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

描述(申请人提供)：大约16%的世界人口在他们生命中的某个时候患有抑郁症。尽管抗抑郁药物是可用的和有用的，但许多患者仍然对治疗无效，目前使用的药物需要几周时间才能见效。最近一个令人振奋的发展是，在外科手术中被广泛用作麻醉剂的氯胺酮，在治疗抵抗的患者中作为一种快速起效的抗抑郁药具有疗效。一次静脉注射(静脉注射)使用亚麻醉剂量的氯胺酮可以迅速改善抑郁患者的情绪，其有益效果可持续约一周。尽管有这些有希望的结果，但氯胺酮作为一种长期抗抑郁药物的潜力是有限的，因为它的成瘾性质、麻醉特性、即使在低剂量下也能产生解离效应的能力，以及其最常见的给药途径(静脉注射)的侵袭性。拟议的项目利用了氯胺酮可能的作用机制(抑制NMDA受体)，但针对受体的一个部位(“甘氨酸B”受体)，这不太可能引发不良反应。具体地说，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-氯尿酸(7-Cl-KYNA)的脑透性前体药物。值得注意的是，4-氯-KYN目前正在开发中，用于治疗神经病理性疼痛，在健康人体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。我们的长期目标是寻求使用4-氯-KYN来治疗人类的主要抑郁障碍。在这里，我们将使用小鼠来测试4-氯-KYN的抗抑郁药样特性和副作用。首先，在具体目标#1中，我们将定义4-氯-KYN对抑郁症相关行为的作用范围。这些研究将评估剂量-反应关系，并包括预测快速治疗作用和验证甘氨酸B受体作为临床干预目标的测试。以特定的目标 #2，我们将定义4-氯-KYN长期治疗的生化和抗抑郁药样效应。我们将根据不同的给药计划(连续/慢性和间歇给药，以及外周给药和口服给药)，测量小鼠的行为以及前体(4-氯-KYN)和有效化合物(7-氯-KYNA)在小鼠大脑中的水平。这里的目标是解决与延长疗效相关的临床相关问题，以及与持续的甘氨酸B受体阻断相关的可能的耐受或致敏现象。最后，在特定的目标#3中，我们将使用从目标#2中选择的治疗范例来比较4-氯-kyn和氯胺酮的副作用概况，并在预测滥用和精神分裂潜力的测试中评估行为。我们预计，4-氯-KYN在几个重要的实验指标上将被证明优于氯胺酮，该项目的成功完成将使我们能够尽可能地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.