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

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.