Depression, a condition of prolonged and disruptive melancholy, has long been termed a disease by psychiatrists and other medical professionals. While classic treatments have varied, in recent decades medication to alleviate many or all of the symptoms has become available to disease sufferers. While some of the earliest proven drugs are more than 50 years old, one of the first antidepressants designed by chemists to specifically treat depression is much newer and is chosen as this week's Molecule of the Week: fluoxetine hydrochloride, best known by the trade name Prozac.

Fluoxetine hydrochloride is a salt prepared from fluoxetine by treatment with hydrochloric acid (HCl). Figure 1 shows this conversion. Formation of the salt confers water solubility on an otherwise largely insoluble organic compound, an important characteristic of many pharmaceuticals.

Fluoxetine is remarkably simple for a drug molecule, with a molecular weight of only 345.8 and just one chiral center (note 1). Most noteworthy is the presence of a trio of fluorine atoms, something of an oddity in most organic molecules. A full, proper chemical name for fluoxetine is (±)-N-methyl-3-phenyl-3-[(α,α,α-trifluoro-p-tolyl)oxy]propylamine; the (±) merely means that the drug comes as a racemic mixture, that is, as both mirror images (enantiomers). Both enantiomers are known to be pharmacologically active.

While numerous small-scale preparations of fluoxetine have been reported (especially as a result of efforts to prepare enantiopure products), and industrial preparation of fluoxetine today no doubt includes processes that are trade secrets, the original fluoxetine patent (U.S. Patent 4,314,081) describes its preparation in the manner depicted in Figure 2.

While the strategy in Figure 2 may seem bewildering to students who have never studied organic chemistry, almost all the steps are routine transformations learned in any introductory organic course. The penultimate step, however, deserves further attention. The conversion of the dimethylamine to a so-called N-methyl cyanamide as shown is called the von Braun reaction and is not a commonly taught reaction. The mechanism of transformation inolves two nucleophilic substitutions, one by the amine and the other by bromide, as shown in Figure 3.

Fluoxetine hydrochloride is a member of the family of compounds known as SSRIs, or Selective Serotonin Reuptake Inhibitors, and while it is best known for its role in treating major depression it has been found useful in a variety of clinical applications. Developed by the pharmaceutical firm Eli Lilly (note 2), Prozac was approved by the FDA in 1987 for treatment of depression, and has since been used to treat obsessive-compulsive disorder, premenstrual dysphoric disorder, ADHD, and many other neurological disorders.

SSRIs, roughly, act to keep more of the neurotransmitter serotonin in the brain. It had been known for some time that increasing available serotonin had a calming effect and even led to euphoria. Biochemists had previously determined the general structure of molecules that inhibit the neuronal serotonin uptake pump, a protein responsible for decreasing the amount of available serotonin. Organic chemists then set about synthesizing a variety of such molecules for biological testing, and fluoxetine was one of the results. Hence the development of fluoxetine in the late 1970s and early 1980s represents one of the early successes of rational drug design, the process by which specific biochemical knowledge informs the development of novel pharmaceuticals from scratch.

Fluoxetine HCl is eliminated very slowly by the body, with the so-called R enantiomer degrading more rapidly than the S enantiomer. The liver metabolizes fluoxetine into norfluoxetine (fluoxetine lacking the N-methyl group), which is also a serotonin reuptake inhibitor.

When sold as Prozac fluoxetine is generally obtained in capsule form, as shown in Figure 4.