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 (CB 2 ) 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 CB 2 ligands. Compound 4e with a piperazine structural moiety demonstrated a K i value of 0.99 μM against CB 2 receptor and did not show binding activity against cannabinoid receptor type I (CB 1 ) at 10 μM. Compounds 1 , 2 , and 4e increased intracellular calcium influx in SH-SY5Y human neuroblastoma cells that were attenuated by CB 2 antagonism or inverse agonism, supporting the results that these compounds are CB 2 agonists. Molecular docking showed that 1 and 4e had similar binding poses, exhibiting a unique interaction with Thr114 within the CB 2 receptor, and that the piperazine structural moiety is required for the binding affinity of 4e . A 200 ns molecular dynamics simulation of CB 2 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 CB 2 ligands for drug discovery.