Allosteric Modulation of the CB1 Receptor

摘要 酒精使用障碍(AUD)给人类健康和社会带来了沉重的负担。现有 治疗AUD的药物(氨基己酸酯、双硫兰和纳曲酮)疗效不高，因此有 继续重视开发新药和有效药物。大麻素1(CB1)受体代表 一种有希望的AUD治疗靶点，其在调节许多酒精相关行为方面的作用已得到明确证明 并对乙醇的激励和增强特性做出了贡献。CB1拮抗剂/逆转剂 激动剂利莫那班有效地降低了酒精消耗量/自我给药、戒断严重程度和提示- 诱发复发。不幸的是，利莫那班在最初被批准用于肥胖后在欧洲被停用 治疗由于人类的不良副作用，包括焦虑和抑郁，以及发展 其他CB1拮抗剂/反向激动剂也已被停用。作为一种替代策略，我们的团队已经 CB1受体负变构调节剂(NAMS)文库的合成与表征 到一个明显的位置而不是正构体(S)，并调节正构体配体的作用。CB1 NAM有 与利莫那班类似，在多项体外试验中已被证明有效地阻断激动剂信号转导。我们的研究 证明了我们团队开发的CB1 NAM RTICBM-74可以剂量依赖性地减少酒精含量 在不影响大鼠蔗糖摄入量的情况下食用。重要的是，RTICBM-74没有表现出焦虑样的行为 在高架迷宫(EPM)和开阔场地中的相同剂量，而利莫那班表现出焦虑样 EPM中张开手臂时间减少的行为。这项建议的目标是进一步优化这些 CB1NAMS有望改善材料的综合性能，特别是增加溶解度和降低 亲脂性(目标1-2)，并评估它们对酒精自我给药、复发样行为、焦虑- 大鼠的相关行为和快感缺失(目标3)。总之，这些研究有可能发现新的CB1 NAMS是治疗AUD的一种可能的治疗策略。

Abstract Alcohol use disorder (AUD) represents a significant burden on human health and society. Existing medications to treat AUD (acamprosate, disulfiram, and naltrexone) have modest efficacy and thus there is continued emphasis on developing novel and effective drugs. The cannabinoid type-1 (CB1) receptor represents a promising AUD treatment target with a clearly demonstrated role in modulating many alcohol-related behaviors and having contributions to the motivational and reinforcing properties of ethanol. The CB1 antagonist/inverse agonist rimonabant effectively reduces alcohol consumption/self-administration, withdrawal severity, and cue- induced relapse. Unfortunately, rimonabant was withdrawn in Europe after its initial approval for obesity treatment because of untoward side effects in humans including anxiety and depression, and development of other CB1 antagonists/inverse agonists has also been halted. As an alternative strategy, our team has synthesized and characterized a library of CB1 receptor negative allosteric modulators (NAMs), ligands that bind to a distinct site than the orthosteric site(s) and modulate the effects of the orthosteric ligands. CB1 NAMs have been shown to effectively block agonist signaling in multiple in vitro assays, similar to rimonabant. Our studies demonstrated that RTICBM-74, a CB1 NAM developed by our team, dose-dependently reduced alcohol consumption without affecting sucrose intake in rats. Importantly, RTICBM-74 showed no anxiety-like behavior at the same dose in an elevated plus maze (EPM) and an open field, whereas rimonabant displayed anxiety-like behavior with decreased time in the open arm in EPM. The goal of this proposal is to further optimize these promising CB1 NAMs to improve the overall properties, particularly increasing solubility and decreasing lipophilicity (Aims 1-2), and evaluate their effects on alcohol self-administration, relapse-like behavior, anxiety- related behavior and anhedonia in rats (Aim 3). Together, these studies have the potential to identify novel CB1 NAMs as a possible therapeutic strategy for the treatment of AUD.