Investigation of Great Plains ethnobotanicals for novel kappa opioid receptor ligands
Chad E. Groer, Robert Gallagher, Barbara N. Timmermann, and Thomas E. Prisinzano Department of Medicinal Chemistry, University of Kansas, Lawrence, KS
Modulation of kappa opioid receptors (KOR) may provide therapeutic benefit for those suffering from depression, anxiety, or drug dependence. Development of KOR ligands as therapeutic agents however, has been hindered by unfavorable side effects, such as dysphoria, hallucinations, and sedation. The discovery of the natural product salvinorin A has suggested that unique structural scaffolds found in nature can activate KORs with divergent downstream signaling, which may be a means to promote the beneficial effects of KOR ligands, while reducing unwanted side-effects. Toward the long-term goal of developing such a KOR ligand, the central hypothesis of this study is that an activity-based, ethnobotanical approach will identify structurally unique KOR ligands with potential as biological probes to better understand how ligand structure determines KOR function. Sixty-one plant species native to the United States Great Plains were chosen based on their use in traditional medicinal practices for conditions in which the kappa opioid system is known to play a role. Species were prioritized based on results from initial KOR agonist screening of crude extracts and subfractions. Two species show evidence of the presence of a KOR active component, including a significant increase in potency of the subfraction compared to the crude extract or a significant rightward shift of the dose-response curve with antagonist pretreatment. Additional subfractions and isolated compounds from these species are currently being prepared and tested for KOR activity. Structural identification will provide novel scaffolds to further investigate how ligand structure determines KOR function, with the long-term goal of developing KOR-directed therapies for depression and drug dependence.