Historical complement concerning amino acid transmitters
This complement indicates the chronology of discovery of drugs acting through GABA and glutamate.
Barbiturates, phenobarbital
Many barbiturates, derived from malonylurea, were marketed as hypnotic. The first released on market in 1903 was diethylmalonylurea, also called barbital, followed a few years later by phenobarbital, called Gardenal * and other derivatives (patents deposited by Bayer in Germany). The only barbiturate (if one rules out sulfur derivatives used in general anesthesia) still available, not as hypnotic but as antiepileptic, is phenobarbital or Gardenal *.
Carbamates, meprobamate
Meprobamate is a carbamate, discovered in the USA , whose patent deposit goes back to 1950s, it was released as a tranquilizer. Meprobamate was different from barbiturates by the fact that it exerted a tranquillizing action, called now anxiolytic, with doses which did not produce a true sleep.
Benzodiazepines, chlordiazepoxide
Chlordiazepoxide the first benzodiazepine, whose patents dates from the 1960s, was marketed under the name Librium *. It was followed, 4 or 5 years later by diazepam or Valium * and then by many other compounds, called benzodiazepines.
The only available antagonist of benzodiazepines as a drug is flumazenil, patented in the 1980s.
It should be noted that another anxiolytic, relatively little used and which does not act via GABA, buspirone, is known since 1972.
Valproic acid
The antiepileptic effect of valproic acid, also called dipropylacetic acid or DPA, was discovered in the early 1960s at Pharmacy and Medicine School of Grenoble (France). Serendipity played an essential part in this discovery: indeed, valproic acid liquid product, was used in the laboratory to make soluble the molecules studied. It was the solvent, DPA, which was active.
Halothane
Halothane, first of the modern inhalational anesthetics, was introduced in therapeutics about 1965.
One can conclude that all these drugs, except perhaps flumazenil, were discovered from screening methods in animals, well before one knew their mode of action and their receptors! The better knowledge of receptors has not yet led to discovery of a higher quality of anxiolytic or hypnotic drugs.
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