Cannabidiol at Nanomolar Concentrations Negatively Affects Signaling through the Adenosine A_2A Receptor

Cannabidiol (CBD) is a phytocannabinoid with potential as a therapy for a variety of diseases. CBD may act via cannabinoid receptors but also via other G-protein-coupled receptors (GPCRs), including the adenosine A(2A) receptor. Homogenous binding and signaling assays in Chinese hamster ovary (CHO) cells expressing the human version of the A(2A) receptor were performed to address the effect of CBD on receptor functionality. CBD was not able to compete for the binding of a SCH 442416 derivative labeled with a red emitting fluorescent probe that is a selective antagonist that binds to the orthosteric site of the receptor. However, CBD reduced the effect of the selective A(2A) receptor agonist, CGS 21680, on G(s)-coupling and on the activation of the mitogen activated kinase signaling pathway. It is suggested that CBD is a negative allosteric modulator of the A(2A )receptor.