ANTICONVULSANT BINDING SITES

抗惊厥药结合位点

• 批准号: 3407997
• 负责人: JOSE M MUSACCHIO
• 金额: $ 13.87万
• 依托单位: NEW YORK UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-02-15 至 1991-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3407997
• 关键词: anticonvulsants; autoradiography; brain disorder chemotherapy; chemical binding; combination chemotherapy; drug screening /evaluation; electrostimulus; epilepsy; guinea pigs; laboratory rat; phenytoin

Studies on the binding of (3H)dextromethorphan demonstrated that phenytoin (diphenylhydantoin, PHT) has a modulatory effect on the dextromethorphan binding sites and suggested that dextromethorphan could have anticonvulsant activity and enhance the pharmacologic activity of PHT. Pretreatment with dextromethorphan results in a dose-related blockage of the maximal electroshock seizure tonic hindlimb extension in the rat supramaximal electroshock test. Moreover, the simultaneous administration of subthreshold dose of dextromethorphan lowers the anticonvulsant ED50 of phenytoin three fold. It is possible that dextromethorphan used alone, or in combination with PHT, may prove to be a novel therapeutic agent for the treatment of epilepsy. We will search for other potential anticonvulsant drugs that bind to the dextromethorphan binding sites. We have recently found that carbetapentane and caramiphen, drugs that bind to the dextromethorphan sites are also anticonvulsant. We will further characterize the relationships between phenytoin and dextromethorphan binding sites by investigating the effects of known anticonvulsant agents, other drugs and toxins on the binding of tritiated dextromethorphan. To better understand the physiological significance of the dextromethorphan binding sites, we will determine their autoradiographic localization in the brain and we will explore the existence of endogenous ligands for the dextromethorphan and phenytoin binding sites. The allosteric interactions of phenytoin and dextromethorphan at their binding sites and the potentiation of its anticonvulsant effects suggest the existence of a novel cooperative mechanism by which drugs acting at two different but interacting sites exert their effects. This mechanism has marked similarities with the allosteric interactions between GABA and benzodiazepines, even though their binding sites are completely different. It is clear that the investigation of the molecular mechanism of the effects observed will help to open new approaches for the understanding of epilepsy and for the development of new, more effective and less toxic anticonvulsants.

对（3H）美沙芬结合的研究表明， 苯妥英（二苯基乙内酰脲，PHT）对 美沙芬结合位点，并表明美沙芬 可能具有抗惊厥活性并增强药理学作用 PHT的活性。 用美沙芬预处理导致 剂量相关性阻断最大电休克发作强直 在大鼠超最大电击试验中后肢伸展。 此外，同时给予阈下剂量的 美沙芬降低苯妥英三的抗惊厥ED 50 折 有可能是美沙芬单独使用，或 与PHT组合，可能被证明是一种新的治疗药物， 癫痫的治疗 我们将寻找其他潜在的抗惊厥药物， 到美沙芬结合位点 我们最近发现， carbetapentane和caramiphen，药物结合到 美沙芬部位也具有抗惊厥作用。 我们将进一步 描述苯妥英与 通过研究以下因素的影响， 已知的抗惊厥剂，其他药物和毒素的结合 氚化美沙芬 更好地了解 美沙芬结合位点的生理学意义， 我们将通过放射自显影确定它们在大脑中的位置 我们将探索内源性配体的存在， 美沙芬和苯妥英结合位点。 苯妥英钠和美沙芬的别构相互作用 它们的结合位点及其抗惊厥作用的增强 影响表明存在一种新的合作机制， 药物作用于两个不同但相互作用的部位， 他们的影响。 这一机制与 GABA和苯二氮卓类药物之间的变构相互作用， 尽管它们的结合位点完全不同 显然 对这些效应的分子机制的研究 观察将有助于开辟新的途径，了解 癫痫和发展新的，更有效，更少 有毒的抗惊厥药