NOVEL GLYCINE/NMDA ANTAGONISTS WITHOUT PCP SIDE EFFECTS

无 PCP 副作用的新型甘氨酸/NMDA 拮抗剂

• 批准号: 2118903
• 负责人: ECKARD WEBER
• 金额: $ 23.55万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-03-01 至 1996-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2118903
• 关键词: NMDA receptors; PCP receptor; Xenopus; affinity labeling; chemical structure function; chemical synthesis; drug adverse effect; drug design /synthesis /production; drug metabolism; drug screening /evaluation; glycine receptors; inhibitor /antagonist; laboratory mouse; laboratory rat; ligands; molecular site; nonhuman therapy evaluation; receptor binding; tritium

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.

N-甲基-D-天冬氨酸（NMDA）受体/离子通道复合物是主要的 大脑中的兴奋性神经递质受体 NMDA受体是 涉及大脑正常和异常功能的许多方面 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， 受体拮抗剂药物具有作为治疗剂的潜力， 各种CNS疾病。最重要的潜在治疗方法之一 这些药物的目标领域是预防缺血性神经元损伤 中风或全脑缺血。然而，治疗 NMDA拮抗剂的开发受到了 苯环己哌啶（PCP）样的行为副作用，是由 NMDA通道阻滞剂如MK 801或竞争性NMDA拮抗剂 例如CPP或CGS 19755。为了制造NMDA的拮抗剂 没有不良行为副作用的受体， 本申请的研究者已经合成了一系列新颖的 具有高亲和性、选择性和拮抗性的喹喔啉二酮类似物 在NMDA受体的甘氨酸促凝剂位点的功效（ 甘氨酸/NMDA受体）。初步研究表明， 甘氨酸/NMDA拮抗剂-不同于以前可用的甘氨酸位点 拮抗剂--在全身给药后在体内具有有效活性。 此外，新的甘氨酸/NMDA拮抗剂被证明不含 两种动物模型中的PCP样行为副作用。本申请中 建议使用新发现的甘氨酸/NMDA拮抗剂作为 用于合成精心选择的类似物的先导化合物， 进行详细的结构/活动研究，以获得见解 进入可能的药效团，其赋予甘氨酸/NMDA拮抗剂 对喹喔啉二酮和相关化合物的有效性和选择性。 在 此外，建议合成[3 H]-标记的大多数 作为放射性配体用于结合测定的有效化合物。进一步 提出创建叠氮基衍生物作为潜在的光亲和标记物， NMDA受体的甘氨酸结合位点。这项工作预计将 导致发现了新的甘氨酸/NMDA拮抗剂，其在 全身给药后的体内活性和缺乏PCP样 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创建 甘氨酸/NMDA受体。新的对抗者应该是宝贵的工具， 在体内和体外研究和表征甘氨酸/NMDA受体。