Norfluoxetine Enantiomers as Inhibitors of Serotonin Uptake in Rat Brain

Abstract

lit fiuoxetine, the N-demethylated metabolite ."" uoxetine exists in R-and S-enantiomeric fonns. S-Norfluoxetine inhibited serotonin (5-HT) uptake and I'Hlptlroxetine binding to 5-HT uptake sites with a pKi of 7.86 and 8.88 or 14 and 1.3 nM, respectively, whereas l-norfluoxetine was 22 and 20 times, respectively, less pDltnt. R-and S-Norfluoxetine were less potent than the tlmSponding enantiomers of fluoxetine as inhibitors of WMpinephrine uptake and [3HJtomoxetine binding to WMpinephrine uptake sites. Ex vivo studies showed that S-norfluoxetine inhibited 5-HT uptake with an ED50 of 3 "8!kg intraperitoneally, 4.7 mglkg subcutaneously, and lEY WORDS: Fluoxetine; Norfluoxetine; Enantiomers; Strotonin 5-HT; Uptake; Inhibitors Ruoxetine, a selective inhibitor of serotonin (5-hydroxy lIyptamine, 5-HT) uptake (Wong et aI., 1974(Wong et aI., , 1975, has been successfully developed as an antidepressant drug (Feighner 1983;Beasley et al. 1990). Fluoxetine is de ftIoped and is marketed as the racemate, i.e., the R (-) and 5 (+) enantiomers of equal amounts. Both enantiomers inhibit 5-HT uptake and effectively pro duce functional responses associated with an increased S-HT transmission. There are no major differences in potency between R-and S-fluoxetine, and their eudis IIic ratio is close to unity (Wong et al., 1985(Wong et al., , 1990 9 mglkg orally (7.3, 11.4 and 21.9 Jimollkg, respectively), while the ED50 for R-norfluoxetine exceeded 20 mglkg intraperitoneally (48.6 Jimollkg). 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. Robertson et aI. 1988). Enzymatic N-demethylation is an early step of fluoxetine metabolism, and the de methylated compound norfluoxetine (Fig. 1) is a major metabolite (Parli and Hicks 1974; Lemberger et aI. 1978;Beasley et al. 1990) in laboratory animals and in man. Norfluoxetine is also a potent and selective inhibitor of 5-HT uptake (Wong et aI. 1975; Horng and Wong 1976;Fuller et al. 1978). In the present communication, we report the pharmacologic pro&les of R-and S-norfluox etine, which have been recently synthesized in high enantiomeric purity. In contrast with the two enan tiomers of fluoxetine, however, we have found that S-norfluoxetine is over 20-fold more potent than the R enantiomer as an inhibitor of 5-HT uptake both in vitro and in vivo. MATERIALS AND METHODSMale Sprague-Dawley rats weighing between 100 and 150 g (Harlan Industries, Cumberland, IN) were housed in a room with a 12-hour dark/light cycle at 23°C, and

R-fluoxetine Increases Extracellular DA, NE, As Well As 5-HT in Rat Prefrontal Cortex and Hypothalamus An in vivo Microdialysis and Receptor Binding Study

“…R-FLX and S-FLX have similar affinity for the human 5-HT transporter and low affinity for the DA and NE transporters. Similar affinity of the enantiomers for 5-HT uptake has been found in studies utilizing monoamine uptake in rat synaptosomes (Wong et al 1993). However, stereoselectivity for human 5-HT 2A and 5-HT 2C receptors was found for R-FLX versus S-FLX with R-FLX having at least 20-fold higher affinity for the two receptors than S-FLX.…”

“…The binding to rat 5-HT 3 receptors was from the method of Wong et al 1993. Inhibition of binding to 5-HT 4 and other neuronal receptors was provided by NovaScreen (Hanover, MD).…”

Fluoxetine and norfluoxetine stereospecifically facilitate pentobarbital sedation by increasing neurosteroids

“…FLX and NFLX are known to be potent SSRIs (11). Thus, it was important to establish whether the difference between the S-and R-stereoisomers in eliciting a normalization of PTB action in SI mice was related to differences in 5-HT reuptake inhibition potency.…”

Pharmacologically Active Metabolites of Currently Marketed Drugs: Potential Resources for New Drug Discovery and Development

“…20) NDemethylation signiˆcantly contributes to produce active metabolites in cases of ‰uoxetine ( Fig. 1 (d)), 22,23) sibutramine, 24) ferroquine 25) and azonaˆde. 26) S-Oxidation of thioridazine and epoxidation of carbamazepine lead to the formation of mesoridazine 27) and carbamazepine-10, 11-epoxide, 28) respectively.…”

“…For instance, 3-hydroxyquinidine, 37) hydroxymetronidazole, 38) (R)-nor‰uoxetine, 22,23) norverapamil, 39) hydroxycyclosporine, 14) N-desmethylazonaˆde, 26) hydroxybupropion and threohydrobupropion, 18) and many active metabolites have weaker activities than their parents. But, in some cases, metabolites are more potent or have similar biological activities to parent drugs.…”