An NMDA Glycine Site Antagonist for the Treatment of Major Depressive Disorder

描述（由申请人提供）：抑郁症折磨着大约16%的世界人口在他们生命中的某个阶段。虽然抗抑郁药物是可用的和有用的，但许多患者仍然难以治疗，目前使用的药物需要几周才能有效。最近一项令人兴奋的进展是，氯胺酮被广泛用作外科手术中的麻醉剂，它在治疗抵抗患者中作为一种快速起效的抗抑郁药具有疗效。单次静脉注射亚麻醉剂量的氯胺酮可迅速改善抑郁症患者的情绪，而且这种有益效果可持续约一周。尽管有这些令人鼓舞的结果，氯胺酮作为长期抗抑郁药物的潜力是有限的，因为它的成瘾性，麻醉特性，即使在低剂量下也能产生解离作用，以及其最常见的给药途径（静脉注射）的侵入性。该计划利用氯胺酮可能的作用机制（抑制NMDA受体），但针对受体的一个位点（甘氨酸b受体），这是不太可能产生不良反应。具体来说，我们将研究4-氯尿氨酸（4-Cl-KYN），这是一种选择性甘氨酸b受体拮抗剂7-氯尿氨酸酸（7-Cl-KYNA）的脑渗透前药。值得注意的是，目前正在开发用于治疗神经性疼痛的4-Cl-KYN，在健康人类志愿者的随机剂量递增研究中，该药物耐受性良好，并显示出良好的口服生物利用度。我们的长期目标是将4-Cl-KYN用于人类重度抑郁症的治疗。在这里，我们将用小鼠来测试4-Cl-KYN的抗抑郁样特性和副作用。首先，在具体目标#1中，我们将定义4-Cl-KYN对抑郁相关行为的作用范围。这些研究将评估剂量-反应关系，包括预测快速治疗作用和验证甘氨酸b受体作为临床干预靶点的试验。具体目标

DESCRIPTION (provided by applicant): Depression afflicts approximately 16 percent of the world population at some point in their lives. Although antidepressant medications are available and useful, many patients remain treatment-refractory, and currently used drugs take several weeks to be effective. A recent exciting development is the finding that ketamine, which is widely used as an anesthetic in surgical settings, has efficacy as a rapidly acting antidepressant in treatment resistant patients. A single intravenous (i.v.) administration of a sub-anesthetic dose of ketamine results in prompt improvement in mood in depressed individuals, and the beneficial effect is sustained for about a week. Despite these promising results, ketamine's potential as a long-term antidepressant medication is limited due to its addictive nature, anesthetic properties, capacity to produce dissociative effects even when administered at low doses, and the invasiveness of its most common route of administration (i.v.). The proposed project takes advantage of ketamine's likely mechanism of action (inhibition of the NMDA receptor) but targets a site of the receptor (the "glycineB" receptor), which is less likely to precipitate adverse effects. Specifically, we will examine 4-chlorokynurenine (4-Cl-KYN), a brain-permeable pro-drug of the selective glycineB receptor antagonist 7-chlorokynurenic acid (7-Cl-KYNA). Notably, 4-Cl-KYN is currently under development for the treatment of neuropathic pain and, in a randomized dose escalation study in healthy human volunteers, was well tolerated and showed good oral bioavailability. Our long-term goal is to pursue the use of 4-Cl-KYN for the treatment of major depressive disorders in humans. Here, we will use mice to test the antidepressant-like properties and the side effect profile of 4-Cl-KYN. We will first, in Specific Aim #1, define the range of 4-Cl-KYN action on depression-related behaviors. These studies will evaluate dose- response relationships and include tests to predict rapid therapeutic action and to validate the glycineB receptor as a target for clinical intervention. In Specific Aim #2, we will define biochemical and antidepressant-like effects of prolonged treatment with 4-Cl-KYN. We will measure behaviors, and the levels of both the precursor (4-Cl-KYN) and the effective compound (7-Cl-KYNA), in the brain of mice following various dosing schedules (continuous/chronic vs. intermittent, and peripheral vs. oral administration). The goal here is to address clinically relevant questions regarding prolonged efficacy, and possible tolerance or sensitization phenomena related to sustained glycineB receptor blockade. Finally, in Specific Aim #3, we will compare the side effect profiles of 4-Cl-KYN and ketamine, using treatment paradigms selected from Aim #2 and assessing behavior in tests that predict abuse and psychotomimetic potential. We anticipate that 4-Cl-KYN will prove superior to ketamine on several important experimental measures, and that successful completion of the project will allow us, to the extent possible using preclinical methods, to realistically evaluate the potential of 4-Cl-KYN as a treatment option for depression in humans.