One-pot heterogeneous synthesis of Δ3-tetrahydrocannabinol analogues and xanthenes showing differential binding to CB1 and CB2 receptors

D9-tetrahydrocannabinol (D9-THC) is the major psychoactive cannabinoid in hemp (Cannabis sativa L.) and responsible for many of the pharmacological effects mediated via cannabinoid receptors. Despite being the major cannabinoid scaffold in nature, D9-THC double bond isomers remain poorly studied. The chemical scaffold of tetrahydrocannabinol can be assembled from the condensation of distinctly substituted phenols and monoterpenes. Here we explored a microwave-assisted one pot heterogeneous synthesis of D3-THC from orcinol (1a) and pulegone (2). Four D3-THC analogues and corresponding D4atetrahydroxanthenes (D4a-THXs) were synthesized regioselectively and showed differential binding affinities for CB1 and CB2 cannabinoid receptors. Here we report for the first time the CB1 receptor binding of D3-THC, revealing a more potent receptor binding affinity for the (S)-() isomer (hCB1 Ki ¼ 5 nM) compared to the (R)-(þ) isomer (hCB1 Ki ¼ 29 nM). Like D9-THC, also D3-THC analogues are partial agonists at CB receptors as indicated by [35S]GTPgS binding assays. Interestingly, the THC structural isomers D4a-THXs showed selective binding and partial agonism at CB2 receptors, revealing a simple non-natural natural product-derived scaffold for novel CB2 ligands.