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.
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