Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL, USA.
Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL, USA.
Pharmacol Biochem Behav. 2021 Jul;206:173192. doi: 10.1016/j.pbb.2021.173192. Epub 2021 Apr 29.
It has been established that the endogenous cannabinoid (endocannabinoid) system plays key modulatory roles in a wide variety of pathological conditions. The endocannabinoid system comprises both cannabinoid receptors, their endogenous ligands including 2-arachidonoylglycerol (2-AG), N-arachidonylethanolamine (anandamide, AEA), and enzymes that regulate the synthesis and degradation of endogenous ligands which include diacylglycerol lipase alpha (DAGL-α), diacylglycerol lipase beta (DAGL-β), fatty acid amide hydrolase (FAAH), monoacylglycerol lipase (MAGL), α/β hydrolase domain 6 (ABHD6). As the endocannabinoid system exerts considerable involvement in the regulation of homeostasis and disease, much effort has been made towards understanding endocannabinoid-related mechanisms of action at cellular, physiological, and pathological levels as well as harnessing the various components of the endocannabinoid system to produce novel therapeutics. However, drug discovery efforts within the cannabinoid field have been slower than anticipated to reach satisfactory clinical endpoints and raises an important question into the validity of developing novel ligands that therapeutically target the endocannabinoid system. To answer this, we will first examine evidence that supports the existence of an endocannabinoid system role within inflammatory diseases, neurodegeneration, pain, substance use disorders, mood disorders, as well as metabolic diseases. Next, this review will discuss recent clinical studies, within the last 5 years, of cannabinoid compounds in context to these diseases. We will also address some of the challenges and considerations within the cannabinoid field that may be important in the advancement of therapeutics into the clinic.
已经确定，内源性大麻素（内源性大麻素）系统在多种病理情况下发挥关键调节作用。内源性大麻素系统既包括大麻素受体，也包括其内源性配体，包括 2-花生四烯酸甘油（2-AG）、N-花生四烯基乙醇胺（大麻素，AEA）以及调节内源性配体合成和降解的酶，包括二酰基甘油脂肪酶 α（DAGL-α）、二酰基甘油脂肪酶 β（DAGL-β）、脂肪酸酰胺水解酶（FAAH）、单酰基甘油脂肪酶（MAGL）、α/β 水解酶结构域 6（ABHD6）。由于内源性大麻素系统在调节体内平衡和疾病方面发挥了相当大的作用，因此人们做出了很大的努力来了解细胞、生理和病理水平的内源性大麻素相关作用机制，并利用内源性大麻素系统的各种成分来产生新的治疗方法。然而，大麻素领域的药物发现工作进展缓慢，未能达到令人满意的临床终点，这引发了一个重要问题，即开发具有治疗作用的新型内源性大麻素配体的有效性。为了回答这个问题，我们首先将检查支持内源性大麻素系统在炎症性疾病、神经退行性变、疼痛、物质使用障碍、情绪障碍以及代谢性疾病中发挥作用的证据。接下来，本综述将讨论过去 5 年内大麻素化合物在这些疾病中的最新临床研究。我们还将讨论大麻素领域中的一些挑战和考虑因素，这些因素可能对将治疗方法推向临床具有重要意义。
