NONCOMPETITIVE NMDA RECEPTOR ANTAGONISTS

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着作用， 神经退行性疾病及其引起的神经元损伤 在缺氧性或缺血性中枢神经系统损伤后。在三个公认的 EAA识别的EAA受体亚型(QuisQualate、Kainate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性、症状性 或改善这些疾病的治疗方法。 NMDA受体亚类被认为存在于大脑中。 此外，一些NMDA受体可能与 解离麻醉剂的作用，因为药物包括 苯环利定(PCP)氯胺酮、右美沙芬、右旋糖醇和MK801 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都是有效的抗惊厥药物和 已被证明可以预防脑缺血和缺氧性损伤。 已知的竞争性NMDA拮抗剂是极性化合物， 对大脑的穿透性差。相反，非竞争性对手 是高度亲脂性的，但通常会引发类似PCP的精神分裂 这些反应使它们不适合长期给药。 最近的证据表明，有可能将 来自拟精神分裂副作用的有益特性 非竞争性对手的责任。 以一系列独特的化合物为基础，这些化合物已经由 Nova将与大脑中的PCP识别位点相互作用，目前 第一阶段提案寻求进一步药用化学品努力的资金 并对这一系列的行为影响进行高级评估。 测试将包括测定抗惊厥剂和 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。 经鉴定具有所需药理作用的化合物 属性将在第二阶段应用程序中进一步评估为 潜在的IND候选人。

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.