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-H T) uptake and [H-3]paroxetine binding to 5-HT uptake sites with a pK(i ) of 7.86 and 8.88 or 14 and 1.3 nM, respectively, whereas R-norfluoxe tine was 22 and 20 times, respectively, less potent. R- and S-Norfluox etine were less potent than the corresponding enantiomers of fluoxetin e as inhibitors of norepinephrine uptake and [H-3]tomoxetine binding t o norepinephrine uptake sites. Ex vivo studies showed that S-norfluoxe tine inhibited 5-HT uptake with an ED50 of 3 mglkg intraperitoneally, 4.7 mg/kg subcutaneously, and 9 mglkg 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 cer ebral cortex ex vivo and decrease in 5-HIAA levels in hypothalamus per sisted for 24 hours after administration of S-norfluoxetine as demonst rated 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.