Addiction Biology Unit, Medicinal Chemistry Section, Molecular Targets and Medications Discovery Branch, Intramural Research Program, National Institute on Drug Abuse, Baltimore, MD 21224, USA.
Cells. 2022 Oct 17;11(20):3262. doi: 10.3390/cells11203262.
Cannabinoid receptor 1 (CB1R) has been one of the major targets in medication development for treating substance use disorders (SUDs). Early studies indicated that rimonabant, a selective CB1R antagonist with an inverse agonist profile, was highly promising as a therapeutic for SUDs. However, its adverse side effects, such as depression and suicidality, led to its withdrawal from clinical trials worldwide in 2008. Consequently, much research interest shifted to developing neutral CB1R antagonists based on the recognition that rimonabant's side effects may be related to its inverse agonist profile. In this article, we first review rimonabant's research background as a potential pharmacotherapy for SUDs. Then, we discuss the possible mechanisms underlying its therapeutic anti-addictive effects its adverse effects. Lastly, we discuss the rationale for developing neutral CB1R antagonists as potential treatments for SUDs, the supporting evidence in recent research, and the challenges of this strategy. We conclude that developing neutral CB1R antagonists without inverse agonist profile may represent attractive strategies for the treatment of SUDs.
大麻素受体 1（CB1R）一直是药物开发治疗物质使用障碍（SUD）的主要靶点之一。早期研究表明，具有反向激动剂特征的选择性 CB1R 拮抗剂利莫那班是治疗 SUD 的一种很有前途的药物。然而，其不良反应，如抑郁和自杀倾向，导致其于 2008 年在全球范围内退出临床试验。因此，人们对开发基于中性 CB1R 拮抗剂的兴趣大增，因为人们认识到利莫那班的副作用可能与其反向激动剂特征有关。在本文中，我们首先回顾了利莫那班作为治疗 SUD 的潜在药物治疗的研究背景。然后，我们讨论了其治疗抗成瘾作用及其不良反应的可能机制。最后，我们讨论了开发具有中性 CB1R 拮抗剂作为治疗 SUD 的潜在治疗方法的基本原理、最近研究中的支持证据以及该策略的挑战。我们的结论是，开发没有反向激动剂特征的中性 CB1R 拮抗剂可能是治疗 SUD 的一种有吸引力的策略。
