PROJECT SUMMARY Natural products are unique sources of new lead compounds for the understanding and ultimate treatment of neurological disease. This proposal focuses on the synthesis and biological characterization of promising new small molecules based on the privileged yohimbine alkaloid scaffold. While these complex natural product alkaloids have been academic targets for synthesis over multiple decades, there is still a surprising lack of efficient, <10 step routes to provide new analogs of these classes of compounds containing high degrees of stereochemical information. Consequently, this dearth has limited the exploration of many yohimbine classes in discovery-based screening of CNS targets and represents a major gap in the knowledge. This high risk, high reward project will support both target and focused library synthesis of new privileged molecules and initial screening/validation of CNS activity in collaboration with a GPCR expert. This proposal brings together the complementary natural products chemistry and neuropharmacological expertise of the Scheidt and McCorvy laboratories. The objectives will be to: (1) synthesize mitragynine to establish the shortest route yet to this compound, and (2) create new mitragynine and yohimbine-like compounds and explore their potential as agonists and/or antagonists in CNS biology. This project will yield novel chemical tools for the pharmacological manipulation of CNS receptors and may lead to new therapeutic strategies for pain management and neurological diseases.