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.

项目总结 酒精使用障碍(AUD)仍然是一个严重的问题，影响着美国2830万成年人 而且是第三大可预防的死因。双硫仑、纳曲酮和氨基己酸酯是唯一的 美国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，还有几种 禁忌症。考虑到社会和经济的巨大负担(2010年为2490亿美元)， 明确未得到满足的有效和耐受性良好的治疗方法，以减少酒精依赖和AUD的复发 病人。AUD的特征是酗酒、醉酒和消极情绪状态的阶段 戒烟。对酒精的预期导致这些阶段的重复，随后是延长的时期 禁欲和经常复发。重要的是，这些阶段中的每一个阶段都伴随着睡眠障碍(SD)。 AUD相关行为涉及三个主要脑区：前额叶皮质(预期)、基底区 神经节(酗酒)和杏仁核(戒断)。几种神经递质在AUD中调节失调， 包括谷氨酸能系统。广泛的实验证据表明，谷氨酸(Glu)对 调节包括酒精在内的滥用药物的行为。因此，谷氨酸活性异常的正常化 由长期饮酒引起的AUD可能代表着一种防止AUD复发的新的治疗策略。这个 用激动剂或正变构激活代谢型谷氨酸受体亚型2和3(mGlu2/3) 调节剂(PAM)减少乙醇(EtoH)的自我给药(SA)以及线索诱导的恢复 在啮齿动物身上寻找乙醇。酒精依赖的啮齿动物和人类都表现出mGlu2的下调 许多研究表明，mGlu2信号的缺陷可能是AUD病理的基础。 此外，临床前研究表明，激活mGlu2/3有望治疗与压力和焦虑相关的疾病。 在人类的紊乱中，可以系统性地增加睡眠，这是与AUD共病的症状。我们 假设mGlu2 PAM代表了一种很有前途的治疗AUD的新药。为了检验这一假设， 我们的团队已经发现并优化了三种小分子mGlu2 PAM，SBP-9330，SBP-1315和 SBP-9220，在多种药物使用障碍模型中显示出疗效。为了实现这一点，我们的特定 目的是：(1)确定mGlu2 PAM对依赖模型大鼠减少乙醇摄取的体内效果。 和非依赖乙醇SA，(2)测定mGlu2 PAM在体内对SD正常化的有效性 Etoh SA后的戒断和戒断，以及(3)确定固定剂量的Etoh对PK的影响 MGlu2 PAM在大鼠体内的分布和最大耐受量。我们已经组建了一个多学科的团队 具有实现这些结果的专业知识和经验的调查人员。成功完成这些任务 研究将促进开发一种新的mGlu2 PAM，以提交一种研究新药(IND) 最终，这是一种安全有效的治疗AUD的方法。