Norfluoxetine enantiomers as inhibitors of serotonin uptake in rat brain.
Like fluoxetine, the N-demethylated metabolite norfluoxetine exists in R- and S-enantiomeric forms. S-Norfluoxetine inhibited serotonin (5-HT) uptake and [3H]paroxetine binding to 5-HT uptake sites with a pKi of 7.86 and 8.88 or 14 and 1.3 nM, respectively, whereas R-norfluoxetine was 22 and 20 times, respectively, less potent. R- and S-Norfluoxetine were less potent than the corresponding enantiomers of fluoxetine as inhibitors of norepinephrine uptake and [3H]tomoxetine binding to norepinephrine uptake sites. Ex vivo studies showed that S-norfluoxetine inhibited 5-HT uptake with an ED50 of 3 mg/kg intraperitoneally, 4.7 mg/kg subcutaneously, and 9 mg/kg orally (7.3, 11.4 and 21.9 mumol/kg, respectively), while the ED50 for R-norfluoxetine exceeded 20 mg/kg intraperitoneally (48.6 mumol/kg). Inhibition of 5-HT uptake in cerebral cortex ex vivo and decrease in 5-HIAA levels in hypothalamus persisted for 24 hours after administration of S-norfluoxetine as demonstrated with the administration of fluoxetine. Thus, S-norfluoxetine is the active N-demethylated metabolite responsible for the persistently potent and selective inhibition of 5-HT uptake in vivo.
Wong
D T
DT
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285.
Bymaster
F P
FP
Reid
L R
LR
Mayle
D A
DA
Krushinski
J H
JH
Robertson
D W
DW
D000818:Animals; D000928:Antidepressive Agents / Q000378:metabolism; D000069445:Atomoxetine Hydrochloride; D001921:Brain / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005473:Fluoxetine / Q000031:analogs & derivatives* / Q000494:pharmacology; D008297:Male; D017374:Paroxetine / Q000378:metabolism; D011437:Propylamines / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D013237:Stereoisomerism
D000928:Antidepressive Agents; D000069445:Atomoxetine Hydrochloride; D005473:Fluoxetine; D017374:Paroxetine; D011437:Propylamines; D017367:Selective Serotonin Reuptake Inhibitors; C036139:norfluoxetine