Allosteric Modulation of the CB1 Receptor

CB1 受体的变构调节

• 批准号: 10592492
• 负责人: JOYCE BESHEER
• 金额: $ 68.19万
• 依托单位: RESEARCH TRIANGLE INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10592492
• 关键词: Acute; Affect; Agonist; Alcohol consumption; Alcohol dependence; Alcohols; Anhedonia; Animal Model; Anxiety; Attenuated; Behavior; Behavior assessment; Binding; Biological Assay; Brain; CNR1 gene; CNR2 gene; Chronic; Cocaine; Computer Models; Consumption; Cue-induced relapse; Data; Dependence; Development; Disulfiram; Dose; Drug Kinetics; Effectiveness; Endocannabinoids; Enzymes; Ethanol; Europe; European; Evaluation; G-Protein-Coupled Receptors; Goals; Health; Human; In Vitro; Intake; Ion Channel; Libraries; Ligand Binding; Ligands; Marketing; Mental Depression; Metabolic; Modeling; Motivation; Naltrexone; Pharmaceutical Preparations; Play; Pre-Clinical Model; Property; Psychological reinforcement; Rattus; Relapse; Reporting; Role; SR141716; Self Administration; Series; Severities; Signal Transduction; Site; Social Interaction; Societies; Solubility; Sucrose; System; Testing; Therapeutic; Time; Urea; Wistar Rats; Withdrawal; acamprosate; alcohol abuse therapy; alcohol behavior; alcohol effect; alcohol reinforcement; alcohol relapse; alcohol seeking behavior; alcohol use disorder; antagonist; anxiety-like behavior; anxiety-related behavior; arm; design; drug-like compound; improved; in silico; in vitro Assay; in vivo; lipophilicity; motor behavior; neurotransmission; nonhuman primate; novel; obesity treatment; process optimization; radioligand; receptor; relapse prevention; response; rimonabant; side effect; translational potential; treatment strategy

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 Unfortunately, rimonabant was withdrawn in Europe after its initial approval for obesity treatment because of untoward side effects in humans including anxiety and depression, and development of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.

抽象的 酒精使用障碍（AUD）对人类健康和社会造成重大负担。现存的 治疗 AUD 的药物（阿坎酸、双硫仑和纳曲酮）疗效有限，因此 继续重视开发新颖有效的药物。 1 型大麻素 (CB1) 受体代表 一个有前途的 AUD 治疗目标，在调节许多酒精相关行为方面具有明确的作用 并对乙醇的激励和强化特性做出贡献。 CB1拮抗剂/逆 激动剂利莫那班可有效降低饮酒量/自我给药、戒断严重程度和提示 诱发复发。不幸的是，利莫那班在最初批准用于治疗肥胖症后在欧洲被撤回 由于对人类产生不良副作用（包括焦虑和抑郁）而进行治疗，以及 其他 CB1 拮抗剂/反向激动剂也已停止。作为替代策略，我们的团队有 合成并表征了 CB1 受体负变构调节剂 (NAM) 库，即结合的配体 到与正位点不同的位点并调节正位配体的作用。 CB1 NAM 有 在多项体外试验中被证明可以有效阻断激动剂信号传导，与利莫那班类似。我们的研究 证明 RTICBM-74（我们团队开发的 CB1 NAM）可剂量依赖性地减少酒精摄入 消耗而不影响大鼠的蔗糖摄入量。重要的是，RTICBM-74 没有表现出类似焦虑的行为 在高架十字迷宫（EPM）和开放视野中以相同剂量进行试验，而利莫那班表现出焦虑样 EPM 中张臂时间减少的行为。该提案的目标是进一步优化这些 有前景的 CB1 NAM 可以改善整体性能，特别是增加溶解度并降低 亲脂性（目标 1-2），并评估其对酒精自我给药、复发样行为、焦虑的影响 大鼠的相关行为和快感缺失（目标 3）。总之，这些研究有可能鉴定出新型 CB1 NAMs 作为治疗 AUD 的一种可能的治疗策略。