Syntheses and evaluation of daphnetin derivatives as novel G protein-coupled receptor inhibitors and activators.

A series of daphnetin (7,8-dihydroxycoumarin) derivatives 1-22 were synthesized including sixteen new compounds (1-5, 7-14, 18, 21 and 22) and six known compounds (6, 15-17, 19 and 20). Their pharmacological activities on G protein-coupled receptors (GPCRs) were evaluated by double antibody sandwich ELISA (DAS-ELISA) in vitro. Daphnetin derivatives with various substitution patterns/groups were obtained from inhibitors to activators on GPCRs. Derivatives 2-5, 8, 15, 16 and 18-20 possessed moderate activation potency on GPCRs. Among them, derivatives 3-5, 16 and 19 presented significant activation potency on GPCRs with EC50 values in the range of 1.18-1.91 nM. Derivatives 6, 11, 14 and 18 showed significant inhibitory potency on GPCRs with IC50 values in the range of 1.26-1.38 nM. Moreover, the structure-activity relationships (SARs) of daphnetin derivatives were discussed in detail. The new daphnetic-based GPCRs activators and inhibitors have potentials as future drug candidates for the treatment of metabolic diseases.