Partial agonists of benzodiazepine receptors for the treatment of epilepsy, sleep, and anxiety disorders.

The classic benzodiazepines produce anxiolytic, anticonvulsant, sedative and myorelaxant effects at overlapping dose ranges. Efforts to reduce the sedative/myorelaxant component of this profile has a long history. Two rational approaches might theoretically lead to the desired drugs. One is based on the combination of partial (low efficacy) agonists of the benzodiazepine receptor with different receptor reserves in neurons subversing various functions. The other approach is based on the existence of GABAA-benzodiazepine receptor polymorphism and assumes that distinct receptor variants may be more prevalent on neurons involved in various CNS functions. Results are presented that were obtained with the partial agonist bretazenil and three other ligands in vitro as well as in vivo. Curves relating fractional receptor occupancy and various effects (potentiation of GABA-induced chloride flux, anticonvulsant, anticonflict and sedative effects) are fully consistent with the view that the particular profile of activity of bretazenil is the result of partial agonism. Comparison of fractional receptor occupancy required for the various effects of both full and partial agonists confirm earlier suggestions that receptor reserves for the individual effects differ with the same order. Clinical aspects of partial benzodiazepine receptor agonists are discussed on the basis of the preliminary information available to date.