ANTICONVULSANT BINDING SITES

对(~3H)右美沙芬结合作用的研究表明 苯妥英(二苯基海因，PHT)对血管内皮细胞的 右美沙芬的结合部位，并提示右美沙芬 具有抗惊厥作用，增强药理作用 PHT活性。右美沙芬的预处理可导致 剂量依赖性阻断最大电休克惊厥强直的作用 大鼠超极大电击试验中的后肢伸展。 此外，亚阈值剂量的同时给药 右美沙芬降低苯妥英三号的抗惊厥药ED50 收牌。有可能右美沙芬单独使用，或在 与PHT联合使用，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来结合 到右美沙芬结合部位。我们最近发现， 卡倍他丁和卡拉米芬，这两种药物与 右美沙芬部位也有抗惊厥作用。我们将进一步 描述苯妥英钠和苯妥英之间的关系 右美沙芬结合位点的研究 已知的抗惊厥药物、其他药物和毒素上的结合 氚化右美沙芬。为了更好地理解 右美沙芬结合部位的生理意义， 我们将确定它们在大脑中的放射自显影定位 我们将探索内源性配体的存在 右美沙芬和苯妥英结合部位。 苯妥英与右美沙芬的变构相互作用 它们的结合部位及其抗惊厥剂的增强作用 结果表明，存在一种新的合作机制，通过 在两个不同但相互作用的部位作用的药物 他们的影响。这种机制与 GABA与苯二氮卓类药物的变构相互作用 尽管它们的结合部位完全不同。很明显 对这种影响的分子机制的研究 观察将有助于开辟新的方法来理解 而对于癫痫的发展，新的，更有效，更少 有毒的抗惊厥药。

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.