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

描述（由申请人提供）：抑郁症困扰着大约16%的世界人口在他们生命中的某个时刻。虽然抗抑郁药物是可用的和有用的，许多患者仍然治疗难治性，目前使用的药物需要几个星期才能有效。最近一个令人兴奋的进展是发现氯胺酮，这是广泛使用的麻醉剂在外科设置，具有疗效作为一种快速作用的抗抑郁药在治疗抵抗性患者。单次静脉内（i. v.）施用亚麻醉剂量的氯胺酮导致抑郁个体的情绪迅速改善，并且有益效果持续约一周。尽管有这些有希望的结果，氯胺酮作为长期抗抑郁药物的潜力是有限的，这是由于其成瘾性，麻醉特性，即使在低剂量给药时也能产生解离效应，以及其最常见的给药途径（i. v.）的侵入性。拟议的项目利用了氯胺酮可能的作用机制（抑制NMDA受体），但靶向受体（“甘氨酸B”受体）的一个位点，这不太可能引起不良反应。具体而言，我们将研究4-氯犬尿氨酸（4-Cl-KYN），选择性甘氨酸B受体拮抗剂7-氯犬尿烯酸（7-Cl-KYNA）的脑渗透前药。值得注意的是，4-Cl-KYN目前正在开发用于治疗神经性疼痛，并且在健康人类志愿者的随机剂量递增研究中，耐受性良好，并显示出良好的口服生物利用度。我们的长期目标是追求使用4-Cl-KYN治疗人类重度抑郁症。在这里，我们将使用小鼠来测试4-Cl-KYN的抗抑郁药样特性和副作用概况。我们将首先在具体目标#1中定义4-Cl-KYN对抑郁相关行为的作用范围。这些研究将评价剂量-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 #2，我们将定义4-Cl-KYN长期治疗的生化和抗抑郁样作用。我们将在各种给药方案（连续/慢性vs.间歇给药，外周vs.口服给药）后测量小鼠脑中的行为以及前体（4-Cl-KYN）和有效化合物（7-Cl-KYNA）的水平。本文的目的是解决与持续甘氨酸B受体阻滞剂相关的长期疗效和可能的耐受性或致敏现象相关的临床相关问题。最后，在具体目标#3中，我们将比较4-Cl-KYN和氯胺酮的副作用特征，使用从目标#2中选择的治疗范例，并在预测滥用和拟精神病潜力的测试中评估行为。我们预计4-Cl-KYN将在几个重要的实验措施上证明上级氯胺酮，并且该项目的成功完成将使我们能够在可能的范围内使用临床前方法来现实地评估其潜力。 4-Cl-KYN作为人类抑郁症的治疗选择。

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.