Synthesis and biological evaluation of paeoveitol D derivatives as new melatonin receptor agonists with antidepressant activities

• Published in: MedChemComm 2022-10, Vol.13 (1), p.1212-1224
• Main Authors: Li, Tian-Ze, Hu, Jing, Sun, Jin-Jin, Huang, Xiao-Yan, Geng, Chang-An, Liu, Shu-Bai, Zhang, Xue-Mei, Chen, Ji-Jun
• Format: Article
• Language: English
• Subjects: Antidepressants; Benzofuran; Biocompatibility; Chemistry; Dopamine; In vivo methods and tests; Pharmacokinetics; Receptors; Serotonin; Toxicity
• ISSN: 2632-8682; 2040-2503; 2632-8682; 2040-2511
• DOI: 10.1039/d2md00156j

Our previous study demonstrated that paeoveitol D, a benzofuran compound isolated from Paeonia veitchii , displayed activity on MT 1 and MT 2 receptors with agonistic ratios of 57.5% and 51.6% at a concentration of 1 mM. To explore the structure-activity relationships, 34 paeoveitol D derivatives were synthesized and evaluated for their MT 1 and MT 2 agonistic activities using the Fluo-8 calcium assay. Among them, 16 and 18 derivatives increased agonistic activities on the MT 1 and MT 2 receptors, respectively. Compound 18 indicated EC 50 values of 21.0 and 298.9 μM on MT 1 and MT 2 receptors in agonistic dose response curves with Tango assays and shortened immobility time in the forced swim test. The preliminary mechanism-of-action investigation manifested that the antidepressant activity of compound 18 may be mediated by promoting serotonin (5-HT) and dopamine (DA) levels in the mice brain. Compound 18 also showed favorable pharmacokinetic profiles and low toxicity in vivo . These results suggest that compound 18 could be a potential antidepressant agent. Paeoveitol D derivatives were synthesized as potent MT 1 and MT 2 receptors agonists with in vivo antidepressant activity.