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 Ki 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 Ki 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.