Obesity and Metabolism Laboratory, The Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 9112001, Israel.
Int J Mol Sci. 2022 May 17;23(10):5610. doi: 10.3390/ijms23105610.
Obesity is a global medical problem; its common form is known as diet-induced obesity (DIO); however, there are several rare genetic disorders, such as Prader-Willi syndrome (PWS), that are also associated with obesity (genetic-induced obesity, GIO). The currently available therapeutics for treating DIO and GIO are very limited, and they result in only a partial improvement. Cannabidiolic acid (CBDA), a constituent of Cannabis sativa, gradually decarboxylates to cannabidiol (CBD). Whereas the anti-obesity properties of CBD have been reasonably identified, our knowledge of the pharmacology of CBDA is more limited due to its instability. To stabilize CBDA, a new derivative, CBDA-O-methyl ester (HU-580, EPM301), was synthesized. The therapeutic potential of EPM301 in appetite reduction, weight loss, and metabolic improvements in DIO and GIO was tested in vivo. EPM301 (40 mg/kg/d, i.p.) successfully resulted in weight loss, increased ambulation, as well as improved glycemic and lipid profiles in DIO mice. Additionally, EPM301 ameliorated DIO-induced hepatic dysfunction and steatosis. Importantly, EPM301 (20 and 40 mg/kg/d, i.p.) effectively reduced body weight and hyperphagia in a high-fat diet-fed mouse model for PWS. In addition, when given to standard-diet-fed mice as a preventive treatment, EPM301 completely inhibited weight gain and adiposity. Lastly, EPM301 increased the oxidation of different nutrients in each strain. All together, EPM301 ameliorated obesity and its metabolic abnormalities in both DIO and GIO. These results support the idea to further promote this synthetic CBDA derivative toward clinical evaluation in humans.
肥胖是一个全球性的医学问题；其常见形式被称为饮食诱导的肥胖（DIO）；然而，还有几种罕见的遗传疾病，如普拉德-威利综合征（PWS），也与肥胖有关（遗传诱导肥胖，GIO）。目前用于治疗 DIO 和 GIO 的治疗方法非常有限，并且只能得到部分改善。大麻二酚酸（CBDA）是大麻的一种成分，会逐渐脱羧生成大麻二酚（CBD）。尽管 CBD 的抗肥胖特性已经得到了合理的证实，但由于其不稳定性，我们对 CBDA 药理学的了解更为有限。为了稳定 CBDA，合成了一种新的衍生物，CBDA-O-甲酯（HU-580，EPM301）。在体内测试了 EPM301 在减少食欲、减肥和改善 DIO 和 GIO 代谢方面的治疗潜力。EPM301（40 mg/kg/d，腹腔注射）成功导致 DIO 小鼠体重减轻、活动增加以及血糖和血脂谱改善。此外，EPM301 改善了 DIO 诱导的肝功能障碍和脂肪变性。重要的是，EPM301（20 和 40 mg/kg/d，腹腔注射）有效减轻了高脂肪饮食喂养的 PWS 小鼠模型的体重和过度摄食。此外，当作为预防治疗给予标准饮食喂养的 小鼠时，EPM301 完全抑制了体重增加和肥胖。最后，EPM301 增加了每种品系中不同营养素的氧化。总而言之，EPM301 改善了 DIO 和 GIO 中的肥胖及其代谢异常。这些结果支持进一步将这种合成 CBDA 衍生物推进到人类临床评估的想法。
