Novel approaches and current challenges with targeting the endocannabinoid system.
Novel approaches and current challenges with targeting the endocannabinoid system.
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DOI：
10.1080/17460441.2020.1752178
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发表时间：
2020-08
影响因子：
6.3
通讯作者：
Jagerovic N
中科院分区：
文献类型：
--
作者：
Morales P;Jagerovic N
内源性大麻素系统的病理生理学相关性已被广泛证明在包括癌症、神经疾病和代谢问题在内的各种疾病中。因此，靶向受体和参与该系统的内源性机制可以提供成功的治疗结果。针对典型的大麻素受体CB1和CB2的配体以及内源性大麻素酶的抑制剂已经在不同的疾病模型中进行了深入的研究。事实上，大麻二酚或Δ9-四氢大麻酚等植物大麻素目前在市场上用于治疗因多发性硬化症痉挛或儿童癫痫发作等引起的神经病理性疼痛。大麻素的药理学挑战来自其药代动力学、非靶点效应和精神活性效应。在此背景下，目前的综述概述了在该领域出现的新的分子方法，讨论了它们的临床潜力。即使正构体CB1和CB2配体在大麻素临床研究中处于领先地位，新出现的策略，如变构或偏向调节这些受体，以及受控的靶外效应，可能会增加大麻素的治疗潜力。
The pathophysiological relevance of the endocannabinoid system has been widely demonstrated in a variety of diseases including cancer, neurological disorders and metabolic issues. Therefore, targeting the receptors and the endogenous machinery involved in this system can provide a successful therapeutic outcome. Ligands targeting the canonical cannabinoid receptors, CB1 and CB2, along with inhibitors of the endocannabinoid enzymes have been thoroughly studied in diverse disease models. In fact, phytocannabinoids such as cannabidiol or Δ9-tetrahydrocannabinol are currently on the market for the management of neuropathic pain due to spasticity in multiple sclerosis, or seizures in children epilepsy amongst others. Challenges in the pharmacology of cannabinoids arise from its pharmacokinetics, off-target effects and psychoactive effects. In this context, the current review outlines the novel molecular approaches emerging in the field discussing their clinical potential. Even if orthosteric CB1 and CB2 ligands are on the forefront in cannabinoid clinical research, emerging strategies such as allosteric or biased modulation of these receptors along with controlled off-targets effects may increase the therapeutic potential of cannabinoids.
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