Fluoxetine enantiomers

Fig. 2-16. The effect of organic modifiers on the resolution of fluoxetine enantiomers on vancomycin CSP (250 X 4.6 mm). The flow rate was 1.0 mL min at ambient temperature (23 °C). (Courtesy of Scott Sharpe, Eli Lilly Co.)...

Guo, X., Fukushima, T., Li, F., Imai, K. (2002). Determination of fluoxetine enantiomers in rat plasma by precolumn fluorescence derivatization and column-switching high-performance liquid chromatography. Analyst 127, 480-484. 

Corey and Reichard described a more efficient synthesis of the fluoxetine enantiomers.This synthesis features a catalytic reduction of prochiral ketone 12 to install the correct absolute stereochemistry at C-3. In this respect this method is very similar to the one previously described by Robertson et However, the major... 

Many other methods utilizing a three-carbon-chain segment have been employed in the syntheses of the fluoxetine enantiomers. Chirality has been established by enzymatic reduction,lipase mediated enzymatic resolution, " oxidative kinetic... 

Scheme 3. Sharpless asymmetric epoxidation route to the fluoxetine enantiomers.

Example 4.18 Fluoxetine (Prozac) TM 4.15 is a well-known antidepressive, an inhibitor of serotonin uptake in the nerve cells. This chiral drug is introduced in therapy as a racemate since numerous biological and pharmacological studies have confirmed that the eudismic ratio for fluoxetine enantiomers is near unity. The eudismic ratio is the ratio of the biological activity of enantiomers, formerly denoted as eutomers (more active) and distomers, less active or inactive enantiomers. 

Zhou J, Yang Y, Wei F, Wu P (2007) Comparison of the performance of chiral stationary phase for separation of fluoxetine enantiomers. J Zhejiang Univ Sci B 8 56-59... 

FIGURE 5.8. Molecular structure of fluoxetine enantiomers. (Prozac is a registered trademark of Eli Lily and Company.)... 

Figure 5.5. Molecular structures of adrenaline enantiomers Figure 5.6. Molecular structures of thalidomide enantiomers Figure 5.7. Molecular structures of ibuprofen enantiomers Figure 5.8. Molecular structures of fluoxetine enantiomers...

Tomoxetine and fluoxetine are antidepressants. Both enantiomers of each compound can be prepared enantiospecifically starting from cinnamyl alcohol. Give a reaction sequence that will accomplish this objective. 

Since the introduction of the first approved SSRI, fluoxetine (1) in 1987 [9], a number of SSRIs have been developed for the treatment of depression [2], Currently, the five most commonly prescribed SSRIs are fluoxetine, escitalopram (2, S-enantiomer of citalopram), sertraline (3), paroxetine (4) and fluvoxamine (5). Recent effort in the clinical development of new SSRIs has focused on the treatment of premature ejaculation (PE) by taking advantage of the ejaculation-delaying side effects of SSRIs [10]. Although SSRIs have been prescribed off-label to treat this condition, an SSRI with rapid onset of action and rapid clearance could be preferred for on-demand treatment of PE [11,12]. Dapoxetine (LY210448, 6), an... 

Examples of specific methods important to neurochemists include separation and quantification of R- and S-fluoxetine and R- and S-norfluoxetine in brain tissue and body fluids using derivatization with (—)-(S)-N-(trifluoracetyl)prolyl chloride, a chiral derivatizing agent (Torok-Both et al., 1992 Aspeslet et al., 1994). A similar method has been used to separate the enantiomers of 3,4-methylenedioxyamphetamine (MDA) and 3,4-methylenedioxymethamphetamine (MDMA) (Hegadoren et al., 1993). Eluoxetine and norfluoxetine enantiomers have also been separated on a chiral column in series with a nonchiral column with NPD detections (Ulrich, 2003). Reviews of the analysis of enantiomers of several drugs of abuse are available (Jirovsky et al., 1998 Tao and Zeng, 2002 Liu and Liu, 2002). 

Aspeslet LJ, Baker GB, Coutts RT, Torok-Both GA. 1994. The effects of desipramine and iprindole on levels of enantiomers of fluoxetine in rat brain and urine. Ghirality 6 86. 

Torok-Both GA, Baker GB, Coutts RT, McKenna KF, Aspeslet LJ. 1992. Simultaneous determination of fluoxetine and norfluoxetine enantiomers in biological samples by gas chromatography with electron-capture detection. J Chromatogr B Biomed Appl 579 99. 

Ulrich S. 2003. Direct stereoselective assay of fluoxetine and norfluoxetine enantiomers in human plasma or serum by two-dimensional gas-liquid chromatography with nitrogen-phosphorus selective detection. J Chromatogr B 783 481. 

These drugs increase synaptic serotonin by selectively blocking the serotonin reuptake transporter. In preclinical and human studies acute doses tend to be anxiogenic (Bell and Nutt 1998) but chronic administration has anxiolytic effects, possibly due to downregulation of presynaptic autoreceptors (Blier et al. 1990). There are five SSRIs widely available citalopram, fluoxetine, fluvoxam-ine, paroxetine and sertraline. Escitalopram, the S-enantiomer of citalopram. 

Fluoxetine is a secondary amine, which is demethy-lated to norfluoxetine. Norfluoxetine is clinically active. Both compounds have S- and R- enantiomers (Wong et ah, 1990, 1993). Unlike citalopram, S- and R-fluoxetine and S-norfluoxetine are active forms. R-fluoxetine is much less potent than the other two compounds. In addition, it appears that R-fluoxetine and R-norfluoxetine are metabolized more rapidly than the S-enantiomers (Torok-Both et ah, 1992). 

Wong, D.T., Fuller, R.W., and Robertson DW. (1990) Fluoxetine and its two enantiomers as selective serotonin uptake inhibitors. Acta Pharm Nord 2 171-180. 

Fluoxetine, commonly known as Prozac , as a racemic mixture is an antidepressant drug, but has no effect on migraine. The pure 5-enantiomer works remarkably well in the prevention of migraine and is now under clinical evaluation. 

The selective serotonin reuptake inhibitors (SSRIs) represent a chemically diverse class of agents that have as their primary action the inhibition of the serotonin transporter (SERT) (Figure 30-3). Fluoxetine was introduced in the United States in 1988 and quickly became one of the most commonly prescribed medications in medical practice. The development of fluoxetine emerged out of the search for chemicals that had high affinity for monoamine receptors but lacked the affinity for histamine, acetylcholine, and adrenoceptors that is seen with the tricyclic antidepressants (TCAs). There are currently six available SSRIs, and they are the most common antidepressants in clinical use. In addition to their use in major depression, SSRIs have indications in GAD, PTSD, OCD, panic disorder, PMDD, and bulimia. Fluoxetine, sertraline, and citalopram exist as isomers and are formulated in the racemic forms, whereas paroxetine and fluvoxamine are not optically active. Escitalopram is the S enantiomer of citalopram. As with all antidepressants,... 

Fluoxetine (4) is marketed as a racemate. Both enantiomers display similar activity both in vitro (Ki of the (R)-(+)-enantiomer is 21 nM and the Ki of the (5)-(-)-enantiomer is 33 nM) and in vivo. However, it is (S)-fluoxetine that is the predominant therapeutic enantiomer since it is eliminated more slowly that the (R)-enantiomer. However, recent debate has argued that the prolonged duration of action of the (S)-enantiomer contributes to the major side-effects of the drug. ... 

Although several SSRIs other than the five listed in Table 6—6 have been synthesized, with the exception of the active enantiomers of currently marketed SSRIs such as fluoxetine and citalopram, it is unlikely any new SSRI will be developed as an antidepressant, as many other novel mechanisms are now available for clinical... 

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