A selective inhibitor of serotonin uptake: Lilly 110140, 3-(p-Trifluoromethylphenoxy)-n-methyl-3-phenylpropylamine

Wong, David T.; Horng, J. S.; Bymaster, Frank P.; Hauser, Kenneth L.; Molloy, Bryan B.

doi:10.1016/0024-3205(74)90345-2

Cited by 489 publications

(244 citation statements)

References 11 publications

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“…Auoxetine and norfluoxetine, as reported previ ously (Wong et al 1975(Wong et al , 1990, and their respective enantiomers as demonstrated in the present study, are weak inhibitors of NE uptake. Using [3Hltomoxetine as a radioligand of NE uptake carrier (Wong et al 1991a) , we further show that norfluoxetine and its enantiomers are indeed weaker ligands for the NE uptake carri er.…”

Section: Discussionsupporting

confidence: 82%

“…The duration of lowering of 5-HT uptake after a sin gle oral administration of S-norfluoxetine at 20 mg/kg was found to be comparable to that caused by a similar treatment with fluoxetine and S-fluoxetine (Wong et al 1975(Wong et al , 1985. Within an hour of treatment, 5-HT uptake in homogenates of cerebral cortex was reduced to be low 30% of control activity, and the decrease persisted for 24 hours.…”

Section: Resultsmentioning

confidence: 94%

“…Consistent with the in vitro ftndings, R-norfluoxetine was relatively inactive as a 5-HT uptake inhibitor ex vivo with EDso doses exceed ing 20 mg/kg. In vivo, fluoxetine and norfluoxetine at !lmg/kg!P, more than twice the ED50 inhibiting 5-HT aptake ex vivo, failed to inhibit the accumulation of ra dioactive NE in rat heart, whereas the tricyclic anti depressant drugs imipramine, desipramine, clomipra mine, and chlorodesipramine at 5 mg/kg IP nearly maximally inhibited accumulation of NE radioactivity it heart (Wong et al 1975).…”

Section: Discussionmentioning

confidence: 92%

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Norfluoxetine Enantiomers as Inhibitors of Serotonin Uptake in Rat Brain

Wong

Bymaster

Reid

et al. 1993

Neuropsychopharmacol

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104

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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

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Section: Discussionsupporting

confidence: 82%

Section: Resultsmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 92%

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Norfluoxetine Enantiomers as Inhibitors of Serotonin Uptake in Rat Brain

Wong

Bymaster

Reid

et al. 1993

Neuropsychopharmacol

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104

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“…As this compound acts inhibiting 5-HT reuptake and, consequently, increasing the extracelullar concentrations of 5-HT (Wong et al, 1974), it is very likely that enhanced 5-HT binding to its receptors in certain mPFC neurons may induce the reported increase in PSA-NCAM expression. The adult rat mPFC is an important target of 5-HT action, because it receives a dense serotoninergic innervation from the raphe nuclei (Azmitia and Segal, 1978;Steinbusch, 1981) and it contains several receptor subtypes for 5-HT Pompeiano et al, 1992).…”

Section: Involvement Of 5-ht In the Modulation Of Psa-ncam Expressionmentioning

confidence: 99%

“…The mPFC receives a dense serotoninergic innervation (Azmitia and Segal, 1978;Steinbusch, 1981) and contains several 5-HT receptor subtypes Pompeiano et al, 1992). Consequently, this cortical region is a good target for antidepressants enhancing extracellular 5-HT levels, such as fluoxetine (Wong et al, 1974). Interestingly, a recent report has shown that treatment with fluoxetine, induces a robust increase in hippocampal pyramidal spine synapse density (Hajszan et al, 2005), indicating that this antidepressant may induce structural reorganization of neurons.…”

Section: Introductionmentioning

confidence: 99%

Chronic Fluoxetine Treatment Increases the Expression of PSA-NCAM in the Medial Prefrontal Cortex

Varea

Blasco-Ibáñez

Gómez-Climent

et al. 2006

Neuropsychopharmacol

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Recent hypotheses suggest that changes in neuronal structure and connectivity may underlie the etiology of depression. The medial prefrontal cortex (mPFC) is affected by depression and shows neuronal remodeling during adulthood. This plasticity may be mediated by the polysialylated form of the neural cell adhesion molecule (PSA-NCAM), which is intensely expressed in the adult mPFC. As the expression of PSA-NCAM is increased by serotonin in other cerebral regions, antidepressants acting on serotonin reuptake may influence PSA-NCAM expression and thus counteract the effects of depression by modulating neuronal structural plasticity. Using immunohistochemistry, we have studied the relationship between serotoninergic fibers and PSA-NCAM expressing neurons in the adult rat mPFC and the expression of serotonin receptors in these cells. The effects of fluoxetine treatment for 14 days on mPFC PSA-NCAM expression have also been analyzed. Although serotoninergic fibers usually do not contact PSA-NCAM immunoreactive neurons, most of these cells express 5-HT3 receptors. In general, chronic fluoxetine treatment induces significant increases in the number of PSA-NCAM immunoreactive neurons and in neuropil immunostaining and coadministration of the 5-HT3 antagonist ondansetron blocks the effects of fluoxetine on PSA-NCAM expression. These results indicate that fluoxetine, acting through 5-HT3 receptors, can modulate PSA-NCAM expression in the mPFC. This modulation may mediate the structural plasticity of this cortical region and opens new perspectives on the study of the molecular bases of depression.

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Antidepressants

Iversen¹,

Glennon²

2003

Burger's Medicinal Chemistry and Drug Discovery

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This chapter reviews the 26 antidepressant drugs currently available in Europe and/or the United States from the perspectives of their clinical efficacy, pharmacokinetics, pharmacology, structure‐activity relationships, metabolism, and mechanisms of action. The older nonselective monoamine oxidase inhibitors (e.g., phenelzine, tranylcypromine) have largely been replaced by compounds that selectively inhibit monoamine oxidase A (e.g., moclobemide) or by inhibitors of norepinephrine/serotonin monoamine transporter reuptake mechanisms. The first generation of such drugs, the tricyclic antidepressants, suffered from a number of dangerous and unpleasant adverse side effects caused by their many other pharmacological actions on the heart and on cholinergic and other monoamine receptors in the brain. Most of the current generation of antidepressants are serotonin‐selective reuptake inhibitors, which possess a safer side‐effect profile. These drugs have gained widespread use in the treatment of depression and a number of related psychiatric conditions. Some agents that act as norepinephrine‐selective reuptake inhibitors (e.g., reboxetine) are also clinically effective and there is considerable overlap between noradrenergic and serotonergic mechanisms in the CNS. Monoamine selectivity can also be altered by the formation of active metabolites in vivo . All antidepressants require several weeks of treatment before the maximum clinical benefit is seen. This may be attributable to drug‐induced alterations in the expression of receptors in brain (e.g., downregulation of 5‐HT 1A receptors) and/or alterations in the expression of neurotrophic factors (e.g., brain derived neurotrophic factor). New approaches to future antidepressant drug discovery include antagonists for glutamate NMDA receptors, substance P NK1 receptors, or corticotrophin releasing factor receptors.

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A selective inhibitor of serotonin uptake: Lilly 110140, 3-(p-Trifluoromethylphenoxy)-n-methyl-3-phenylpropylamine

Cited by 489 publications

References 11 publications

Norfluoxetine Enantiomers as Inhibitors of Serotonin Uptake in Rat Brain

Norfluoxetine Enantiomers as Inhibitors of Serotonin Uptake in Rat Brain

Chronic Fluoxetine Treatment Increases the Expression of PSA-NCAM in the Medial Prefrontal Cortex

Antidepressants

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