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Front Pharmacol. 2018 Jun 21;9:632. doi: 10.3389/fphar.2018.00632. eCollection 2018.

Cannabigerol Action at Cannabinoid CB1 and CB2 Receptors and at CB1-CB2 Heteroreceptor Complexes.

Author information

1
Department of Biochemistry and Physiology, Faculty of Pharmacy, University of Barcelona, Barcelona, Spain.
2
Centro de Investigación Biomédica en Red, Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain.
3
Department of Medical Sciences, Institute of Pharmacology, University of Ferrara, Ferrara, Italy.
4
Molecular Neurobiology Laboratory, Department of Biochemistry and Molecular Biomedicine, University of Barcelona, Barcelona, Spain.
5
Department of R&D - Extraction, Phytoplant Research S.L., Córdoba, Spain.
6
Department of Analytical Chemistry, Phytoplant Research S.L., Córdoba, Spain.
7
Department of Breeding and Cultivation, Phytoplant Research S.L., Córdoba, Spain.

Abstract

Cannabigerol (CBG) is one of the major phytocannabinoids present in Cannabis sativa L. that is attracting pharmacological interest because it is non-psychotropic and is abundant in some industrial hemp varieties. The aim of this work was to investigate in parallel the binding properties of CBG to cannabinoid CB1 (CB1R) and CB2 (CB2R) receptors and the effects of the compound on agonist activation of those receptors and of CB1-CB2 heteroreceptor complexes. Using [3H]-CP-55940, CBG competed with low micromolar Ki values the binding to CB1R and CB2R. Homogeneous binding in living cells, which is only technically possible for the CB2R, provided a 152 nM Ki value. Also interesting, CBG competed the binding of [3H]-WIN-55,212-2 to CB2R but not to CB1R (Ki: 2.7 versus >30 μM). The phytocannabinoid modulated signaling mediated by receptors and receptor heteromers even at low concentrations of 0.1-1 μM. cAMP, pERK, β-arrestin recruitment and label-free assays in HEK-293T cells expressing the receptors and treated with endocannabinoids or selective agonists proved that CBG is a partial agonist of CB2R. The action on cells expressing heteromers was similar to that obtained in cells expressing the CB2R. The effect of CBG on CB1R was measurable but the underlying molecular mechanisms remain uncertain. The results indicate that CBG is indeed effective as regulator of endocannabinoid signaling.

KEYWORDS:

G-protein-coupled receptor; TR-FRET; cannabigerol; cannabinoid receptor; partial agonist; phytocannabinoid

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