title: One-pot heterogeneous synthesis of Δ(3)-tetrahydrocannabinol analogues and xanthenes showing differential binding to CB(1) and CB(2) receptors.
abstract: Δ(9)-tetrahydrocannabinol (Δ(9)-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, Δ(9)-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 Δ(3)-THC from orcinol (1a) and pulegone (2). Four Δ(3)-THC analogues and corresponding Δ(4a)-tetrahydroxanthenes (Δ(4a)-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 Δ(3)-THC, revealing a more potent receptor binding affinity for the (S)-(-) isomer (hCB1Ki = 5 nM) compared to the (R)-(+) isomer (hCB1Ki = 29 nM). Like Δ(9)-THC, also Δ(3)-THC analogues are partial agonists at CB receptors as indicated by [(35)S]GTPγS binding assays. Interestingly, the THC structural isomers Δ(4a)-THXs showed selective binding and partial agonism at CB2 receptors, revealing a simple non-natural natural product-derived scaffold for novel CB2 ligands.
authors: Department of Pharmaceutical Sciences, University of Perugia, Via del Liceo, 1, 06128 Perugia, Italy. Electronic address: ornelio.rosati@unipg.it.
authors: Ornelio
authors: O
authors: Rosati
authors: Department of Pharmaceutical Sciences, University of Perugia, Via del Liceo, 1, 06128 Perugia, Italy.
authors: Federica
authors: F
authors: Messina
authors: Department of Pharmaceutical Sciences, University of Perugia, Via del Liceo, 1, 06128 Perugia, Italy.
authors: Azzurra
authors: A
authors: Pelosi
authors: Department of Pharmaceutical Sciences, University of Perugia, Via del Liceo, 1, 06128 Perugia, Italy.
authors: Massimo
authors: M
authors: Curini
authors: Institute of Biochemistry and Molecular Medicine, University of Bern, Bühlstrasse, 28, CH-3012 Bern, Switzerland.
authors: Vanessa
authors: V
authors: Petrucci
authors: Institute of Biochemistry and Molecular Medicine, University of Bern, Bühlstrasse, 28, CH-3012 Bern, Switzerland.
authors: Jürg
authors: J
authors: Gertsch
authors: Institute of Biochemistry and Molecular Medicine, University of Bern, Bühlstrasse, 28, CH-3012 Bern, Switzerland. Electronic address: andrea.chicca@ibmm.unibe.ch.
authors: Andrea
authors: A
authors: Chicca
mesh_terms: D060326:Chemistry Techniques, Synthetic; D013759:Dronabinol / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000378:metabolism*; D006801:Humans; D008872:Microwaves; D011485:Protein Binding; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism*; D043885:Receptor, Cannabinoid, CB2 / Q000378:metabolism*; D013379:Substrate Specificity; D014966:Xanthenes / Q000138:chemical synthesis* / Q000378:metabolism*
chemical_list: D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D014966:Xanthenes; D013759:Dronabinol
keywords: Cannabinoid receptor; Cannabis sativa; Heterogeneous assisted catalysis; Tetrahydroxanthene; Ytterbium triflate; Δ(3)-Tetrahydrocannabinol; Δ(9)-Tetrahydrocannabinol