NOVEL GLYCINE/NMDA ANTAGONISTS WITHOUT PCP SIDE EFFECTS

N-甲基-D-天冬氨酸(NMDA)受体/离子通道复合体是主要的 大脑中的兴奋性神经递质受体。NMDA受体是 涉及正常和异常大脑功能的多个方面 包括神经元兴奋，大脑可塑性，学习和记忆， 缺血性神经元损伤、癫痫、伤害性感受等。因此，NMDA 受体拮抗剂药物具有潜在的治疗作用。 各种中枢神经系统疾病。最重要的潜在治疗方法之一 这些药物的靶向是预防缺血性神经元损伤。 中风或全脑缺血后。然而，治疗性的 NMDA拮抗剂的开发受到了严重的限制 苯环利定(PCP)样行为副作用由 NMDA通道阻滞剂，如MK801或由竞争性NMDA拮抗剂 例如CPP或CGS19755。试图制造NMDA的拮抗者 没有不良行为副作用的受体，主要是 这一应用的研究人员已经合成了一系列新颖的 具有高亲和力、高选择性和拮抗剂的喹恶烷二酮类似物 N-甲基-D-天冬氨酸受体甘氨酸协同激动剂的作用 甘氨酸/NMDA受体)。初步工作表明，这些小说 甘氨酸/NMDA拮抗剂--不同于以前可用的甘氨酸位点 拮抗剂--全身给药后在体内具有很强的活性。 此外，新的甘氨酸/NMDA拮抗剂被证明不存在 两种动物模型的五氯苯酚样行为副作用。在此应用程序中 建议将新发现的甘氨酸/NMDA拮抗剂用作 用于合成精心挑选的类似物的先导化合物 进行详细的结构/活动研究以获得洞察力 转化为可能的药效团，赋予甘氨酸/NMDA拮抗剂 对喹恶啉二酮类及相关化合物的有效性和选择性。在……里面 此外，还建议合成[~3H]标记的大多数类似物 作为结合分析的放射性配体的有效化合物。它更远了 建议创造叠氮衍生物作为潜在的光亲和标记 NMDA受体的甘氨酸结合部位。这项工作有望实现 导致发现新型甘氨酸/NMDA拮抗剂，这些拮抗剂在 全身给药后的体内活性和缺乏五氯苯酚样物 行为副作用。此外，这项工作预计将导致 用于生物化学表征的新型探针的建立 甘氨酸/NMDA受体。新的对手应该是非常宝贵的工具 体内和体外甘氨酸/NMDA受体的研究和特性。

The N-methyl-D-aspartate (NMDA) receptor/ion channel complex is the major excitatory neurotransmitter receptor in the brain. NMDA receptors are involved in numerous aspects of normal and abnormal brain function including neuronal excitation, brain plasticity, learning and memory, ischemic neuronal damage, epilepsy, nociception etc. Consequently, NMDA receptor antagonist drugs have potential as therapeutic agents in a variety of CNS disorders. Among the most important potential therapeutic target areas for these drugs is prevention of ischemic neuronal damage following stroke or global brain ischemia. However, the therapeutic exploitation of NMDA antagonists has been severely limited by the phencyclidine (PCP)-like behavioral side effects that are caused by the NMDA channel blockers such as MK801 or by the competitive NMDA antagonists such as CPP or CGS19755. In an attempt to create antagonists of the NMDA receptor that would lack adverse behavioral side effects, the principal investigators of this application have synthesized a series of novel quinoxalinedione analogs with high affinity, selectivity and antagonist efficacy at the glycine coagonist site of the NMDA receptor (the glycine/NMDA receptor). Preliminary work has shown that these novel glycine/NMDA antagonists--unlike previously available glycine site antagonists--are potently active in vivo after systemic administration. Furthermore, the novel glycine/NMDA antagonists were shown to be devoid of PCP-like behavioral side-effects in two animal models. In this application it is proposed to use the newly discovered glycine/NMDA antagonists as lead compounds for the synthesis of carefully selected analogs and to conduct detailed structure/activity studies in order to obtain insights into the likely pharmacophore which confers glycine/NMDA antagonist efficacy and selectivity to quinoxalinediones and related compounds. In addition, it is proposed to synthesize [3H]-labelled analogs of the most potent compounds as radioligands for binding assays. It is further proposed to create azido-derivatives as potential photoaffinity labels for the glycine binding site of the NMDA receptor. This work is expected to lead to the discovery of novel glycine/NMDA antagonists that are active in vivo activity after systemic administration and that lack PCP-like behavioral side-effects. Furthermore, this work is expected to result in the creation of novel probes for the biochemical characterization of glycine/NMDA receptors. The new antagonists should be invaluable tools to study and characterize glycine/NMDA receptors in vivo and in vitro.