Duloxetine (LY248686, [ + ]-N-methyl-3-(1-napthalenyloxy)-2-thiophene-propanamine) is a potent dual inhibitor of serotonin (5-hydroxytryptamine, 5-HT) and norepinephrine (NE) uptake in hypothalamus and cerebral cortex of rat brain (Wong et al. 1993; Fuller et al. 1994). Consistent with the dual mechanisms of inhibiting 5-HT and NE uptake, duloxetine at 15 mg/kg IP produced large increases in extracellular levels of 5-HT (250%) and NE (1,100%) 30 minutes after systemic administration. Levels of 3-methoxy-4-hydroxy-phenylethyleneglycol (MHPG) and 5-hydroxyindoleacetic acid (5-HIAA), metabolites of NE and 5-HT, respectively, were reduced, whereas those of dopamine (DA) and its metabolite 3, 4-dihydroxyphenylacetic acid (DOPAC) were not significantly altered. Duloxetine at 7 mg/kg produced less pronounced increases while no consistent effects were observed at 4 mg/kg. In this dose range, duloxetine inhibited 5-HT uptake in platelets ex vivo without inhibiting striatal dopamine (DA) uptake. In the present study we also found that the primary amine (a racemate) of duloxetine is about one-fourth as active as duloxetine to inhibit 5-HT and NE uptake. The potential primary amine metabolite of duloxetine might contribute, in part, to the inhibition of 5-HT and NE uptake in vivo. Thus the ability to produce robust increases of extracellular 5-HT and NE levels suggests that duloxetine may potentially be a highly effective antidepressant agent.

LY248686 is an inhibitor of serotonin (5-hydroxytryptamine; 5-HT) and norepinephrine (NE) uptake in synaptosomal preparations of hypothalamus and cerebral cortex, and 5-HT uptake in human blood platelets, with inhibitor constants near nanomolar concentrations. Upon administration to rats 1 hour before sacrifice, LY248686 caused dose-dependent and parallel decreases of 5-HT and NE uptake in hypothalamus homogenates ex vivo. LY248686 is a positive enantiomer and was slightly more potent than its negative isomer, LY248685, as an inhibitor of 5-HT uptake. Both isomers were only weak inhibitors of dopamine (DA) uptake in striatal synaptosomes. The inhibitory effects on 5-HT and NE uptake after a single administration of LY248686 followed similar time courses and simultaneously persisted for as long as 6 hours. LY248686 in vivo could effectively antagonize the p-chloroamphetamine-induced decreases of 5-HT uptake and levels of 5-HT and 5-hydroxyindoleacetic acid in cerebral cortex, and block the accumulation of 14C-NE in rat hearts. In food deprived rats, LY248686 suppressed food intake synergistically with 5-hydroxytryptophan, a precursor amino acid of 5-HT. Because of its lack of affinity for receptors of 5-HT, NE, DA, acetylcholine, histamine and naloxone, and its ability to inhibit 5-HT and NE uptake simultaneously, LY248686 has a favorable pharmacological profile as a potential antidepressant drug.

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.