Uncarialins J-M from Uncaria rhynchophylla and Their Anti-depression Mechanism in Unpredictable Chronic Mild Stress-Induced Mice via Activating 5-HT1A Receptor

摘要

Main observation and conclusion Uncaria rhynchophylla has been widely used to treat central nervous system diseases for a long history.After investigation of U.rhynchophylla,eleven monoterpene indole alkaloids,including four new compounds uncarialins J-M (1-4) and seven known ana-logues (5-11),were isolated and identified.Their structural characterization was conducted using HRESIMS,1D and 2D NMR,elec-tronic circular dichroism (ECD) spectra,and quantum chemical computations.Compounds 1,2,7,and 9-11 displayed significant ag-onistic effects towards 5-HT1A receptor,and their EC50 values were 7.86,7.32,2.24,1.18,1.52,and 3.75 μmol/L,respectively.Fur-thermore,in vivo experimental results fully revealed that hirsuteine (7) displayed a significant antidepression effect in unpredictable chronic mild stress (UCMS)-induced depression mice mainly via regulating 5-HT1A signaling pathway.Molecular docking and site-directed amino acid mutation verified that amino acid residues Asp116 and Asn386 were the binding sites of hirsuteine (7) with 5-HT1A receptor.In addition,pre-treatment of mice with WAY 100635 also blocked the anti-depression effect of hirsuteine (7),which further demonstrated that 5-HT1A receptor was a potential target of hirsuteine (7) to effectively treat depression.These findings indi-cated the therapeutic material basis of U.rhynchophylla and the anti-depression underlying mechanism of hirsuteine (7),and further provided the useful guidance for the development of hirsuteine (7) as a potential antidepressant candidate.