50 Mephenesin was an old drug; it was first, produced by the condensation of ocresol with glycerine by Zivkovic in 1908. Berger moved to the United States in 1948, and in the same year mephenesin was released for clinical use for muscular relaxation during light anesthesia, under the trade name Tolserol by

E. R. Squibb. The drug was already in clinical use when it, was recognized that it, could relieve anxiety Inhibitors,research,lifescience,medical and tension. However, mephenesin had serious drawbacks, eg, short, duration of action and greater effect on the spinal cord than on supraspinal structures. To overcome these disadvantages, Berger succeeded in initiating a program that yielded the synthesis of meprobamate, or 2-methyl-2-n-propyl-l,3-propanediol dicarbamate, by B. J. Ludwig, at the Wallace Inhibitors,research,lifescience,medical Laboratories of Carter Products, in May 1950.48,51 The duration of action of the new drug was about eight times longer than that of the parent, substance. Similar to mephenesin, pharmacologically meprobamate was a tranquilizer. It depressed multineuronal reflexes without significantly affecting monosynaptic Inhibitors,research,lifescience,medical reflexes; counteracted pentylenetetrazol-induced convulsions, and produced a loss of the righting reflex in mice without causing significant excitement prior to the onset of the

paralysis. In the spring of 1955 Lowell Selling was first to report on Inhibitors,research,lifescience,medical the therapeutic effect of meprobamate in anxiety and tension states. A few months later, in the summer of 1955, meprobamate was introduced into clinical use by Wallace Laboratories with the brand name of M’iltown,the name of the small community in New

Jersey where Berger lived at, the time,52 Inhibitors,research,lifescience,medical and by Wyeth Laboratories with the brand name of Equanil.51 By the late 1950s meprobamate was the most widely used prescription drug in the United States and in many other countries. It retained its lead until the late 1960s when it succumbed to diazepam, the second drug from the benzodiazepine series introduced into clinical use.48,53 Chlordiazepoxide The synthesis of benzodiazepines is linked to the name of Leo Sternbach, a pharmacist and chemist, working Rutecarpine at Hoffmann-La Roche’s P505-15 cell line research facility at Nutley, New Jersey (USA). In the early 1930s Sternbach was a postgraduate student at the Jagellonian University in Cracow, Poland, and synthesized several, heptoxdiazine compounds in an effort to develop synthetic dyes. In 1954, inspired by the phenomenal success of chlorpromazine and early reports on meprobamate, he resumed his research with heptoxdiazines with the hope of finding compounds with psychopharmacological activity.54 In the course of this research he recognized that the drugs he perceived in the 1930s as heptoxdiazines were benzoxadiazepines, and synthesized about 40 benzoxadiazepine compounds.