Pharmacological data of cannabidiol- and cannabigerol-type phytocannabinoids acting on cannabinoid CB1, CB2 and CB1/CB2 heteromer receptors. (September 2020)

• Record Type: Journal Article
• Authors: Navarro, Gemma; Varani, Katia; Lillo, Alejandro; Vincenzi, Fabrizio; Rivas-Santisteban, Rafael; Raïch, Iu; Reyes-Resina, Irene; Ferreiro-Vera, Carlos; Borea, Pier Andrea; Sánchez de Medina, Verónica; Nadal, Xavier; Franco, Rafael
• Is Part Of: Pharmacological research. Volume 159(2020)
• Publication Date: 2020-09
• Subjects: Δ9-THC Δ9Tetrahidrocannabinol -- 5-HT2Areceptor serotonin2A receptor -- BRET Bioluminescence Resonance Energy Transfer -- cAMP cyclic adenosine monophosphate -- CB1R cannabinoid receptor 1 -- CB2R cannabinoid receptor 2 -- CB1/2RHets CB1R- CB2R heteroreceptor complexes -- CBD cannabidiol -- CBDA cannabidiolic acid -- CBDV cannabidivarin -- CBG cannabigerol -- CBGA cannabigerolic acid -- CBGV cannabigerivarin -- CHO Chinese Hamster Ovary -- D1R dopamine receptor 1 -- DMEM Dulbecco's Modified Eagle Medium -- DMR dynamic mass redistribution -- ERK extracellular signal-regulated kinases -- GFP2 green fluorescent protein 2 -- GPCRs G-protein-coupled receptors -- GTP guanosine 5 triphosphate -- HEK Human Embryonic Kidney -- HTRF Homogeneous time-resolved fluorescence resonance energy transfer -- IC50 half maximal inhibitory concentration -- KD dissociation constant -- Ki inhibition constant -- MAPK mitogen-activated protein kinase -- PBS phosphate-buffered saline -- PKA protein kinase A -- RLuc Renilla luciferase -- TLB Tag-lite buffer -- YFP yellow fluorescent protein; Cytocrin -- Phytocannabinoids -- Biased signaling -- Homogeneous binding -- Radioligand binding -- GPCR structure; Pharmacology -- Periodicals; Pharmacology -- Periodicals; Research -- Periodicals; Médicaments -- Recherche -- Périodiques; Pharmacologie -- Périodiques; 615.105
• DOI: 10.1016/j.phrs.2020.104940
• Languages: English
• ISSNs: 1043-6618

Abstract

Graphical abstract: Abstract: Background: Recent approved medicines whose active principles are Δ 9 Tetrahidrocannabinol (Δ 9 -THC) and/or cannabidiol (CBD) open novel perspectives for other phytocannabinoids also present in Cannabis sativa L. varieties. Furthermore, solid data on the potential benefits of acidic and varinic phytocannabinoids in a variety of diseases are already available. Mode of action of cannabigerol (CBG), cannabidiolic acid (CBDA), cannabigerolic acid (CBGA), cannabidivarin (CBDV) and cannabigerivarin (CBGV) is, to the very least, partial. Hypothesis/Purpose: Cannabinoid CB1 or CB2 receptors, which belong to the G-protein-coupled receptor (GPCR) family, are important mediators of the action of those cannabinoids. Pure CBG, CBDA, CBGA, CBDV and CBGV from Cannabis sativa L. are differentially acting on CB1 or CB2 cannabinoid receptors. Study Design: Determination of the affinity of phytocannabinoids for cannabinoid receptors and functional assessment of effects promoted by these compounds when interacting with cannabinoid receptors. Methods: A heterologous system expressing the human versions of CB1 and/or CB2 receptors was used. Binding to membranes was measured using radioligands and binding to living cells using a homogenous time resolved fluorescence resonance energy transfer (HTRF) assay. Four different functional outputs were assayed: determination of cAMP levels and of extracellular-signal-related-kinase phosphorylation, label-free dynamic mass redistribution (DMR) and ß-arrestin recruitment. Results: Affinity of cannabinoids depend on the ligand of reference and may be different in membranes and in living cells. All tested phytocannabinoids have agonist-like behavior but behaved as inverse-agonists in the presence of selective receptor agonists. CBGV displayed enhanced potency in many of the functional outputs. However, the most interesting result was a biased signaling that correlated with differential affinity, i.e. the overall results suggest that the binding mode of each ligand leads to specific receptor conformations underlying biased signaling outputs. Conclusion: Results here reported and the recent elucidation of the three-dimensional structure of CB1 and CB2 receptors help understanding the mechanism of action that might be protective and the molecular drug-receptor interactions underlying biased signaling.