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

Automated summary

Bioassay-guided fractionation of Santalum album essential oil led to the identification of α-santalol (1) and β-santalol (2) as new chemotypes of CB2 ligands. Nine structurally new derivatives were synthesized to find more selective and potent CB2 ligands. Compound 4e showed high affinity for CB2 receptor and no binding activity for CB1 receptor. Molecular docking and dynamics simulation confirmed the stability of the complex and provided insights for designing more potent and selective α-santalol-based CB2 ligands.