Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts
Mol Pharmacol. 2021 Feb;99(2):125-132. doi: 10.1124/molpharm.120.000083. Epub 2020 Nov 25.
A first-in-class cannabinoid analog called lenabasum that is a CB2 agonist is being developed as an inflammation-resolving drug candidate. Thus far, specific therapeutic targets include scleroderma, cystic fibrosis, dermatomyositis, and lupus, all of which represent unmet medical needs. Two somewhat-independent molecular mechanisms for this type of action are here proposed. Both pathways initially involve the release of free arachidonic acid after activation of the CB2 receptor and phospholipase A2 by lenabasum. The pathways then diverge into a cyclooxygenase 2-mediated and a lipoxygenase-mediated route. The former leads to increased levels of the cyclopentenone prostaglandin 15-deoxy-Δ-prostaglandin-J that can activate the NLPR3 inflammasome, which in turn releases caspase-3, leading to apoptosis and the resolution of chronic inflammation. The lipoxygenase-mediated pathway stimulates the production of lipoxin A as well as other signaling molecules called specialized proresolving mediators. These also have inflammation-resolving actions. It is not well understood under which conditions each of these mechanisms operates and whether there is crosstalk between them. Thus, much remains to be learned about the mechanisms describing the actions of lenabasum. SIGNIFICANCE STATEMENT: The resolution of chronic inflammation is a major unmet medical need. The synthetic nonpsychoactive cannabinoid lenabasum could provide a safe and effective drug for this purpose. Two putative molecular mechanisms are suggested to better understand how lenabasum produces this action. In both, different metabolites of arachidonic acid act as mediators.
一种名为 lenabasum 的新型大麻素类似物，作为一种 CB2 激动剂，正在被开发为一种炎症缓解药物候选物。迄今为止，特定的治疗靶点包括硬皮病、囊性纤维化、皮肌炎和狼疮，所有这些都代表着未满足的医疗需求。这里提出了两种针对此类作用的相对独立的分子机制。这两种途径最初都涉及 lenabasum 激活 CB2 受体和磷脂酶 A2 后游离花生四烯酸的释放。然后，这些途径分为两条途径：一条是环氧合酶 2 介导的途径，另一条是脂氧合酶介导的途径。前者导致环戊烯酮前列腺素 15-去Δ-前列腺素-J 的水平增加，这种物质可以激活 NLPR3 炎性体，进而释放半胱天冬酶-3，导致细胞凋亡和慢性炎症的消退。脂氧合酶介导的途径刺激脂氧素 A 以及其他称为特异性促解决介质的信号分子的产生。这些也具有抗炎作用。目前尚不清楚每种机制在何种条件下起作用，以及它们之间是否存在串扰。因此，关于 lenabasum 作用机制的研究还有很多工作要做。意义陈述：慢性炎症的消退是一个主要的未满足的医疗需求。合成的非精神活性大麻素 lenabasum 可以为此提供一种安全有效的药物。提出了两种假设的分子机制，以更好地理解 lenabasum 如何产生这种作用。在这两种机制中，花生四烯酸的不同代谢物作为介质发挥作用。
