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

Rosati, Ornelio; Messina, Federica; Pelosi, Azzurra; Curini, Massimo; Petrucci, Vanessa; Gertsch, Jürg; Chicca, Andrea (2014). One-pot heterogeneous synthesis of Δ(3)-tetrahydrocannabinol analogues and xanthenes showing differential binding to CB(1) and CB(2) receptors. European journal of medicinal chemistry, 85, pp. 77-86. Elsevier Masson SAS 10.1016/j.ejmech.2014.07.062

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Biochemistry and Molecular Medicine

UniBE Contributor:

Petrucci, Vanessa; Gertsch, Jürg and Chicca, Andrea

Subjects:

500 Science > 570 Life sciences; biology
600 Technology > 610 Medicine & health

ISSN:

0223-5234

Publisher:

Elsevier Masson SAS

Language:

English

Submitter:

Barbara Järmann-Bangerter

Date Deposited:

02 Apr 2015 08:29

Last Modified:

02 Sep 2015 10:20

Publisher DOI:

10.1016/j.ejmech.2014.07.062

PubMed ID:

25072877

Uncontrolled Keywords:

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

BORIS DOI:

10.7892/boris.66266

URI:

https://boris.unibe.ch/id/eprint/66266

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