内源性大麻素系统作为治疗靶点的利弊：30 年的经验教训。
Goods and Bads of the Endocannabinoid System as a Therapeutic Target: Lessons Learned after 30 Years.
机构信息
Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, Italy (M.M.); European Center for Brain Research, Santa Lucia Foundation, Rome, Italy (M.M.); Canada Excellence Research Chair on the Microbiome-Endocannabinoidome Axis in Metabolic Health, University of Laval, Quebec, Canada (V.D.); Institute of Biochemistry and Molecular Medicine, NCCR TransCure, University of Bern, Bern, Switzerland (J.G.); Roche Pharma Research & Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Basel, Switzerland (U.G.); Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Winston-Salem, North Carolina (A.C.H.); iHuman Institute, ShanghaiTech University, Shanghai, China (T.H.); Center for Drug Discovery and Department of Pharmaceutical Sciences, Northeastern University, Boston, Massachusetts (A.M.); Departments of Pharmaceutical Sciences and Biological Chemistry, University of California, Irvine, California (D.P.); Department of Biochemistry, Kagawa University School of Medicine, Miki, Kagawa, Japan (N.U.); Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University, Leiden, Netherlands (M.S.)
Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, Italy (M.M.); European Center for Brain Research, Santa Lucia Foundation, Rome, Italy (M.M.); Canada Excellence Research Chair on the Microbiome-Endocannabinoidome Axis in Metabolic Health, University of Laval, Quebec, Canada (V.D.); Institute of Biochemistry and Molecular Medicine, NCCR TransCure, University of Bern, Bern, Switzerland (J.G.); Roche Pharma Research & Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Basel, Switzerland (U.G.); Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Winston-Salem, North Carolina (A.C.H.); iHuman Institute, ShanghaiTech University, Shanghai, China (T.H.); Center for Drug Discovery and Department of Pharmaceutical Sciences, Northeastern University, Boston, Massachusetts (A.M.); Departments of Pharmaceutical Sciences and Biological Chemistry, University of California, Irvine, California (D.P.); Department of Biochemistry, Kagawa University School of Medicine, Miki, Kagawa, Japan (N.U.); Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University, Leiden, Netherlands (M.S.).
出版信息
Pharmacol Rev. 2023 Sep;75(5):885-958. doi: 10.1124/pharmrev.122.000600. Epub 2023 May 10.
The cannabis derivative marijuana is the most widely used recreational drug in the Western world and is consumed by an estimated 83 million individuals (∼3% of the world population). In recent years, there has been a marked transformation in society regarding the risk perception of cannabis, driven by its legalization and medical use in many states in the United States and worldwide. Compelling research evidence and the Food and Drug Administration cannabis-derived cannabidiol approval for severe childhood epilepsy have confirmed the large therapeutic potential of cannabidiol itself, Δ-tetrahydrocannabinol and other plant-derived cannabinoids (phytocannabinoids). Of note, our body has a complex endocannabinoid system (ECS)made of receptors, metabolic enzymes, and transportersthat is also regulated by phytocannabinoids. The first endocannabinoid to be discovered 30 years ago was anandamide (-arachidonoyl-ethanolamine); since then, distinct elements of the ECS have been the target of drug design programs aimed at curing (or at least slowing down) a number of human diseases, both in the central nervous system and at the periphery. Here a critical review of our knowledge of the goods and bads of the ECS as a therapeutic target is presented to define the benefits of ECS-active phytocannabinoids and ECS-oriented synthetic drugs for human health. SIGNIFICANCE STATEMENT: The endocannabinoid system plays important roles virtually everywhere in our body and is either involved in mediating key processes of central and peripheral diseases or represents a therapeutic target for treatment. Therefore, understanding the structure, function, and pharmacology of the components of this complex system, and in particular of key receptors (like cannabinoid receptors 1 and 2) and metabolic enzymes (like fatty acid amide hydrolase and monoacylglycerol lipase), will advance our understanding of endocannabinoid signaling and activity at molecular, cellular, and system levels, providing new opportunities to treat patients.
大麻衍生的大麻素是西方世界使用最广泛的消遣性药物，据估计有 8300 万人（约占世界人口的 3%）使用过。近年来，由于美国和全球许多州大麻合法化和医用，大麻的风险认知在社会上发生了显著转变。有说服力的研究证据和食品和药物管理局批准大麻衍生大麻二酚用于治疗严重儿童癫痫症，证实了大麻二酚本身、Δ-四氢大麻酚和其他植物衍生大麻素（植物大麻素）具有巨大的治疗潜力。值得注意的是，我们的身体有一个复杂的内源性大麻素系统（ECS），由受体、代谢酶和转运体组成，也受植物大麻素的调节。30 年前发现的第一种内源性大麻素是花生四烯酸乙醇胺；从那时起，ECS 的不同元素一直是药物设计项目的目标，旨在治疗（或至少减缓）许多人类疾病，包括中枢神经系统和外周疾病。在这里，我们对 ECS 作为治疗靶点的优缺点进行了批判性的回顾，以确定 ECS 活性植物大麻素和 ECS 定向合成药物对人类健康的益处。意义陈述：内源性大麻素系统在我们身体的几乎所有部位都发挥着重要作用，它要么参与调节中枢和外周疾病的关键过程，要么代表治疗的靶点。因此，了解这个复杂系统的组成部分的结构、功能和药理学，特别是关键受体（如大麻素受体 1 和 2）和代谢酶（如脂肪酸酰胺水解酶和单酰基甘油脂肪酶），将促进我们对内源性大麻素信号和活动的分子、细胞和系统水平的理解，为治疗患者提供新的机会。
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