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

Over the past 20 years, several members of the 2,3-benzodiazepine family ha ve been synthesized, Some of these compounds-tofisopam (Grandaxin(R)), giri sopam, nerisopam-exert significant anxiolytic and antipsychotic activities. Sites where actions of 2,3-benzodiazepines ale mediated differ from those of 1,4-benzodiazepines. Binding of 2,3-benzodiazepines to neuronal cells in the central nervous sys tem shows a unique and specific distribution pattern: their binding sites a re located exclusively to the basal ganglia. Chemical lesioning of the striato-pallido-nigral system, surgical transecti ons of the striato-nigral pathway and the activation of c-fos expression in the basal ganglia after application of 2,3-benzodiazepines suggest that th ese compounds mainly bind to projecting neurons of the striatum. The bindin g sites are transported from the striatum to the substantia nigra and the e ntopeduncular nucleus. Recent studies on mechanism of action of 2,3-benzodiazepines indicate their possible role in opioid signal transduction since 2,3-benzodiazepines augm ent 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 proc ess. Agents affecting emotional responses evoked by endogenous opioids without d anger of tolerance and dependence may represent a new therapeutic tool in t he treatment of addiction and affective disorders. (C) 2000 Elsevier Scienc e Ltd. All rights reserved.