Inhibitors of serine racemase as novel therapeutics for treatment-resistant depression

丝氨酸消旋酶抑制剂作为治疗难治性抑郁症的新疗法

• 批准号: MC_PC_MR/S026339/1
• 负责人: Olivera Grubisha
• 金额: $ 1.89万
• 依托单位: CARDIFF UNIVERSITY
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MC_PC_MR%2FS026339%2F1
• 关键词: Inhibitors; serine; racemase; novel; therapeutics

Major depressive disorder (MDD) is a disorder that causes persistent feelings of sadness, low self-esteem and apathy and in 2-8% of adults it leads to suicide. According to the World Health Organisation, MDD is the second leading cause of global disability, with an estimated economic burden of ~$210 billion in the US alone. The standard treatment for MDD is anti-depressant drugs, such as serotonin-reuptake inhibitors. However, around one-third of patients do not respond to these common antidepressants. In these treatment-resistant depression patients, the experimental use of the intravenous anaesthetic ketamine has shown promising results as has a related drug called esketamine which is administered via the nose. Nevertheless, ketamine has several serious side effects including psychosis, cognitive and physical impairment and it is also a recreational drug with potential for addiction. Therefore, a drug that works on the same protein as ketamine but has a very different mechanism of action will likely have a safer profile which along with an easier route of administration would make it much better tolerated than ketamine by this patient population. Common antidepressants, which modulate levels of the so-called "mood chemical" serotonin whereas ketamine acts by altering the function of a different chemical in the brain, glutamate. Hence, ketamine works by blocking the effects of glutamate at proteins called N-methyl-D-aspartate receptors (NMDARs). However, in addition to glutamate, NMDARs also require a second chemical, D-serine to perform their function. Consequently, we hypothesise that by reducing the amount of D-serine in the brain by inhibiting the protein that makes it (serine racemase) we should be able to alter the function of NMDARs in a manner analogous to how ketamine produces its therapeutic benefits in treatment-resistant depression. Importantly, however, the different mechanism of action of a serine racemase inhibitor drug means that it will be a safer therapeutic option than ketamine since its restricted distribution in the brain means that is will not produce the unpleasant side-effects associated with ketamine.

重度抑郁症（MDD）是一种导致持续悲伤，低自尊和冷漠感的疾病，2-8%的成年人会导致自杀。根据世界卫生组织的数据，MDD是全球残疾的第二大原因，仅在美国估计经济负担约为2100亿美元。MDD的标准治疗是抗抑郁药，如曲马多宁再摄取抑制剂。然而，大约三分之一的患者对这些常见的抗抑郁药没有反应。在这些难治性抑郁症患者中，静脉麻醉剂氯胺酮的实验性使用已经显示出有希望的结果，因为通过鼻子给药的相关药物称为艾司氯胺酮。然而，氯胺酮有几个严重的副作用，包括精神病，认知和身体损害，它也是一种娱乐性药物，有可能上瘾。因此，与氯胺酮作用于相同蛋白质但具有非常不同作用机制的药物可能具有更安全的特征，沿着更容易的给药途径将使其在该患者人群中比氯胺酮耐受性更好。常见的抗抑郁药，调节所谓的“情绪化学物质”血清素的水平，而氯胺酮通过改变大脑中不同化学物质谷氨酸的功能来发挥作用。因此，氯胺酮通过阻断谷氨酸对称为N-甲基-D-天冬氨酸受体（NMDAR）的蛋白质的作用而起作用。然而，除了谷氨酸盐，NMDAR还需要第二种化学物质D-丝氨酸来执行其功能。因此，我们假设，通过抑制蛋白质（丝氨酸消旋酶）来减少大脑中D-丝氨酸的量，我们应该能够以类似于氯胺酮如何在难治性抑郁症中产生治疗益处的方式改变NMDAR的功能。然而，重要的是，丝氨酸消旋酶抑制剂药物的不同作用机制意味着它将是比氯胺酮更安全的治疗选择，因为它在脑中的受限分布意味着它不会产生与氯胺酮相关的令人不快的副作用。