EXCITATORY AMINO ACID ANTAGONISTS AS ANTIEPILEPTIC DRUGS

我们在建立药物发现和开发计划方面寻求援助 导致了治疗癫痫的新的和改进的药物。尽管有 目前美国使用的16种主要类型的抗癫痫药物， 没有一种被证明是完全有效的，而且许多最常见的 处方化合物会产生显著和普遍的不良反应 效果。在NIN.C.D.S和其他地方普遍认为 临床上需要新的、更有选择性和更有效的 抗癫痫药。最近的一卷基础研究表明 癫痫可能是由过量引发的神经退行性变过程 用后续细胞刺激海马神经元或颞叶神经元 死亡。作用于特定受体位置的兴奋性氨基酸已经被 与这一过程有关，包括“内源性脑兴奋性毒素”，如 就是喹啉酸。作为一种或多种特定拮抗剂的药物 兴奋性氨基酸受体的不同亚型可能是有希望的 作为有用和有效的抗癫痫药物。一种这样的化合物， (-)-2-氨基-7-膦庚酸(-APH)已被证明 在动物实验中具有显著的抗惊厥活性。我们建议 制定一项计划以开发和筛选APH类似物以实现 提高药效和口服疗效，最终导致临床试验 一种铅化合物。总体而言，我们的计划将包括化学物质 结合和生化在受体水平上的合成、筛选 实验(与体内简单活动性相关 抗惊厥筛选)，然后是更详细的受体 放射自显影分析，单单位电生理学和脑电研究， 有前景的先导化合物。随后，常规毒理学和 将进行生物利用度测定。最初的资金是 要求建立相关的受体、生化和行为 -APH等系列兴奋性氨基酸拮抗剂活性的筛选 将由我们合成的类似物。

We seek assistance in setting up a drug discovery and development program leading to new and improved drugs to treat epilepsy. Although there are currently 16 major types of antiepileptic medications in use in the U.S., none has proven completely effective, and many of the most commonly prescribed compounds give rise to significant and prevalent adverse side effects. It is generally recognized at the N.I.N.C.D.S. and elsewhere that there is a clinical need for new, more selective and effective, anti-epileptic agents. A volume of recent basic research indicates that epilepsy may be a neurodegenerative process precipitated by excessive stimulation of hippocampal or temporal lobe neurons, with subsequent cell death. Excitatory amino acids acting at specific receptor sites have been implicated in this process, including "endogenous brain excitotoxins," such as quinolinic acid. Drugs acting as specific antagonists at one or more of the distinct subtypes of excitatory amino acid receptors may hold promise as useful and efficacious anti-epileptic agents. One such compound, (-)-2-amino-7-phosphonoheptanoic acid (-APH) has already been shown to possess significant anti-convulsant activity in animal tests. We propose to institute a program to develop and screen APH analogues to achieve increased potency and oral efficacy, leading ultimately to clinical trials of a lead compound. Overall, our program will consist of chemical synthesis, screening at the receptor level in binding and biochemical experiments (to be correlated with activity in simple in vivo anticonvulsant screens), followed by more detailed receptor autoradiographic analysis, single unit electrophysiology, and EEG studies, with promising lead compounds. Subsequently, routine toxicologic and bioavailability determinations would be undertaken. Initial funding is requested to establish the correlative receptor, biochemical and behavioral screens for excitatory amino acid antagonist activity in -APH and a series of analogues to be synthesized by us.