Neurological and neurodegenerative diseases are debilitating conditions, and frequently lack an effective treatment. Monoacylglycerol lipase (MAGL) is a key enzyme involved in the metabolism of 2-AG (2-arachidonoylglycerol), a neuroprotective endocannabinoid intimately linked to the generation of pro- and anti-inflammatory molecules. Consequently, synthesizing selective MAGL inhibitors has become a focus point in drug design and development. The purpose of this review was to summarize the diverse synthetic scaffolds of MAGL inhibitors concerning their potency, mechanisms of action and potential therapeutic applications, focusing on the results of studies published in the past five years. The main irreversible inhibitors identified were derivatives of hexafluoroisopropyl alcohol carbamates, glycol carbamates, azetidone triazole ureas and benzisothiazolinone, whereas the most promising reversible inhibitors were derivatives of salicylketoxime, piperidine, pyrrolidone and azetidinyl amides. We reviewed the results of in-depth chemical, mechanistic and computational studies on MAGL inhibitors, in addition to the results of in vitro findings concerning selectivity and potency of inhibitors, using the half maximal inhibitory concentration (IC₅₀) as an indicator of their effect on MAGL. Further, for highlighting the potential usefulness of highly selective and effective inhibitors, we examined the preclinical in vivo reports regarding the promising therapeutic applications of MAGL pharmacological inhibition.

中文翻译：

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以单酰甘油脂肪酶为靶点寻求神经系统和神经退行性疾病的治疗


神经系统疾病和神经退行性疾病是使人衰弱的疾病，并且常常缺乏有效的治疗方法。单酰甘油脂肪酶 (MAGL) 是参与 2-AG（2-花生四烯酰甘油）代谢的关键酶，2-AG 是一种神经保护性内源性大麻素，与促炎和抗炎分子的生成密切相关。因此，合成选择性MAGL抑制剂已成为药物设计和开发的焦点。本综述的目的是总结 MAGL 抑制剂的各种合成支架的效力、作用机制和潜在的治疗应用，重点关注过去五年发表的研究结果。确定的主要不可逆抑制剂是六氟异丙醇氨基甲酸酯、乙二醇氨基甲酸酯、氮杂环丁酮三唑脲和苯并异噻唑啉酮的衍生物，而最有前途的可逆抑制剂是水杨酮肟、哌啶、吡咯烷酮和氮杂环丁酰胺的衍生物。我们回顾了对 MAGL 抑制剂的深入化学、机械和计算研究的结果，以及有关抑制剂选择性和效力的体外研究结果，使用半数最大抑制浓度 (IC ₅₀ ) 作为其效果的指标在 MAGL 上。此外，为了强调高选择性和有效抑制剂的潜在用途，我们检查了有关 MAGL 药理学抑制的有前景的治疗应用的临床前体内报告。