Discovery of Diazepam

Discovery of Diazepam

Diazepam is a drug belonging to the family of compounds known as benzodiazepines. These drugs are primarily used in the treatment of anxiety, alcohol withdrawal and occasionally sleep disorders. Originally released in 1963, diazepam (in addition to other benzodiazepines) was a revolutionary compound for its targeted symptoms and that was reflected in the fact that it was the most sold drug between the years of 1968 to 1982 in the US (Calcaterra and Barrow). The compounds origins are traced back to synthetic sources, however, multiple studies have shown it to possibly be a natural product found in humans and plants (Fischer).

Although diazepam was not the first benzodiazepine discovered, the initial synthesis of this class of compounds is fascinating and equally important as the discovery of diazepam itself. Benzodiazepines were discovered almost by complete accident by the pharmacist Leo Sternbach. Originally, Sternbach developed the compounds for the purpose of researching synthetic dyes in the 1930s. Two decades later, Sternbach revisited the benzodiazepine compounds (which he originally believed to be heptoxdiazines) in “the hope of finding compounds with psychopharmacological activity” (Ban 340). He chose to stabilize one of these compounds and placed it on a shelf in the laboratory. Sometime later this compound was found while the lab was being cleaned and was shown to exhibit similar properties of the leading anxiolytic compound at the time. In 1960, this compound was released as chlordiazepoxide (Librium). This benzodiazepine was quickly improved upon and in 1963 diazepam was released under the name Valium by Hoffmann-La Roche (Ban 340).

Diazepam targets the γ-aminobutyric type A (GABA_A) receptor. When it binds to the GABA_A receptor, it acts a positive allosteric modulator. This means that instead of affecting the function of the protein that it binds to, it rather “increases neuronal chloride-ion influx upon Gaba binding… thus enhancing CNS depression response” (Calcaterra and Barrow). This increased CNS depression response is what triggers the calming effect of diazepam. Once in the body, a large portion of the initial dosage is circulated and allowed to bind to GABA_A receptors making it a bioavailable compound – typically in the range of 93-100% (Calcaterra and Barrow). Wide therapeutic indexes is also an important property of diazepam as the previous generation of anxiolytic drugs, primarily meprobamate, was narrow in its treatment.

Diazepam has been proven to create adverse respiratory affects when administered intravenously as well as when rectal diazepam is given in the case of a seizure (Aronson). It has also been associated with self-aggressive behavior and impairment of motor functions at higher doses. Despite this, adverse effects “are most often a consequence of interaction with another drug (such as opiates or alcohol)” (Calcaterra and Barrow). Diazepam has historically been linked to abuse and dependence and as a result is often linked do addiction.

            Although dependence that results from chronic use of diazepam is not something that likely can be improved upon, its tendency to react with other drugs is perhaps something that can. As benzodiazepines are a relatively old class of compounds, I find the most compelling pathway for future refinement to be searching in new types of compounds for similar, equal calming effects. Perhaps this is the case with the newer, similar drug zolpidem (Ambien).

Bibliography

Aronson, Dr. Jeffrey. “Diazepam.” Meyler's Side Effects of Drugs, 16th ed., Elsevier B.V., 2016, pp. 930–937.

Ban, Thomas MD. “The Role of Serendipity in Drug Discovery.” Dialogues in Clinical Neuroscience, vol. 8, no. 3, Sept. 2006, pp. 335–344.

Calcaterra, Nicholas E., and James C. Barrow. “Classics in Chemical Neuroscience: Diazepam (Valium).” ACS Chemical Neuroscience 5.4 (2014): 253–260. PMC. Web. 25 Sept. 2018.

Fischer, Dr. Margarete. “Occurrence of ‘Natural’ Benzodiazepines.” Life Science, vol. 48, no. 3, 1991, pp. 209–215.