Negative Allosteric Modulators (NAMs) of Metabotropic Glutamate Receptors 2 & 3 (mGlu2/3) for the Treatment of Depression

代谢型谷氨酸受体 2 的负变构调节剂 (NAM)

• 批准号: 10183332
• 负责人: Reto Andreas Gadient
• 金额: $ 44.95万
• 依托单位: CAMINO PHARMA, LLC
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-05 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10183332
• 关键词: AMPA Receptors; Acids; Acute; Adult; Affect; Anesthetics; Anhedonia; Animal Experiments; Antidepressive Agents; Behavioral; Behavioral Model; Brain; Brain-Derived Neurotrophic Factor; Chemosensitization; Clinical; Data; Disease; Dose; Electrophysiology (science); FRAP1 gene; Failure; Fluoxetine; Future; Glutamates; Habenula; Hippocampus (Brain); Hour; Human; Injections; Intravenous; Investigational Drugs; Ketamine; Lead; Learning; Major Depressive Disorder; Measurement; Measures; Medial; Mediating; Medical; Mental Depression; Metabotropic Glutamate Receptors; Microdialysis; Modeling; Molecular; Motivation; N-Methyl-D-Aspartate Receptors; Neurobiology; Neurons; Norepinephrine; Oral; Patients; Pharmaceutical Preparations; Pharmacology; Phase; Plasma; Play; Prefrontal Cortex; Procedures; Property; Prosencephalon; Rattus; Rewards; Rodent; Rodent Model; Role; Safety; Sedation procedure; Selective Serotonin Reuptake Inhibitor; Serotonin; Small Business Technology Transfer Research; Structure; Synapses; Therapeutic; Treatment Efficacy; Tricyclic Antidepressive Agents; analog; antidepressant effect; brain tissue; depression model; dorsal raphe nucleus; drug candidate; forced swim test; glutamatergic signaling; improved; in vivo; inhibitor/antagonist; metabotropic glutamate receptor 2; motivated behavior; novel; novel drug class; preclinical development; programs; receptor; release factor; research clinical testing; reuptake; side effect; small molecule; standard of care; treatment-resistant depression

SUMMARY Treatment-resistant depression (TRD) affects 20-30% of major depressive disorder (MDD) patients and is defined as a failure to respond to at least two adequate rounds of treatment with standard of care antidepressants. TRD represents a substantial unmet medical need, requiring novel treatments with rapid and sustained antidepressant activity and good safety and tolerability profiles. (S)-Ketamine (Spravato, Esketamine) was recently approved for the treatment of TRD; however, it has several adverse side effects including sedation, dissociative effects, and abuse liability. The precise mechanism of action (MOA) of ketamine remains unclear; while described as a noncompetitive N-methyl-D-aspartate receptor (NMDAR) antagonist, it has additional non- NMDAR effects. In humans, ketamine is rapidly metabolized and some metabolites, such as (2R,6R)- hydroxynorketamine (HNK), have rapid antidepressant-like activity in rodent models. The antidepressant-like activity of HNK is partially mediated through metabotropic glutamate receptor subtype 2 (mGlu2). Thus, we propose that negative allosteric modulation of mGlu2/3 represents a promising new strategy to treat TRD. Our rationale is four-fold: (1) mGlu2/3 receptors are expressed in the forebrain regions affected in depression, with particular enrichment in the medial prefrontal cortex, hippocampus and medial habenula, (2) inhibition of mGlu2/3 leads to molecular and cellular changes similar to those caused by ketamine, including α-amino-3-hydroxy-5- methyl-4-isoxazolepropionic acid (AMPA) receptor potentiation, brain-derived neurotrophic factor (BDNF) release, activation of mammalian target of rapamycin (mTOR) and ultimately synaptic remodeling, (3) mGlu2/3 orthosteric antagonists produce ketamine-like behavioral effects with sustained efficacy in multiple rodent procedures that model aspects of depression, and (4) the antidepressant-like activity of the ketamine metabolite (2R,6R)-HNK in rodent models is partially mediated by mGlu2. Thus, mGlu2/3 negative allosteric modulators (NAMs) are predicted to produce antidepressant effects similar to ketamine without the psychotomimetic side effects. Our objective is to advance a mGlu2/3 NAM into preclinical development and IND-enabling studies. To this end, we have identified a lead and a backup mGlu2/3 NAM with excellent drug-like properties. The specific aims are the following: (1) Determine the efficacy of our lead mGlu2/3 NAM in the rodent Probabilistic Reward Task (PRT) and Effort-related Choice (ERC) task after acute oral dosing; and (2) Determine target engagement of our lead mGlu2/3 NAM in vivo. On completion of this Phase I STTR, we will be able to determine if the lead compound and/or the backup have the efficacy and pharmacological profile to be advanced into preclinical development, which would become the basis of a Phase II application. Hence, the studies proposed here are important precedents to support a future clinical program for MDD and TRD.

概括 难治性抑郁症 (TRD) 影响 20-30% 的重度抑郁症 (MDD) 患者，并且 定义为未能对至少两轮适当的标准护理治疗做出反应 抗抑郁药。 TRD 代表了巨大的未满足的医疗需求，需要快速、有效的新疗法 持续的抗抑郁活性以及良好的安全性和耐受性。 (S)-氯胺酮（Spravato、Esketamine） 最近被批准用于治疗TRD；然而，它有一些不良副作用，包括镇静作用， 解离效应和滥用责任。氯胺酮的确切作用机制 (MOA) 仍不清楚； 虽然被描述为非竞争性 N-甲基-D-天冬氨酸受体 (NMDAR) 拮抗剂，但它具有额外的非竞争性 NMDAR 效应。在人体中，氯胺酮快速代谢，一些代谢物，如 (2R,6R)- 羟基去甲氯胺酮 (HNK) 在啮齿动物模型中具有快速的抗抑郁样活性。类似抗抑郁药 HNK 的活性部分通过代谢型谷氨酸受体亚型 2 (mGlu2) 介导。因此，我们 提出 mGlu2/3 的负变构调节代表了一种有前途的治疗 TRD 的新策略。我们的 其基本原理有四个方面：(1) mGlu2/3 受体在抑郁症受影响的前脑区域表达， 内侧前额皮质、海马体和内侧缰核特别丰富，(2) mGlu2/3 的抑制 导致类似于氯胺酮引起的分子和细胞变化，包括 α-氨基-3-羟基-5- 甲基-4-异恶唑丙酸 (AMPA) 受体增强、脑源性神经营养因子 (BDNF) 哺乳动物雷帕霉素靶标 (mTOR) 的释放、激活以及最终的突触重塑，(3) mGlu2/3 正位拮抗剂产生类似氯胺酮的行为效应，对多种啮齿动物具有持续疗效 模拟抑郁症各个方面的程序，以及（4）氯胺酮代谢物的抗抑郁样活性 啮齿动物模型中的 (2R,6R)-HNK 部分由 mGlu2 介导。因此，mGlu2/3 负变构调节剂 (NAM) 预计会产生与氯胺酮类似的抗抑郁作用，但不含拟精神病成分 影响。我们的目标是将 mGlu2/3 NAM 推进临床前开发和 IND 支持研究。到 为此，我们确定了具有优异药物样特性的先导 mGlu2/3 NAM 和备用 mGlu2/3 NAM。具体的 目标如下： (1) 确定我们的领先 mGlu2/3 NAM 在啮齿动物概率奖励中的功效 急性口服给药后的任务（PRT）和努力相关选择（ERC）任务； (2) 确定目标参与度 我们体内的领先 mGlu2/3 NAM。完成第一阶段 STTR 后，我们将能够确定领先者是否 化合物和/或备份具有可进入临床前阶段的功效和药理学特征 开发，这将成为第二阶段应用的基础。因此，这里提出的研究是 支持 MDD 和 TRD 未来临床计划的重要先例。