would benefit public health enormously through helping inform and mitigate drugs'potential side effects in the CNS, and by helping develop pharmaceuticals to treat various serious CNS disorders, such as Parkinson's disease, Alzheimer's disease, epilepsy etc.. Specifically, the proposed studies will be invaluable for evaluating off-target effects of both CNS and peripherally acting drugs on critical CNS transporters of physiological and/or pharmacological significance, which could potentially lead to discovering new therapeutic indications for marketed CNS drugs, and identifying/validating novel molecular targets for therapeutic intervention.
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