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Cannabidiol skews biased agonism at cannabinoid CB1 and CB2 receptors with smaller effect in CB1-CB2 heteroreceptor complexes.
Biochem Pharmacol 2018; 157:148-158BP

Abstract

Currently, biased agonism is at the center stage of drug development approaches. We analyzed effects of a battery of cannabinoids plus/minus cannabidiol (CBD) in four functional parameters (cAMP levels, phosphorylation of extracellular signal-regulated kinases (ERK1/2), β-arrestin recruitment and label-free/DMR) in HEK-293T cells expressing cannabinoid receptors, CB1 or CB2, or CB1-CB2 heteroreceptor complexes. In all cases two natural agonists plus two selective synthetic agonists were used. Furthermore, the effect of cannabidiol, at a dose (100 nM) that does not allow significant binding to the orthosteric center of either receptor, was measured. From the huge amount of generated data, we would like to highlight that the two psychotropic molecules (Δ9-tetrahydrocannabinol/THC and CP-55940) showed similar bias in CB1R and that the bias of THC was particularly relevant toward MAPK pathway. Furthermore, THC did not activate the Gi protein coupled to CB2R. Interestingly, the biased agonism was reduced when assays were performed in cells expressing the two receptors, thus suggesting that the heteromer allows less functional selectivity. In terms of cannabidiol action, the phytocannabinoid altered the functional responses, likely by allosteric means, and modified potency, agonist IC50/EC50 values and biased agonism in qualitative and/or quantitative different ways depending on the agonist. The effect of cannabidiol on anandamide actions on both cannabinoid receptors was particularly noteworthy as was significantly different from that of other compounds. Results are a compendium of data on biased agonism on cannabinoid receptors in the absence and presence of cannabidiol. In addition, for the first time, GPCR biased agonism is characterized in an heteromeric context.

Authors+Show Affiliations

Molecular Neurobiology Laboratory, Department of Biochemistry and Physiology, Universitat de Barcelona, Barcelona, Spain; Centro de Investigación en Red, Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain.Centro de Investigación en Red, Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain; Molecular Neurobiology Laboratory, Department of Biochemistry and Molecular Biomedicine, Universitat de Barcelona, Barcelona, Spain.Centro de Investigación en Red, Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain; Molecular Neurobiology Laboratory, Department of Biochemistry and Molecular Biomedicine, Universitat de Barcelona, Barcelona, Spain.Phytoplant Research S.L., Córdoba, Spain.Instituto de Química Médica, Consejo Superior de Investigaciones Científicas, Madrid, Spain.Phytoplant Research S.L., Córdoba, Spain.Phytoplant Research S.L., Córdoba, Spain.Molecular Neurobiology Laboratory, Department of Biochemistry and Molecular Biomedicine, Universitat de Barcelona, Barcelona, Spain.Molecular Neurobiology Laboratory, Department of Biochemistry and Molecular Biomedicine, Universitat de Barcelona, Barcelona, Spain.Instituto de Química Médica, Consejo Superior de Investigaciones Científicas, Madrid, Spain.Phytoplant Research S.L., Córdoba, Spain. Electronic address: x.nadal@phytoplant.es.Centro de Investigación en Red, Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain; Molecular Neurobiology Laboratory, Department of Biochemistry and Molecular Biomedicine, Universitat de Barcelona, Barcelona, Spain. Electronic address: rfranco@ub.edu.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

30194918

Citation

Navarro, Gemma, et al. "Cannabidiol Skews Biased Agonism at Cannabinoid CB1 and CB2 Receptors With Smaller Effect in CB1-CB2 Heteroreceptor Complexes." Biochemical Pharmacology, vol. 157, 2018, pp. 148-158.
Navarro G, Reyes-Resina I, Rivas-Santisteban R, et al. Cannabidiol skews biased agonism at cannabinoid CB1 and CB2 receptors with smaller effect in CB1-CB2 heteroreceptor complexes. Biochem Pharmacol. 2018;157:148-158.
Navarro, G., Reyes-Resina, I., Rivas-Santisteban, R., Sánchez de Medina, V., Morales, P., Casano, S., ... Franco, R. (2018). Cannabidiol skews biased agonism at cannabinoid CB1 and CB2 receptors with smaller effect in CB1-CB2 heteroreceptor complexes. Biochemical Pharmacology, 157, pp. 148-158. doi:10.1016/j.bcp.2018.08.046.
Navarro G, et al. Cannabidiol Skews Biased Agonism at Cannabinoid CB1 and CB2 Receptors With Smaller Effect in CB1-CB2 Heteroreceptor Complexes. Biochem Pharmacol. 2018;157:148-158. PubMed PMID: 30194918.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Cannabidiol skews biased agonism at cannabinoid CB1 and CB2 receptors with smaller effect in CB1-CB2 heteroreceptor complexes. AU - Navarro,Gemma, AU - Reyes-Resina,Irene, AU - Rivas-Santisteban,Rafael, AU - Sánchez de Medina,Verónica, AU - Morales,Paula, AU - Casano,Salvatore, AU - Ferreiro-Vera,Carlos, AU - Lillo,Alejandro, AU - Aguinaga,David, AU - Jagerovic,Nadine, AU - Nadal,Xavier, AU - Franco,Rafael, Y1 - 2018/09/06/ PY - 2018/05/31/received PY - 2018/08/31/accepted PY - 2018/9/9/pubmed PY - 2018/9/9/medline PY - 2018/9/9/entrez KW - BRET KW - CNS KW - Drug discovery KW - Endocannabinoids KW - G-protein-coupled receptor KW - Phytocannabinoids SP - 148 EP - 158 JF - Biochemical pharmacology JO - Biochem. Pharmacol. VL - 157 N2 - Currently, biased agonism is at the center stage of drug development approaches. We analyzed effects of a battery of cannabinoids plus/minus cannabidiol (CBD) in four functional parameters (cAMP levels, phosphorylation of extracellular signal-regulated kinases (ERK1/2), β-arrestin recruitment and label-free/DMR) in HEK-293T cells expressing cannabinoid receptors, CB1 or CB2, or CB1-CB2 heteroreceptor complexes. In all cases two natural agonists plus two selective synthetic agonists were used. Furthermore, the effect of cannabidiol, at a dose (100 nM) that does not allow significant binding to the orthosteric center of either receptor, was measured. From the huge amount of generated data, we would like to highlight that the two psychotropic molecules (Δ9-tetrahydrocannabinol/THC and CP-55940) showed similar bias in CB1R and that the bias of THC was particularly relevant toward MAPK pathway. Furthermore, THC did not activate the Gi protein coupled to CB2R. Interestingly, the biased agonism was reduced when assays were performed in cells expressing the two receptors, thus suggesting that the heteromer allows less functional selectivity. In terms of cannabidiol action, the phytocannabinoid altered the functional responses, likely by allosteric means, and modified potency, agonist IC50/EC50 values and biased agonism in qualitative and/or quantitative different ways depending on the agonist. The effect of cannabidiol on anandamide actions on both cannabinoid receptors was particularly noteworthy as was significantly different from that of other compounds. Results are a compendium of data on biased agonism on cannabinoid receptors in the absence and presence of cannabidiol. In addition, for the first time, GPCR biased agonism is characterized in an heteromeric context. SN - 1873-2968 UR - https://www.unboundmedicine.com/medline/citation/30194918/Cannabidiol_skews_biased_agonism_at_cannabinoid_CB1_and_CB2_receptors_with_smaller_effect_in_CB1_CB2_heteroreceptor_complexes_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0006-2952(18)30382-4 DB - PRIME DP - Unbound Medicine ER -