2014 Jul 19;85C:77-86. doi: 10.1016/j.ejmech.2014.07.062. [Epub ahead of print]
One-pot heterogeneous synthesis of Δ3-tetrahydrocannabinol analogues and xanthenes showing differential binding to CB1 and CB2 receptors.
Abstract
Δ9-tetrahydrocannabinol (Δ9-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, Δ9-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 Δ3-THC from orcinol (1a) and pulegone (2). Four Δ3-THC analogues and corresponding Δ4a-tetrahydroxanthenes (Δ4a-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 Δ3-THC, revealing a more potent receptor binding affinity for the (S)-(-) isomer (hCB1Ki = 5 nM) compared to the (R)-(+) isomer (hCB1Ki = 29 nM). Like Δ9-THC, also Δ3-THC analogues are partial agonists at CB receptors as indicated by [35S]GTPγS binding assays. Interestingly, the THC structural isomers Δ4a-THXs showed selective binding and partial agonism at CB2 receptors, revealing a simple non-natural natural product-derived scaffold for novel CB2 ligands.
Copyright © 2014 Elsevier Masson SAS. All rights reserved.
Copyright © 2014 Elsevier Masson SAS. All rights reserved.
KEYWORDS:
Cannabinoid receptor; Cannabis sativa; Heterogeneous assisted catalysis; Tetrahydroxanthene; Ytterbium triflate; Δ(3)-Tetrahydrocannabinol; Δ(9)-Tetrahydrocannabinol
- PMID:
- 25072877
- [PubMed – as supplied by publisher]
