Research Triangle Institute, Research Triangle Park, NC 27709, United States.
Curr Top Med Chem. 2019;19(16):1418-1435. doi: 10.2174/1568026619666190708164841.
The Cannabinoid CB1 Receptor (CB1R) is involved in a variety of physiological pathways and has long been considered a golden target for therapeutic manipulation. A large body of evidence in both animal and human studies suggests that CB1R antagonism is highly effective for the treatment of obesity, metabolic disorders and drug addiction. However, the first-in-class CB1R antagonist/inverse agonist, rimonabant, though demonstrating effectiveness for obesity treatment and smoking cessation, displays serious psychiatric side effects, including anxiety, depression and even suicidal ideation, resulting in its eventual withdrawal from the European market. Several strategies are currently being pursued to circumvent the mechanisms leading to these side effects by developing neutral antagonists, peripherally restricted ligands, and allosteric modulators. In this review, we describe the progress in the development of therapeutics targeting the CB1R in the last two decades.
大麻素 CB1 受体（CB1R）参与多种生理途径，长期以来一直被认为是治疗干预的黄金靶点。动物和人类研究的大量证据表明，CB1R 拮抗剂对肥胖症、代谢紊乱和药物成瘾的治疗非常有效。然而，作为首个 CB1R 拮抗剂/反向激动剂的利莫那班，尽管在肥胖症治疗和戒烟方面显示出有效性，但表现出严重的精神副作用，包括焦虑、抑郁甚至自杀意念，最终导致其从欧洲市场撤出。目前正在通过开发中性拮抗剂、外周受限配体和变构调节剂来探索规避导致这些副作用的机制的几种策略。在这篇综述中，我们描述了过去二十年中针对 CB1R 开发治疗药物的进展。
