EXCITATORY AMINO ACID ANTAGONISTS AS ANTIEPILEPTIC DRUGS

作为抗癫痫药物的兴奋性氨基酸拮抗剂

• 批准号: 3509110
• 负责人: JOHN W FERKANY
• 金额: $ 17.92万
• 依托单位: NOVA PHARMACEUTICAL CORPORATION
• 依托单位国家: 美国
• 财政年份: 1985
• 资助国家: 美国
• 起止时间: 1985-09-23 至 1987-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3509110
• 关键词: aminoacid analog; aminoacid inhibitor; aminophosphonate; anticonvulsants; autoradiography; chromatography; drug adverse effect; drug design /synthesis /production; drug metabolism; drug screening /evaluation; electroencephalography; electrophysiology; epilepsy; high performance liquid chromatography; histology; neurochemistry; neurotoxins; neurotransmitters; nontherapeutic iontophoresis; pharmacokinetics; single cell analysis; tissue /cell culture

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.

我们寻求援助，建立一个药物发现和开发计划， 从而产生治疗癫痫的新的和改进的药物。 虽然有 目前在美国使用的抗癫痫药物有16种， 没有一种被证明是完全有效的，许多最常见的 处方化合物引起显著和普遍的不利副作用 方面的影响. 这是公认的在N.I.N.C.D.S.和其他地方 临床上需要新的、更具选择性和有效的， 抗癫痫药。 最近的一项基础研究表明， 癫痫可能是一种神经退行性过程， 刺激海马或颞叶神经元，随后细胞 死亡 作用于特定受体位点的兴奋性氨基酸已被发现。 参与这一过程，包括“内源性脑兴奋毒素”， 如喹啉酸。 作为一种或多种特异性拮抗剂的药物 兴奋性氨基酸受体的不同亚型 作为有用和有效的抗癫痫剂。 一种这样的化合物， （-）-2-氨基-7-膦酰基庚酸（-APH）已经被证明 在动物试验中具有显著的抗惊厥活性。 我们提出 建立一个项目来开发和筛选APH类似物， 增加效力和口服效力，最终导致临床试验 一种铅化合物 总的来说，我们的计划将包括化学 在结合和生物化学中在受体水平上的合成、筛选 实验（与简单的体内活性相关 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EEG研究， 有前途的先导化合物 随后，常规毒理学和 将进行生物利用度测定。 初始资金为 要求建立相关的受体、生化和行为 筛选兴奋性氨基酸拮抗剂活性在-APH和一系列 类似物的合成。

项目成果

Pharmacological profile of NPC 12626, a novel, competitive N-methyl-D-aspartate receptor antagonist.

NPC 12626 的药理学概况，一种新型竞争性 N-甲基-D-天冬氨酸受体拮抗剂。

• 发表时间: 1989
• 期刊: The Journal of pharmacology and experimental therapeutics
• 作者: Ferkany,JW;Kyle,DJ;Willets,J;Rzeszotarski,WJ;Guzewska,ME;Ellenberger,SR;Jones,SM;Sacaan,AI;Snell,LD;Borosky,S
• 通讯作者: Borosky,S

Pharmacological profile of novel cyclic analogs of 2-amino-7-phosphonoheptanoic acid.

2-氨基-7-膦酰庚酸新型环状类似物的药理学概况。

• DOI: 10.1016/b978-0-444-89710-7.50033-1
• 发表时间: 1992
• 期刊: Epilepsy research. Supplement
• 作者: Ferkany,JW;Kyle,DJ;Ellenberger,WP;Narayanan,BA;Ellenberger,SR;Hudkins,R;Guzewska,ME;Rzeszotarski,WJ;Conti,L;Patch,R
• 通讯作者: Patch,R