Pharmacological data of cannabidiol- and cannabigerol-type phytocannabinoids acting on cannabinoid CB1, CB2 and CB1/CB2 heteromer receptors
Pharmacological data of cannabidiol- and cannabigerol-type phytocannabinoids acting on cannabinoid CB1, CB2 and CB1/CB2 heteromer receptors
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DOI：
10.1016/j.phrs.2020.104940
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发表时间：
2020-09-01
影响因子：
9.3
通讯作者：
Franco, Rafael
中科院分区：
文献类型：
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作者：
Navarro, Gemma;Varani, Katia;Franco, Rafael
背景：新近批准的有效成分为Delta(9)四氢大麻酚(Delta(9)-THC)和/或大麻二酚(CBD)的药物为大麻品种中也存在的其他植物大麻类化合物开辟了新的前景。此外，关于酸性和变种植物大麻素在各种疾病中的潜在益处的可靠数据已经存在。大麻素(CBG)、大麻二酚酸(CBDA)、大麻酸(CBGA)、大麻地黄素(CBDV)和大麻黄素(CBGV)的作用方式很少。假设/目的：大麻素CB1或CB2受体属于G蛋白偶联受体家族，是这些大麻素作用的重要介体。从大麻中提取的纯CBG、CBDA、CBGA、CBDV和CBGV对CB1或CB2受体有不同的作用。研究设计：测定植物大麻素对大麻素受体的亲和力，并对这些化合物与大麻素受体相互作用时的作用进行功能评估。用放射性配基测定与膜的结合，用均相时间分辨荧光共振能量转移(HTRF)法测定与活细胞的结合。四种不同的功能输出：cAMP水平和细胞外信号相关蛋白磷酸化的测定，无标记动态质量重分布(DMR)和β-芳香素募集。结果：大麻素的亲和力取决于参考配体，在膜和活细胞中可能不同。所有测试的植物大麻素都有类似激动剂的行为，但在选择性受体激动剂存在的情况下表现为反向激动剂。CBGV在许多功能输出中显示出增强的效力。然而，最有趣的结果是与差异亲和力相关的偏向信号，即总体结果表明，每个配体的结合模式导致了偏向信号输出背后的特定受体构象。结论：本文报道的结果和最近对CB1和CB2受体三维结构的阐明有助于理解可能具有保护作用的作用机制以及偏向信号背后的分子药物-受体相互作用。
Background: Recent approved medicines whose active principles are Delta(9) Tetrahidrocannabinol (Delta(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 beta-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.