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

总结 难治性抑郁症（TRD）影响20-30%的重性抑郁症（MDD）患者， 定义为对至少两轮适当的标准治疗无效 抗抑郁药TRD代表了大量未满足的医疗需求，需要具有快速和高效的新治疗方法。 持续的抗抑郁活性和良好的安全性和耐受性特征。（S）-氯胺酮（Spravato、艾司氯胺酮） 最近被批准用于治疗TRD;然而，它有几个不良副作用，包括镇静， 分离效应和虐待倾向氯胺酮的确切作用机制（MOA）尚不清楚; 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。在人体内，氯胺酮被快速代谢，一些代谢物，如（2 R，6 R）- 羟基去甲氯胺酮（HNK）在啮齿动物模型中具有快速抗抑郁样活性。抗抑郁样 HNK的活性部分通过代谢型谷氨酸受体亚型2（mGlu 2）介导。因此我们 提出mGlu 2/3的负变构调节代表了治疗TRD的有希望的新策略。我们 理由是四方面的：（1）mGlu 2/3受体在受抑郁症影响的前脑区域表达， 特别是在内侧前额叶皮层、海马和内侧缰核中富集，（2）抑制mGlu 2/3 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） 释放、激活哺乳动物雷帕霉素靶蛋白（mTOR）并最终进行突触重塑，（3）mGlu 2/3 正构拮抗剂在多种啮齿动物中产生氯胺酮样行为效应并具有持续效力 模拟抑郁症方面的程序，以及（4）氯胺酮代谢物的抗抑郁样活性 (2R，6 R）-HNK在啮齿动物模型中部分由mGlu 2介导。因此，mGlu 2/3负变构调节剂 据预测，NAMs产生的抗抑郁作用与氯胺酮相似，但没有拟精神病的副作用。 方面的影响.我们的目标是推进mGlu 2/3 NAM进入临床前开发和IND使能研究。到 为此，我们鉴定了具有优异的药物样性质的先导和备用mGlu 2/3 NAM。具体 目的如下：（1）确定我们的前导mGlu 2/3 NAM在啮齿动物Probably Reward中的功效 任务（PRT）和努力相关选择（ERC）任务;和（2）确定目标参与 mGlu 2/3 NAM的体内表达。在完成第一阶段STTR后，我们将能够确定 所述化合物和/或所述备份具有推进到临床前的功效和药理学特征 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未来临床项目的重要先例。

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.