NONCOMPETITIVE NMDA RECEPTOR ANTAGONISTS

非竞争性 NMDA 受体拮抗剂

• 批准号: 3504311
• 负责人: JOHN W FERKANY
• 金额: $ 4.59万
• 依托单位: NOVA PHARMACEUTICAL CORPORATION
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-07-01 至 1989-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3504311
• 关键词: PCP receptor; anticonvulsants; aspartate; cerebral ischemia /hypoxia; drug adverse effect; epilepsy; gerbil /jird; glutamate receptor; inhibitor /antagonist; laboratory mouse; laboratory rat; nervous system disorder chemotherapy; neural degeneration; neuropharmacology; neurotransmitters

Substantial evidence indicates that excitatory amino acid (EAA) neurotransmission plays a role in the pathophysiology of epilepsy, neurodegenerative disorders and the neuronal damage that occurs following hypoxic or ischemic CNS insult. Of the three recognized EAA recognized EAA receptor subtypes (quisqualate, kainate and N- methyl-D-aspartate: NMDA), animal experiments clearly indicate that NMDA antagonists may provide an effective prophylactic, symptomatic or ameliorative approach to treatment of these disorders. Subclasses of NMDA receptors are thought to exist in brain. Furthermore, some NMDA receptors may be linked to the site of action of dissociative anesthetics since agents including phencyclidine (PCP) ketamine, dextrorphan, dexoxadrol and MK801 noncompetitively antagonize NMDA receptor-mediated responses. Notably, many of these compounds are potent anti-convulsants and have been shown to prevent ischemic and hypoxic damage to brain. Known competitive NMDA antagonists are polar compounds which penetrate poorly to brain. Conversely, noncompetitive antagonists are highly lipophilic, but often elicit PCP-like psychotomimetic responses making them unsuitable for chronic administration. Recent evidence suggests it may be possible to separate the beneficial properties from the psychotomimetic side-effect liabilities of noncompetitive antagonists. Building upon a unique series of compounds already identified by NOVA to interact with PCP recognition sites in brain, the current Phase 1 proposal seeks funds for further medicinal chemical efforts and advanced evaluation of the behavioral effects of this series. Testing will include determination of the anticonvulsant and neuroprotective properties of these agents as well as the potential side-effect liabilities using drug discrimination paradigms. Compounds identified as having the desired pharmacological properties would be further evaluated in a Phase II application as potential IND candidates.

大量证据表明，兴奋性氨基酸（EAA） 神经传递在癫痫的病理生理学中起作用， 神经退行性疾病和神经元损伤 缺氧或缺血性CNS损伤后。 在三个公认的 EAA识别EAA受体亚型（使君子酸，红藻氨酸和N- 甲基-D-天冬氨酸：NMDA），动物实验清楚地表明， NMDA拮抗剂可提供有效的预防、对症 或改善方法来治疗这些病症。 NMDA受体的亚类被认为存在于大脑中。 此外，一些NMDA受体可能连接到 解离性麻醉剂的作用，因为药剂包括 苯环己哌啶（PCP）氯胺酮、右啡烷、右沙卓醇和MK 801 非竞争性拮抗NMDA受体介导的反应。 值得注意的是，这些化合物中的许多是有效的抗惊厥剂， 已被证明可以预防大脑缺血和缺氧损伤。 已知的竞争性NMDA拮抗剂是极性化合物， 对大脑的渗透性差。 相反，非竞争性拮抗剂 具有高度亲脂性，但通常会引发PCP样精神病模拟剂 反应使其不适合长期给药。 最近的证据表明，有可能将 从拟精神病药的副作用中获益 非竞争对手的责任。 基于一系列独特的化合物， NOVA与大脑中的PCP识别位点相互作用， 第1阶段提案为进一步的药用化学品工作寻求资金 以及对这一系列行为影响的高级评估。 测试将包括抗惊厥药的测定， 这些药物的神经保护特性以及潜在的 使用药物歧视范例的副作用责任。 被鉴定为具有所需药理作用的化合物 性能将在第二阶段应用中进一步评估， 潜在的IND候选人。