Uncarialins J-M from Uncaria rhynchophylla and Their Anti-depression Mechanism in Unpredictable Chronic Mild Stress-Induced Mice via Activating 5-HT_(1A) Receptor

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 ag-onistic effects towards 5-HT_(1A) receptor,and their EC_(50) values were 7.86,732,2.24,1.18,1.52,and 3.75μmol/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-HT_(1A) signaling pathway.Molecular docking and site-directed amino acid mutation verified that amino acid residues Aspll6 and Asn386 were the binding sites of hirsuteine(7)with 5-HT_(1A) receptor.In addition,pre-treatment of mice with WAY 100635 also blocked the anti-depression effect of hirsuteine(7),which further demonstrated that 5-HT_(1A) 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.

Discovery of New Iridoids as Farnesoid X Receptor Agonists from Morinda officinalis: Agonistic Potentials and Molecular Stimulation

The investigation of Morinda officinalis led to the isolation of twelve compounds(1-12),including three new iridoid glycosides morindallns A-C(1-3)and nine known compounds(4-12).Their structural identifications were conducted using HRMS,1D and 2D NMR,and electronic circular dichroism(ECD)spectra as well as quantum chemical computations.Compound 6 displayed the most significantly agonistic activity against farnesoid X receptor(FXR)with an EC_(50) value of 7.18 μM,and its agonistic effect was verified through the investigation of FXR downstream target genes including small heterodimer partner 1(SHP1),bile salt export pump(BSEP),and organic solute transporter subunit alpha and beta(OSTα and OSTβ).The potential interaction of compound 6 with FXR was analyzed by molecular docking and molecular dynamics stimulation,revealing that amino acid residues Leu287;Thr288,and Ser332 played a crucial role in the activation of compound 6 towards FXR.These findings suggested that compound 6 could be regarded as a potential candidate for the development of FXR agonists.