Cannabigerol Action at Cannabinoid CB and CB Receptors and at CB-CB Heteroreceptor Complexes.

Cannabigerol (CBG) is one of the major phytocannabinoids present in 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 CB (CBR) and CB (CBR) receptors and the effects of the compound on agonist activation of those receptors and of CB-CB heteroreceptor complexes. Using [H]-CP-55940, CBG competed with low micromolar values the binding to CBR and CBR. Homogeneous binding in living cells, which is only technically possible for the CBR, provided a 152 nM value. Also interesting, CBG competed the binding of [H]-WIN-55,212-2 to CBR but not to CBR (: 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 CBR. The action on cells expressing heteromers was similar to that obtained in cells expressing the CBR. The effect of CBG on CBR was measurable but the underlying molecular mechanisms remain uncertain. The results indicate that CBG is indeed effective as regulator of endocannabinoid signaling.