Classics in chemical neuroscience: diazepam (valium)

Abstract

Diazepam (Valium) is among the most successful drugs from the onset of the psychopharmacological revolution that began during the 1950s. Efficacious in treating a wide-spectrum of CNS disorders, including anxiety and epilepsy, it set the standard for pharmacotherapy in terms of potency, onset of action, and safety. In this Review, the legacy of diazepam to chemical neuroscience will be considered along with its synthesis, pharmacology, drug metabolism, adverse events and dependence, clinical use, and regulatory issues.

Figure 1

First marketed benzodiazepines and the classical sedative hypnotics.

Scheme 1. Several Routes to Diazepam Disclosed by Sternbach and Colleagues at Roche

Scheme 2. Metabolic Fate of Diazepam through the Principally Acting CYP 450 Enzymes, Predominately via Demethylation to 10 Followed by Hydroxylation

Notably, each major metabolite was developed and separately marketed.

Figure 2

Notable diazepam analogues and second generation compounds.