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

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 analogues (5-11), were isolated and identified. Their structural characterization was conducted using HRESIMS, 1D and 2D NMR, electronic circular dichroism (ECD) spectra, and quantum chemical computations. Compounds 1, 2, 7, and 9-11 displayed significant agonistic effects towards 5-HT1A receptor, and their EC50 values were 7.86, 7.32, 2.24, 1.18, 1.52, and 3.75 mu mol/L, respectively. Furthermore, 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 indicated 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.