Details
| Stereochemistry | ABSOLUTE |
| Molecular Formula | C17H18F3NO |
| Molecular Weight | 309.3261 |
| Optical Activity | UNSPECIFIED |
| Defined Stereocenters | 1 / 1 |
| E/Z Centers | 0 |
| Charge | 0 |
SHOW SMILES / InChI
SMILES
CNCC[C@@H](OC1=CC=C(C=C1)C(F)(F)F)C2=CC=CC=C2
InChI
InChIKey=RTHCYVBBDHJXIQ-MRXNPFEDSA-N
InChI=1S/C17H18F3NO/c1-21-12-11-16(13-5-3-2-4-6-13)22-15-9-7-14(8-10-15)17(18,19)20/h2-10,16,21H,11-12H2,1H3/t16-/m1/s1
| Molecular Formula | C17H18F3NO |
| Molecular Weight | 309.3261 |
| Charge | 0 |
| Count |
|
| Stereochemistry | ABSOLUTE |
| Additional Stereochemistry | No |
| Defined Stereocenters | 1 / 1 |
| E/Z Centers | 0 |
| Optical Activity | UNSPECIFIED |
The selective serotonin reuptake inhibitor fluoxetine consists of equal amounts of R and S stereoisomers (antidepressant Prozac (racemic fluoxetine). Binding to the transporter confirmed selectivity of R- and S-fluoxetine for the 5-HT transporter versus the dopamine (DA) and norepinephrine (NE) human transporters. In addition, receptor binding studies demonstrated significant affinity of R-fluoxetine, but not S-fluoxetine, for human 5-HT(2A) and 5-HT(2C) receptor subtypes. R-fluoxetine acts as an antagonist at 5-HT(2A) and 5-HT(2C) receptors. The attempt to develop a single-enantiomer formulation of fluoxetine for the treatment of depression was unsuccessful. Eli Lilly has terminated its licensing and development agreement with Marlborough, Mass.-based Sepracor for (R)-fluoxetine, the single-isomer version of Lilly's antidepressant Prozac.R-enantiomer of fluoxetine, at its highest administered dose, led to statistically significant prolongation of cardiac repolarization in phase II studies; the studies were subsequently stopped.
Originator
Curator's Comment: Racemic fluoxetine was originally developed at Eli Lilly. Eli Lilly has terminated its licensing and development agreement with Marlborough, Mass.-based Sepracor for ( R )-fluoxetine, the single-isomer version of Lilly's antidepressant Prozac (racemic fluoxetine). # Eli Lilly, Sepracor
Approval Year
PubMed
| Title | Date | PubMed |
|---|---|---|
| Fluoxetine. | 1994 Nov 17 |
|
| (R)-, (S)-, and racemic fluoxetine N-demethylation by human cytochrome P450 enzymes. | 2000 Oct |
|
| Identification of the human cytochromes p450 responsible for in vitro formation of R- and S-norfluoxetine. | 2001 Jun |
|
| Second-generation SSRIs: human monoamine transporter binding profile of escitalopram and R-fluoxetine. | 2001 Sep 1 |
|
| A comparison of brain and serum pharmacokinetics of R-fluoxetine and racemic fluoxetine: A 19-F MRS study. | 2005 Aug |
Patents
Sample Use Guides
In all, 13 healthy volunteers received study drug for 5 weeks using a dosing schedule designed to achieve steady state for 20 mg/day racemic fluoxetine, 80 mg/day R-fluoxetine, or 120 mg/day R-fluoxetine. The resulting brain drug levels were measured using 19-F MRS. At 5 weeks, the racemate, 80 and 120 mg/day R-fluoxetine groups had mean brain levels of 25.5, 34.9, and 41.4 microM, respectively. In the serum, R-norfluoxetine, which is thought to be an inactive metabolite, accounted for 17, 71, and 63% of the fluoxetine/norfluoxetine concentration, respectively. When the relative proportion of active to total species in serum are taken into account, the data suggest that doses of R-fluoxetine greater than 120 mg/day would be needed to achieve brain levels of active drug comparable to 20 mg/day of racemate. The 120 mg/day R-fluoxetine group experienced a mean increase in QTc interval of 44 ms, with one individual having an increase of 89 ms, which suggests that higher doses may not be tolerable.
Route of Administration:
Oral
R-fluoxetine did not stimulate GTPS binding to the G protein Gq in cell lines transfected with 5-HT2A and 5-HT2C receptors, indicating a lack of agonist activity. However, R-fluoxetine antagonized 5-HT (100 nM and 10 nM) stimulated GTPS binding in cell lines transfected with 5-HT2A and 5-HT2C receptors, respectively. The inhibition constants (Ki) of R-fluoxetine for blocking 5-HT stimulated 35S-GTPS binding in cell lines were 193 nM and
493 nM for the 5-HT2A and 5-HT2C receptors, respectively.
| Substance Class |
Chemical
Created
by
admin
on
Edited
Sat Dec 16 00:38:02 UTC 2023
by
admin
on
Sat Dec 16 00:38:02 UTC 2023
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| Record UNII |
F279341RUQ
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| Record Status |
Validated (UNII)
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F279341RUQ
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1548970
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86991
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DTXSID10872290
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DB08472
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