Monday, October 22, 2018

Fluoxetine


                                        

Fluoxetine

by John Lyons  

Before plunging into the breakthrough drug – fluoxetine – it is important to address the history of antidepressants. In the 1960s and 1970s, treating depression began with inhibiting monoamine oxidase (MAO) or noradrenaline (NA) through selective serotonin reuptake inhibitors (SSRIs). Tricyclic antidepressant drugs (TCAs), such as imipramine, inhibited the reuptake of these neurotransmitters, causing them to build up in the synaptic cleft. Most importantly, it was discovered that compounds like imipramine inhibited 5-HT (5-hydroxytryptamine) more than NA, which is associated with mood-elevating action.

Fluoxetine, like TCAs, is an SSRI, which means it targets the 5-HT transporter. Uniquely, fluoxetine specifically targets 5-HT and not other neurotransmitters. 5-HT is synthesized from tryptophan. First, tryptophan is catalyzed by tryptophan hydroxylase into 5-HTP, and aromatic amino acid decarboxylase (AADC) then catalyzes 5-HTP into 5-HT. Through exocytosis, the neuron expels 5-HT into the synaptic cleft, and 5-HT activates receptors on the postsynaptic neuron to initiate as well as continue signal transduction. Fluoxetine blocks the transporter that allows 5-HT back into the presynaptic neuron1.

Fluoxetine is a synthetic compound belonging to the phenoxyphenylpropylamine (PPPA) family. The discovery of fluoxetine began with Molloy and Rathbun in 1970. Molloy and Rathbun aspired to find a drug similar to TCAs, without the cardiovascular and anticholinergic adverse effects. They designed a test scheme where TCAs acted as antagonists in the reversal of apomorphine-induced hypothermia in mice. At the time, it was known that diphenhydramine inhibited monoamine uptake and antagonized histamine receptors. Therefore, derivatives of diphenhydramine were synthesized and tested for the ability to reverse the apomorphine-induced hypothermia. LY86032 was discovered to effectively antagonize apomorphine hypothermia. Further analysis led to the discovery of nisoxetine hydrochloride, which added a methoxy group to the ortho position on one of the rings. Finally, fluoxetine was identified when a trifluoride group was added para in the ring, while removing the ortho-methoxy group1.

The primary therapeutic use for fluoxetine, as previously mentioned, is to treat depression. Because 5-HT is present in brain tissue, fluoxetine is effective at treating other psychological diseases.  Such diseases include “anorexia nervosa, bulimia nervosa, obsessive–compulsive disorder, panic disorder, premenstrual dysphoria and generalized anxiety disorder.”1 Like any other medication, fluoxetine also has side effects. The most common adverse effects (10-25% of patients) are nausea, insomnia, headache, anxiety, tremor, sweating, drowsiness, diarrhea, and dry mouth2.

During my research, I was highly interested in how they developed fluoxetine from diphenhydramine. I learned in organic chemistry that minute changes in a molecule can have drastic effects on its properties. Having the trifluoride group in the para position greatly enhanced inhibition of 5-HT reuptake, instead of a methoxy group in the para or ortho positions, or having the trifluoride in the ortho or meta positions. This seems to be a good place to start for future modification – there’s no need to reinvent the wheel if one can yield a variety of results through small changes in molecular structure.

Works Cited

1.   Wong, David T., Kenneth W. Perry, Frank P. Bymaster. “The Discovery of Fluoxetine                                   Hydrochloride (Prozac)”. Nature Publishing Group, vol. 4, 2005, pp. 764-774,                                     http://www.nature.com.ezproxy.uky.edu/articles/nrd1821
2.   Aronson, J.K. “Meyler’s Side Effects of Drugs, the International Encyclopedia of Adverse Drug                   Reactions and Interactions.” Elsevier Science, 2015, pp. 395-401, https://www-clinicalkey-                 com.ezproxy.uky.edu/#!/content/book/3-s2.0-B9780444537171007629

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