The story of flumazenil

The story of flumazenil is a typical example of a serendipitous preclinical drug discovery. Our search for specific benzodiazepine receptor (BZR) blockers in the early seventies, based on a hypothetical explanation of acute tolerance to diazepam, was unsuccessful. However, we discovered such compounds in 1979 in a programme aimed at more selective anxiolytics within a series of imidazobenzodiazepinones. Synthetic and pharmacological investigations of benzodiazepinones (BZ) are reviewed here. The discovery of flumazenil confirmed the mechanism of action of BZs through specific BZRs. It also demonstrated the feasibility of obtaining BZR ligands covering a broad spectrum of intrinsic efficacies, from full agonists, partial agonists, antagonists, partial inverse agonists to full inverse agonists.