Benzodiazepines, the Story of the Antagonist Flumazenil and of the Partial Agonist Bretazenil

Abstract

The story of flumazenil and bretazenil is a typical example of a serendipitious drug discovery. In 1979 benzodiazepine antagonists were unknown. No one was looking for them, but they were discovered nevertheless. Ro 15-1788 was selected for clinical trial. Today 'this compound has the generic name flumazenil, the trade name Anexate, and is registered in 70 countries. It is the first specific benzodiazepine receptor antagonist for clinical use. Minor structural modifications of benzodiazepine antagonists led to partial agonists, compounds with powerful anxiolytic and anticonvulsant properties. Compared with full agonists they have markedly reduced sedative and alcohol-potentiating effects. Bretazenil is in clinical trial; it exhibits promising anxiolytic activity especially in patients with panic attacks. In open clinical studies it has shown remarkable antipsychotic activity. Structure-activity relationships and spin-offs are discussed.