Cannabinoid receptor type II ligands from sandalwood oil and synthetic alpha-santalol derivatives

Authors: PAUDEL, PRADEEP - University Of Mississippi; PANDEY, PANKAJ - University Of Mississippi; PARIS, JASON - University Of Mississippi; ASHPOLE, NICOLE - University Of Mississippi; MAHDI, FAKHRI - University Of Mississippi; TIAN, JUN-MIAN - University Of Mississippi; LEE, JOSEPH - University Of Mississippi; Wang, Mei; XU, MIN - Kunming University Of Science And Technology; CHITTIBOYINA, AMAR - University Of Mississippi; KHAN, IKHLAS - University Of Mississippi; ROSS, SAMIR - University Of Mississippi; LI, XINGCONG - University Of Mississippi

Submitted to: Journal of Natural Products
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 6/7/2023
Publication Date: 4/14/2023
Citation: Paudel, P., Pandey, P., Paris, J.J., Ashpole, N.M., Mahdi, F., Tian, J., Lee, J., Wang, M., Xu, M., Chittiboyina, A.G., Khan, I.A., Ross, S.A., Li, X. 2023. Cannabinoid receptor type II ligands from sandalwood oil and synthetic alpha-santalol derivatives. Journal of Natural Products. https://doi.org/10.1021/acs.jnatprod.3c00282.
DOI: https://doi.org/10.1021/acs.jnatprod.3c00282

Interpretive Summary: The endocannabinoid system (ECS) is canonically comprised of cannabinoid receptor type I (CB1) and type II (CB2), endogenous ligands, and their degrading enzymes. Activation of CB1 receptors does not only influence cognitive processing and pain response, but also induce psychoactive effects, limiting the use of CB1 agonists in clinical practice. CB2 receptors are highly expressed in peripheral immune tissues and to a lesser extent in neurons and microglial cells. They act to modulate immune cell function throughout the body and have emerged as a potential therapeutic target for multiple diseases. Plant-derived essential oils (EOs) have long been used as traditional medicine and aromatherapy for the management of various ailments including neurological disorders. In the present investigation, screening a collection of more than 300 EOs led to the identification of sandalwood EO (Santalum album L.) as a CB2 hit due to its potent CB2 binding affinity. Bioassay-guided fractionation of sandalwood EO was conducted to characterize active CB2 ligands. In addition, synthesis of a-santalol derivatives for identification of more potent CB2 ligands was attempted. Identification of alpha- and beta-santalol as CB2 ligands has provided new evidence to explain the medicinal properties of sandalwood EO. Synthesis of alpha-santalol derivatives and computational modeling has generated structural insight into a potent CB2 ligand which can serve as a lead for future structural optimization to improve CB2 binding potency and druggable properties.

Technical Abstract: Bioassay-guided fractionation of the essential oil of Santalum album led to the identification of alpha-santalol (1) and beta-santalol (2) as a new chemotype of cannabinoid receptor type II (CB2) ligands with Ki values of 10.49 and 8.19 uM, respectively. Nine structurally novel alpha-santalol derivatives (4a-4h and 5) were synthesized to identify more potent CB2 ligands. Compound 4e with a piperazine structural moiety demonstrated a Ki value of 0.99 uM against CB2 receptor, and did not show binding activity against cannabinoid receptor type I (CB1) at 10 uM. Compounds 1, 2 and 4e increased intracellular calcium influx in SH-SY5Y human neuroblastoma cells that was attenuated by CB2 antagonism or inverse agonism, supporting the notion 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 the piperazine structural moiety is required for the potent 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 design and synthesize more potent, selective alpha-santalol-based CB2 ligands for drug discovery.