Cannabinoid Receptor Type II Ligands from Sandalwood Oil and Synthetic α-Santalol Derivatives

Bioassay-guided fractionation of the essential oil of Santalum album led to the identification of α-santalol (1) and β-santalol (2) as new chemotypes of cannabinoid receptor type II (CB₂) ligands with K_i values of 10.49 and 8.19 μM, respectively. Nine structurally new α-santalol derivatives (4a-4h and 5) were synthesized to identify more selective and potent CB₂ ligands. Compound 4e with a piperazine structural moiety demonstrated a K_i value of 0.99 μM against CB₂ receptor and did not show binding activity against cannabinoid receptor type I (CB₁) at 10 μM. Compounds 1, 2, and 4e increased intracellular calcium influx in SH-SY5Y human neuroblastoma cells that were attenuated by CB₂ antagonism or inverse agonism, supporting the results that these compounds are CB₂ agonists. Molecular docking showed that 1 and 4e had similar binding poses, exhibiting a unique interaction with Thr114 within the CB₂ receptor, and that the piperazine structural moiety is required for the binding affinity of 4e. A 200 ns molecular dynamics simulation of CB₂ complexed with 4e confirmed the stability of the complex. This structural insight lays a foundation to further design and synthesize more potent and selective α-santalol-based CB₂ ligands for drug discovery.