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
No comments:
Post a Comment