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Eur J Med Chem. 2014 Oct 6;85:77-86. doi: 10.1016/j.ejmech.2014.07.062. Epub 2014 Jul 19.

One-pot heterogeneous synthesis of Δ(3)-tetrahydrocannabinol analogues and xanthenes showing differential binding to CB(1) and CB(2) receptors.

Author information

1
Department of Pharmaceutical Sciences, University of Perugia, Via del Liceo, 1, 06128 Perugia, Italy. Electronic address: ornelio.rosati@unipg.it.
2
Department of Pharmaceutical Sciences, University of Perugia, Via del Liceo, 1, 06128 Perugia, Italy.
3
Institute of Biochemistry and Molecular Medicine, University of Bern, Bühlstrasse, 28, CH-3012 Bern, Switzerland.
4
Institute of Biochemistry and Molecular Medicine, University of Bern, Bühlstrasse, 28, CH-3012 Bern, Switzerland. Electronic address: andrea.chicca@ibmm.unibe.ch.

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.

KEYWORDS:

Cannabinoid receptor; Cannabis sativa; Heterogeneous assisted catalysis; Tetrahydroxanthene; Ytterbium triflate; Δ(3)-Tetrahydrocannabinol; Δ(9)-Tetrahydrocannabinol

PMID:
25072877
DOI:
10.1016/j.ejmech.2014.07.062
[Indexed for MEDLINE]

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