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

摘要 难治性抑郁症(TRD)影响20%-30%的严重抑郁障碍(MDD)患者和IS 被定义为未能对至少两轮适当的治疗做出反应，并符合护理标准 抗抑郁药。TRD代表着大量未得到满足的医疗需求，需要使用快速和 持续的抗抑郁活性和良好的安全性和耐受性。(S)-氯胺酮(西班牙、埃斯氯胺酮) 最近被批准用于治疗TRD；然而，它有几个副作用，包括镇静， 分离效果和滥用责任。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 NMDAR效果。在人体内，氯胺酮代谢迅速，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药样活性。类抗抑郁药 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的负变构调节是治疗TRD的一种有前景的新策略。我们的 理由有四个：(1)mGlu2/3受体在抑郁症患者的前脑区域表达， 内侧前额叶皮质、海马和内侧缰核的特别丰富，(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 哺乳动物雷帕霉素靶标(MTOR)的释放、激活和最终突触重构，(3)mGlu2/3 正构体拮抗剂在多只啮齿动物身上产生持续有效的氯胺酮样行为效应 模拟抑郁症各方面的程序，以及(4)氯胺酮代谢物的抗抑郁药样活性 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)被预测产生类似于氯胺酮的抗抑郁作用，而没有精神分裂的一面 效果。我们的目标是推动mGlu2/3NAM进入临床前开发和IND使能研究。至 为此，我们确定了具有良好类药物特性的先导和备用mGlu2/3 NAM。具体的 目的如下：(1)确定我们的先导mGlu2/3NAM在啮齿动物概率奖赏中的有效性 急性口服给药后的任务(PRT)和努力相关选择(ERC)任务；以及(2)确定目标投入 我们的主要mGlu2/3NAM在体内。在完成此第一阶段STTR后，我们将能够确定Lead是否 化合物和/或制剂具有进入临床前阶段的疗效和药理作用 开发，这将成为第二阶段应用程序的基础。因此，这里提出的研究是 支持未来MDD和TRD临床计划的重要先例。

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.