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 , displayed activity on MT and MT 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 and MT agonistic activities using the Fluo-8 calcium assay. Among them, 16 and 18 derivatives increased agonistic activities on the MT and MT receptors, respectively. Compound 18 indicated EC values of 21.0 and 298.9 μM on MT and MT 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 . These results suggest that compound 18 could be a potential antidepressant agent.