NONCOMPETITIVE AMPA ANTAGONISTS FOR STROKE

非竞争性 AMPA 拮抗剂治疗中风

• 批准号: 2868145
• 负责人: CHRISTOPHER S KONKOY
• 金额: $ 10万
• 依托单位: COCENSYS, INC.
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-06-15 至 1999-11-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2868145
• 关键词: AMPA receptors; Xenopus oocyte; cerebral ischemia /hypoxia; drug design /synthesis /production; drug screening /evaluation; electrophysiology; head /neck injury; inhibitor /antagonist; laboratory rat; neural degeneration; neuroprotectants; stroke; trauma

DESCRIPTION: (Verbatim from the Applicant's Abstract) The pharmaceutical treatment of stroke and head trauma has been an elusive goal. Recent studies suggest that blockade of the AMPA class of glutamate receptors may limit neuronal degeneration following stroke/neurotrauma by blocking the excitotoxic cascade ultimately leading to cell death. Noncompetitive AMPA receptor antagonists show promise as neuroprotective drugs, and one such compound, GYKI 52466, is active in animal models of stroke. Based on structural modification of GYKI 52466, the applicants have synthesized Co 200010 which they claim to be the most potent noncompetitive AMPA receptor antagonist reported to date. In Phase I we will test whether Co200010 reduces cortical infarct size in a rat transient focal ischemia model. We will synthesize 10-20 analogs of Co200010 to improve critical determinants of therapeutic utility including potency, water solubility and bioavailability. After evaluating these compounds for potency and bioavailability by electrophysiological and behavioral assays, we will choose one or two of the best analogs for further testing in the ischemia studies. In Phase II we will evaluate additional compounds, test potential development leads in additional stroke models. And identify the best two compounds as preclinical development candidates. The foal of this project is to discover a noncompetitive AMPA receptor antagonist for the treatment of stroke and head trauma. PROPOSED COMMERCIAL APPLICATION: NOT AVAILABLE

描述：（逐字来自申请人的摘要） 中风和头部创伤的治疗一直是难以实现的目标。最近的研究 表明AMPA类谷氨酸受体阻断可能限制 通过阻断兴奋性毒性作用，中风/神经创伤后神经元变性 最终导致细胞死亡。非竞争性AMPA受体 拮抗剂显示出作为神经保护药物的前景，并且一种这样的化合物GYKI 52466在中风动物模型中具有活性。基于结构修改 根据GYKI 52466的描述，申请人合成了Co 200010， 迄今为止报道的最有效的非竞争性AMPA受体拮抗剂。在 第一阶段，我们将测试Co200010是否减少大鼠皮质梗死面积 短暂局灶性脑缺血模型。我们将合成10-20种Co200010类似物， 改善治疗效用的关键决定因素，包括效力、水 溶解度和生物利用度。在评估这些化合物的效力后 和生物利用度的电生理和行为分析，我们将 选择一个或两个最好的类似物用于进一步的缺血试验 问题研究在第二阶段，我们将评估其他化合物，测试潜力， 开发导致了额外的中风模型。找出最好的两个 化合物作为临床前开发候选物。这个项目的目的是 发现一种用于治疗中风的非竞争性AMPA受体拮抗剂 和头部创伤 拟议商业应用：不可用