SYNTHETIC NEUROPROTECTIVE GLUTAMATE RELEASE BLOCKERS

合成神经保护谷氨酸释放阻滞剂

• 批准号: 3509292
• 负责人: STANLEY M GOLDIN
• 金额: $ 25万
• 依托单位: CAMBRIDGE NEUROSCIENCE
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-12-17 至 1995-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3509292
• 关键词: NMDA receptors; aminoacid inhibitor; calcium channel; calcium channel blockers; cerebral ischemia /hypoxia; chemical models; chemical structure function; chemical substitution; conformation; drug design /synthesis /production; drug interactions; drug screening /evaluation; electrophysiology; gerbil /jird; glutamates; guanidines; laboratory rat; molecular biology; neuropharmacology; neuroprotectants; neurotransmitter transport; sodium channel; voltage /patch clamp; voltage gated channel

Brain damage in stroke and in cardiac arrest results from an inadequate supply of blood to the brain, termed brain ischemia. Brain ischemia depletes the energy stores of affected brain regions and causes the excessive release of glutamate and other neurotransmitters from metabolically compromised nerve terminals. Our goal is to discover synthetic, selective antagonists of the ion channels controlling the release of glutamate and other neurotransmitters. Such compounds may be employed as drugs to limit brain damage in focal ischemia (stroke) and global ischemia (resulting from cardiac arrest or complications of cardiac surgery). Using novel drug discovery methology based on a proprietary method for monitoring neurotransmitter release from brain nerve terminals, we have developed a novel compound series of synthetic glutamate release blockers, members of which are highly neuroprotective in an animal model of brain ischemia. During Phase II, we hope to incorporate rational drug design strategies resulting from knowledge on the structure of the site of interaction of these neuroprotective compounds with its ion channel targets. Candidates for drug development are likely to emerge from the Phase II project period, and selection of such candidates is the central goal of the project.

中风和心脏骤停时的脑损伤是由于药物不足造成的 血液供应到大脑，称为脑缺血。脑缺血 耗尽受影响大脑区域的能量储存，并导致 谷氨酸和其他神经递质的过度释放 新陈代谢受损的神经末梢。我们的目标是发现 合成的、选择性的控制离子通道的拮抗剂 释放谷氨酸和其他神经递质。这种化合物可能是 用作限制局灶性缺血(中风)和脑损伤的药物 全脑缺血(由心脏骤停或并发症引起 心脏手术)。使用新的药物发现方法学基于 监测大脑神经递质释放的专有方法 神经末梢，我们开发了一系列新颖的化合物合成 谷氨酸释放阻滞剂，其成员具有高度的神经保护作用 在一个脑缺血的动物模型中。在第二阶段，我们希望 纳入合理的药物设计策略，这些策略源于对 这些神经保护作用的相互作用部位的结构 与其离子通道靶标的化合物。药物开发的候选对象 可能会在第二阶段项目期出现，并选择 这样的候选人是该项目的中心目标。