Benzodiazepines

   , A CLASS OF ANTIANXIETY DRUGS (from 1960). Stimulated by the success of such drugs as chlorpromazine in the mid-1950s, the branch of the Hoffmann La Roche company in Nutley, New Jersey, asked chemist Leo Sternbach (1908–) to lead the search for other innovative compounds. Born in Abbazia on the Istrian Peninsula, then part of Austria, Sternbach had been working for Roche in Basel when the Second World War began, and the company sent him and other Jewish scientists to their American branch for safety. In Nutley, as a group chief in organic chemistry, in 1955 he created the chemical class of benzodiazepines, the first of which, chlordiazepoxide—a so-called 1,4 benzo because of nitrogen atoms at positions 1 and 4 on the diazepine ring—was patented in 1959 and marketed as Librium in 1960. The "benzos," or "BZDs," were a highly successful drug class because they acted effectively on anxiety, mixed anxiety–depression, and other conditions while at the same time being comparatively safe. Although they were later taxed with addictiveness, it remains unclear how addictive they were compared to other related classes of psychoactive compounds.

   In 1963, Roche launched the benzodiazepine that was to become by the late 1960s the then most successful drug in pharmaceutical history: Valium (generic name, diazepam). Diazepam was ultimately marketed worldwide under some 87 different brand names and figured as "mother’s little helper" in a song by Mick Jagger of the Rolling Stones. By 1971, Librium and Valium accounted for $200 million of Roche’s $280 million in sales in the United States, and Fortune magazine was calling the two drugs "the greatest commercial successes in the history of prescription drugs." By 1977, about 8000 tons of benzodiazepines were being consumed annually in the United States.

   Among other popular benzodiazepines, on the basis of year patented (year of marketing refers to the United States), were the following:

   ♣ 1963: flurazepam (marketed by Roche as Dalmane in 1970)

   ♣ 1963: lorazepam (marketed by Wyeth as Ativan in 1977)

   ♣ 1963: flunitrazepam (marketed by Roche as Roipnol in Italy in 1976; not licensed in the United States)

   ♣ 1964: clonazepam (marketed by Roche as Clonopin in 1975)

   ♣ 1965: temazepam (marketed by Sandoz as Restoril in 1981)

   ♣ 1965: oxazepam (marketed by Wyeth as Serax in 1965)

   ♣ 1970: triazolam (marketed by Upjohn as Halcion in 1982)

   ♣ 1970: alprazolam (marketed by Upjohn as Xanax in 1981)

   In April 1977, Richard F. Squires (1933–), a scientist at A/S Ferrosan Research Laboratories in Soeborg, Denmark, aided by Claus Braestrup (1945–), then a Ph.D. student on work-study at Ferrosan, announced in Nature that they had evidence for the existence of a single binding site on brain membranes (a receptor) for diazepam. This initial discovery of a benzodiazepine receptor was followed later that year, in November, by a similar find of Hanns Möhler (1940–), a biochemist at Roche in Basel and lecturer in nearby Freiburg University, and Toshikazu Okada, a pharmacologist at Nippon-Roche Research Center, Kamakura City, Japan (see their report in Science). Locating a specific site of action for the benzos helped to explain the mechanism of action of these drugs.

   By the 1990s, there were more than a hundred different benzodiazepines on world markets. In retrospect, the benzodiazepines were one of the safest and most efficacious drug classes in the history of psychopharmacology. They virtually drove the barbiturates from the field as the hypnotics and sedatives of choice.