Allosteric modulation of dextromethorphan binding sites

Abstract

The nonopioid antitussives dextromethorphan (DM), carbetapentane and caramiphen are efficacious anticonvulsant agents in the rat MES test. The findings presented strongly suggest the existence of a novel allosteric mechanism by which drugs acting at two different but interacting sites, exert their effects. This mechanism has marked similarities with the gamma-aminobutyric acid (GABA)-benzodiazepine interactions, even though their binding sites are different. The allosteric interactions of dextromethorphan and phenytoin in the binding assay and the potentiation of the anticonvulsant effects of phenytoin by dextromethorphan suggest that drugs that bind to the dextromethorphan sites could be used to reduce the effective dose of phenytoin and reduce its side effects, at least those which are not an extension of its specific pharmacological actions. It is evident that the investigation of the molecular mechanisms described may help to open new approaches to understand and treat convulsive disorders, to find novel anticonvulsant drugs and to further explain some of the molecular mechanisms of neuronal excitability.