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

Bioassay-guided fractionation of the essential oil of Santalumalbum led to the identification of & alpha;-santalol (1) and & beta;-santalol (2) as new chemotypesof cannabinoid receptor type II (CB2) ligands with K (i) values of 10.49 and 8.19 & mu;M, respectively.Nine structurally new & alpha;-santalol derivatives (4a-4h and 5) were synthesized to identifymore selective and potent CB2 ligands. Compound 4e with a piperazine structural moiety demonstrated a K (i) value of 0.99 & mu;M against CB2 receptorand did not show binding activity against cannabinoid receptor typeI (CB1) at 10 & mu;M. Compounds 1, 2, and 4e increased intracellular calcium influxin SH-SY5Y human neuroblastoma cells that were attenuated by CB2 antagonism or inverse agonism, supporting the results thatthese compounds are CB2 agonists. Molecular docking showedthat 1 and 4e had similar binding poses,exhibiting a unique interaction with Thr114 within the CB2 receptor, and that the piperazine structural moiety is requiredfor the binding affinity of 4e. A 200 ns molecular dynamicssimulation of CB2 complexed with 4e confirmedthe stability of the complex. This structural insight lays a foundationto further design and synthesize more potent and selective & alpha;-santalol-basedCB(2) ligands for drug discovery.