Design, syntheses, structure–activity relationships and docking studies of coumarin derivatives as novel selective ligands for the CB2 receptor

• Pharmacophore-leading coumarin derivatives were designed and synthesized.
• Compounds show high bioactivities and selectivities for the CB2 receptor over CB1.
• Some compounds display higher bioactivities than leads.
• The functionality of a ligand is controlled by the substituent on the nucleus.
• Docking studies were performed to simulate the receptor-ligand interactions.

The CB2 receptor has been considered as an inspiring drug target for the treatment of pain and immune-related diseases. In the current manuscript, a novel series of coumarin derivatives is reported to be designed and synthesized by combining the structural features of some known ligands for the cannabinoid receptors based on the CoMFA model of the lead compounds. The compounds were evaluated to be highly selective ligands for the CB2 receptor over the CB1 receptor by calcium mobilization assays. Furthermore, SAR results indicate that the functionality of a ligand is controlled by the substituent on the nucleus. Therefore, molecular docking simulations were performed to calculate the receptor-ligand interactions of our synthesized compounds binding to the CB2 receptor. The understanding of the binding modes could be advantageous for further development of selective ligands for the CB2 receptor.

Guided by a CoMFA model of lead compounds, coumarin derivatives were designed and synthesized with high CB2 receptor bioactivities and selectivities. Docking simulations were performed to calculate the receptor-ligand interactions.Figure optionsDownload as PowerPoint slide