Anxiolytic 2,3-benzodiazepines, their specific binding to the basal ganglia

Over the past 20 years, several members of the 2,3-benzodiazepine family have been synthesized. Some of these compounds--tofisopam (Grandaxin), girisopam, nerisopam--exert significant anxiolytic and antipsychotic activities. Sites where actions of 2,3-benzodiazepines are mediated differ from those of 1,4-benzodiazepines. Binding of 2,3-benzodiazepines to neuronal cells in the central nervous system shows a unique and specific distribution pattern: their binding sites are located exclusively to the basal ganglia. Chemical lesioning of the striato-pallido-nigral system, surgical transections of the striato nigral pathway and the activation of c-fos expression in the basal ganglia after application of 2,3-benzodiazepines suggest that these compounds mainly bind to projecting neurons of the striatum. The binding sites are transported from the striatum to the substantia nigra and the entopeduncular nucleus. Recent studies on mechanism of action of 2,3-benzodiazepines indicate their possible role in opioid signal transduction since 2,3-benzodiazepines augment the agonist potency of morphine to induce catalepsy and analgesia, and their action is diminished in morphine tolerant animals. The possible biochemical target of 2,3-benzodiazepines is an alteration in the phosphorylation of protein(s) important in the signal transduction process. Agents affecting emotional responses evoked by endogenous opioids without danger of tolerance and dependence may represent a new therapeutic tool in the treatment of addiction and affective disorders.