Synthesis and SAR evaluation of coumarin derivatives as potent cannabinoid receptor agonists

We report the development and extensive structure-activity relationship evaluation of a series of modified coumarins as cannabinoid receptor ligands. In radioligand, and [³⁵S]GTPγS binding assays the CB receptor binding affinities and efficacies of the new ligands were determined. Furthermore, we used a ligand-based docking approach to validate the empirical observed results. In conclusion, several crucial structural requirements were identified. The most potent coumarins like 3-butyl-7-(1-butylcyclopentyl)-5-hydroxy-2H-chromen-2-one (36b, K_i CB₂ 13.7 nM, EC₅₀ 18 nM), 7-(1-butylcyclohexyl)-5-hydroxy-3-propyl-2H-chromen-2-one (39b, K_i CB₂ 6.5 nM, EC₅₀ 4.51 nM) showed a CB₂ selective agonistic profile with low nanomolar affinities.