Preclinical validation of mGlu2 PAMs in alcohol use disorder

mGlu2 PAM 在酒精使用障碍中的临床前验证

• 批准号: 10815668
• 负责人: Reto Andreas Gadient
• 金额: $ 97.39万
• 依托单位: CAMINO PHARMA, LLC
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-20 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10815668
• 关键词: Abstinence; Acute; Adult; Adverse event; Affect; Agonist; Alcohol consumption; Alcohol dependence; Alcohol withdrawal syndrome; Alcohols; Amygdaloid structure; Attenuated; Basal Ganglia; Behavior; Blinded; Brain region; Cause of Death; Cessation of life; Chronic; Clinical Research; Corpus striatum structure; Coupled; Cues; Data; Development; Devices; Disulfiram; Dose; Double-Blind Method; Down-Regulation; Drug Kinetics; Drug usage; Economic Burden; Electroencephalography; Emergency Situation; Ethanol; Ethanol dependence; Exclusion; Exposure to; GTP-Binding Proteins; Glutamates; Goals; Health; Hippocampus; Homeostasis; Human; Implant; Intoxication; Investigational New Drug Application; Maximum Tolerated Dose; Medical; Medicine; Metabotropic Glutamate Receptors; Modeling; Mus; Naltrexone; Neurons; Neurotransmitters; Outcome; Pathology; Patients; Pharmaceutical Preparations; Pharmacological Treatment; Phase; Placebo Control; Plasma; Play; Prefrontal Cortex; Randomized; Rattus; Relapse; Reporting; Research; Research Personnel; Rodent; Rodent Model; Self Administration; Serious Adverse Event; Severities; Signal Transduction; Sleep; Sleep Fragmentations; Sleep disturbances; Smoker; Societies; Stress; Substance Use Disorder; Surveys; Symptoms; System; Testing; Toxic effect; United States; United States Food and Drug Administration; Universities; Validation; Visit; Withdrawal; acamprosate; alcohol abuse therapy; alcohol effect; alcohol relapse; alcohol seeking behavior; alcohol use disorder; anxiety-related disorders; associated symptom; attenuation; binge drinking; chronic alcohol ingestion; clinical development; drug action; drug misuse; effective therapy; effectiveness validation; experience; forest; in vivo; medical schools; metabotropic glutamate receptor 2; multidisciplinary; negative emotional state; non-smoker; novel; novel drug class; novel therapeutic intervention; positive allosteric modulator; pre-clinical; preclinical development; preclinical study; presynaptic; relapse prevention; small molecule; smoking cessation; vapor; wireless

PROJECT SUMMARY Alcohol Use Disorder (AUD) continues to be a significant problem, affecting 28.3 million adults in the United States, and is the third leading preventable cause of death. Disulfiram, naltrexone, and acamprosate are the only drugs approved by the Food and Drug Administration, but all three have limited efficacy and several contraindications. Given the substantial burden on society and the economy ($249 billion in 2010), there is a clear unmet need for effective and well-tolerated therapies that reduce alcohol dependence and relapse in AUD patients. AUD is characterized by phases of binge drinking, intoxication, and negative emotional states during withdrawal. The anticipation of alcohol leads to a repetition of these phases followed by periods of extended abstinence and frequent relapse. Importantly, each of these phases is accompanied by sleep disturbances (SDs). Three primary brain regions are involved in AUD-associated behavior: the prefrontal cortex (anticipation), basal ganglia (binge drinking), and amygdala (withdrawal). Several neurotransmitters are dysregulated in AUD, including the glutamatergic system. Extensive experimental evidence suggests that glutamate (Glu) critically modulates the actions of drugs of misuse, including alcohol. Therefore, normalization of aberrant Glu activity caused by chronic alcohol use potentially represents a novel therapeutic strategy to prevent relapse in AUD. The activation of metabotropic Glu receptor subtypes 2 and 3 (mGlu2/3) using agonists or positive allosteric modulators (PAMs) decreases ethanol (EtOH) self-administration (SA) as well as cue-induced reinstatement of EtOH seeking in rodents. Both alcohol-dependent rodents and humans show downregulation of mGlu2 expression, and many studies suggest that deficiencies in mGlu2 signaling may underlie AUD pathology. Moreover, preclinical studies indicate that mGlu2/3 activation has promise for treating stress- and anxiety-related disorders in humans and can systematically augment sleep, symptoms that are comorbid with AUD. We hypothesize that mGlu2 PAMs represent a promising new class of drugs to treat AUD. To test this hypothesis, our team has discovered and optimized three small molecule mGlu2 PAMs, SBP-9330, SBP-1315, and SBP-9220, that show efficacy in multiple models of substance-use disorders. To accomplish this, our specific aims are (1) Determine the in vivo efficacy of mGlu2 PAMs to decrease EtOH intake in rat models of dependent and non-dependent EtOH SA, (2) Determine the in vivo efficacy of mGlu2 PAMs to normalize SDs during withdrawal and abstinence following EtOH SA, and (3) Determine the effect of a fixed dose of EtOH on the PK profile and maximum tolerated dose of mGlu2 PAMs in rats. We have assembled a multidisciplinary team of investigators with the expertise and experience to achieve these outcomes. Successful completion of these studies will facilitate the development of a novel mGlu2 PAM towards filing of an investigational new drug (IND) application and ultimately, a safe and effective treatment for AUD.

项目概要 酒精使用障碍 (AUD) 仍然是一个严重问题，影响着美国 2,830 万成年人 州，是第三大可预防的死亡原因。双硫仑、纳曲酮和阿坎酸是唯一 食品和药物管理局批准的药物，但这三种药物的疗效都有限，而且有几种 禁忌症。鉴于社会和经济的沉重负担（2010 年为 2,490 亿美元）， 对减少 AUD 酒精依赖和复发的有效且耐受性良好的疗法的明显未满足需求 患者。 AUD 的特点是酗酒、中毒和消极情绪状态 撤回。对酒精的预期导致这些阶段的重复，随后是延长的时期 戒断和频繁复发。重要的是，每个阶段都伴随着睡眠障碍（SD）。 三个主要大脑区域参与 AUD 相关行为：前额皮质（预期）、基底皮质 神经节（酗酒）和杏仁核（戒断）。 AUD 中多种神经递质失调， 包括谷氨酸能系统。大量实验证据表明，谷氨酸 (Glu) 至关重要 调节滥用药物的作用，包括酒精。因此，异常 Glu 活性的正常化 由长期饮酒引起的可能代表一种预防 AUD 复发的新治疗策略。这 使用激动剂或正变构激活代谢型 Glu 受体亚型 2 和 3 (mGlu2/3) 调节剂 (PAM) 减少乙醇 (EtOH) 自我给药 (SA) 以及提示诱导的恢复 在啮齿动物中寻找乙醇。酒精依赖型啮齿动物和人类均表现出 mGlu2 下调 许多研究表明 mGlu2 信号传导缺陷可能是 AUD 病理学的基础。 此外，临床前研究表明 mGlu2/3 激活有望治疗压力和焦虑相关的疾病 人类疾病，可以系统地增强睡眠，这是与 AUD 共存的症状。我们 假设 mGlu2 PAM 代表一类有前景的治疗 AUD 的新型药物。为了检验这个假设， 我们的团队发现并优化了三种小分子 mGlu2 PAM：SBP-9330、SBP-1315 和 SBP-9220，在多种物质使用障碍模型中显示出功效。为了实现这一目标，我们的具体 目标是 (1) 确定 mGlu2 PAM 在依赖大鼠模型中减少 EtOH 摄入量的体内功效 和非依赖性 EtOH SA，(2) 确定 mGlu2 PAM 在体内使 SD 正常化的功效 EtOH SA 后戒断和戒断，以及 (3) 确定固定剂量的 EtOH 对 PK 的影响 大鼠体内 mGlu2 PAM 的概况和最大耐受剂量。我们组建了一支多学科团队 具有实现这些结果的专业知识和经验的研究人员。顺利完成这些 研究将促进新型 mGlu2 PAM 的开发，以申请研究性新药 (IND) 应用并最终为 AUD 提供安全有效的治疗方法。