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

• Published in: Chinese journal of chemistry Vol. 39; no. 5; pp. 1331 - 1343
• Main Authors: Yu, Zhen‐Long, Bai, Rong, Zhou, Jun‐Jun, Huang, Hui‐Lian, Zhao, Wen‐Yu, Huo, Xiao‐Kui, Yang, Ya‐Hui, Luan, Zhi‐Lin, Zhang, Bao‐Jing, Sun, Cheng‐Peng, Ma, Xiao‐Chi
• Format: Journal Article
• Language: English
• Published: Weinheim WILEY‐VCH Verlag GmbH & Co. KGaA 01.05.2021; Wiley; Wiley Subscription Services, Inc
• Subjects: 5‐HT1A receptor; Amino acids; Antidepressants; Binding sites; Central nervous system; Central nervous system diseases; Chemical compounds; Chemistry; Chemistry, Multidisciplinary; Circular dichroism; Depression; Dichroism; Hirsuteine; Indoles; Mental depression; Molecular docking; Monoterpene indole alkaloids; Mutation; NMR; Nuclear magnetic resonance; Physical Sciences; Quantum chemistry; Receptors; Science & Technology; Signal transduction; Site‐directed amino acid mutation; Structural analysis; Uncaria rhynchophylla; ANTIDEPRESSANT; DOWN-REGULATION; INCREASES; Depression; HT1A receptor; ISORHYNCHOPHYLLINE; MESSENGER-RNA; SEROTONIN 1A; Site‐ DISORDER; DOPAMINE; Hirsuteine; directed amino acid mutation; INDOLE ALKALOIDS; 5‐ EXPRESSION; Monoterpene indole alkaloids
• ISSN: 1001-604X; 1614-7065
• DOI: 10.1002/cjoc.202000652

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 μmol/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. The investigation of U. rhynchophylla led to the isolation of four new compounds uncarialins J—M (1—4) and seven known analogues (5—11). Compounds 1, 2, 7, and 9—11 displayed significant agonistic effects towards 5‐HT1A receptor with EC50 values of 1.18—7.86 μmol/L. Hirsuteine (7) displayed a significant antidepression effect in UCMS‐induced depression mice via regulating 5‐HT1A receptor interacted with Asp116 and Asn386.