Second-generation SSRIs: human monoamine transporter binding profile of escitalopram and R-fluoxetine

  title={Second-generation SSRIs: human monoamine transporter binding profile of escitalopram and R-fluoxetine},
  author={Michael J. Owens and David L. Knight and Charles B. Nemeroff},
  journal={Biological Psychiatry},
BACKGROUND Single isomers of the selective serotonin reuptake inhibitors citalopram (escitalopram, S-citalopram) and fluoxetine (R-fluoxetine) are currently under development for the treatment of depression and other psychiatric disorders. Previous studies conducted in laboratory animals have revealed that the biological effects on serotonin reuptake for citalopram reside in the S enantiomer. In contrast, both enantiomers of fluoxetine contribute to its biological activity. METHODS In the… Expand
[Escitalopram: a selective inhibitor and allosteric modulator of the serotonin transporter].
Citalopram exerts a stabilizing effect on this association to SERT, resulting in an effective inhibition of 5-HT reuptake activity, and an allosteric interaction between the enantiomers and the 5- HT transporter (SERT) has been proposed. Expand
PET measurement of serotonin transporter occupancy: a comparison of escitalopram and citalopram.
The small but significant difference in occupancy and K(i),(app) found between R,S-citalopram and S-cITALopram suggests that not only S- citaloprams but also R-citalsopram to some degree occupies the 5-HTT in the human brain in vivo. Expand
Escitalopram: A Second-Generation SSRI
Escitalopram is a promising candidate for use as a first-line antidepressant because of its receptor binding properties and activity in preclinical animal models of depression, and because of the most selective SSRI yet developed. Expand
The interaction of escitalopram and R-citalopram at the human serotonin transporter investigated in the mouse
No evidence is found that R-citalopram directly antagonizes escitalo-induced 5-HTExt elevation or that the putative allosteric site is important for hSERT inhibition by escITALopram. Expand
L’escitalopram : un inhibiteur sélectif et un modulateur allostérique du transporteur de la sérotonine
Citalopram (Seropram) is an antidepressant of the selective serotonin (5-HT) reuptake inhibitor (SSRI) class, composed of equal amounts of S-enantiomer, escitalopram, and R-enantiomer, R-citalopram.Expand
Pharmacological properties of the active metabolites of the antidepressants desipramine and citalopram.
The pharmacological effects of desipramine in rats may be attributed not only to the inhibition of the norepinephrine transporter by desipramsine but also toThe inhibition of serotonin transporter by the active metabolite desmethyldesipramines. Expand
Milnacipran: a comparative analysis of human monoamine uptake and transporter binding affinity
Milnacipran's binding and uptake inhibition profile more closely resembles that of the tricyclic antidepressants than that of duloxetine and whether these differences observed in vitro manifest themselves in vivo is not clear. Expand
The S-enantiomer of R,S-citalopram, increases inhibitor binding to the human serotonin transporter by an allosteric mechanism. Comparison with other serotonin transporter inhibitors
Escitalopram shows a unique interaction with the hSERT compared with other 5-HT reuptake inhibitors (SSRIs) and displays a pronounced effect via an affinity-modulating allosteric site that stabilised the [3H]-escITALopram/SERT complex via anallosteric effect at a low-affinity binding site. Expand
Managing depressive and anxiety disorders with escitalopram
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Pharmacoeconomic models suggest that the greater drug acquisition cost of this patent-protected compound may be offset by greater efficacy (relative to generic citalopram) and tolerability (compared with extended release venlafaxine). Expand
Investigating the Potential Role of Serotonin-2B Receptor Antagonism in the Neuronal Actions of Adjunctive Aripiprazole
5-HT2B receptor blockade rescues an SSRI-mediated decrease in DA firing activity and increases mPFC pyramidal neuron firing and bursting activity mediated by aripiprazole and in combination with escitalopram may be, at least partly, moderated by 5- HT2B receptors expressed in this brain area. Expand


Pharmacological profile of antidepressants and related compounds at human monoamine transporters.
Using radioligand binding assays, the equilibrium dissociation constants (KD's) for 37 antidepressants, three of their metabolites, some mood stabilizers, and assorted other compounds for the human serotonin, norepinephrine, and dopamine transporters are determined to help predict some possible adverse effects and drug-drug interactions of antidepressants and related compounds. Expand
Affinities of fluoxetine, its enantiomers, and other inhibitors of serotonin uptake for subtypes of serotonin receptors.
The new antidepressant drugs, fluoxetine (and its enantiomers), citalopram, indalpine, paroxetine, and femoxetine show relatively weak affinities for 5-HT receptors as measured by radioligand bindingExpand
Neurotransmitter receptor and transporter binding profile of antidepressants and their metabolites.
Novel findings, not widely described previously, suggest that many of the individual drugs studied in these experiments possess some structural characteristic that determines affinity for several G protein-coupled, but not muscarinic, receptors. Expand
Comparison of norfluoxetine enantiomers as serotonin uptake inhibitors in vivo
The enantiomers of norfluoxetine have markedly different potencies as inhibitors of the uptake of serotonin, based on their antagonism of p-chloroamphetamine-induced depletion of serotonin in brain and their lowering of concentrations of the metabolite of serotonin. Expand
Absolute configurations and pharmacological activities of the optical isomers of fluoxetine, a selective serotonin-uptake inhibitor.
The goals of this study were to determine the absolute configurations of the enantiomers of fluoxetine and to examine whether the actions of fluxetine in behavioral tests were enantiospecific, and to ensure that the eudismic ratio for the fluoxettine enantiomer is near unity. Expand
Blockade by newly-developed antidepressants of biogenic amine uptake into rat brain synaptosomes.
Although none of the drugs was potent for [3H]dopamine uptake blockade, sertraline was the most potent (Ki = 260 nM). Expand
Blockage of 5HT2C serotonin receptors by fluoxetine (Prozac).
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The results show that fluoxetine is a competitive and reversible antagonist of 5HT2C receptors and suggest that some therapeutic effects of fluoxettine may involve blockage of 5 HT receptors, in addition to its known blockage to 5HT transporters. Expand
Interaction of the enantiomers of fluoxetine and norfluoxetine with human liver cytochromes P450.
The data indicate that the enantiomers of fluoxetine and norfluoxetines are potent inhibitors of P450 2D6 and that P450 forms other than P4502D6 appear to be responsible for the majority of microsomal fluoxettine N-demethylation. Expand
Analysis of Enantiomers of Citalopram and Its Demethylated Metabolites in Plasma of Depressive Patients Using Chiral Reverse‐Phase Liquid Chromatography
The results suggest the need for studies on the relationships between clinical response and plasma levels of CIT enantiomers, and the co-medications seemed to have little influence on enantiomer ratios. Expand
Plasma levels of citalopram enantiomers and metabolites in elderly patients.
It is hypothesized that quantification of S(+) citalopram will permit a more accurate examination of dose/response relationships, and seems to be especially important for older subjects, given the wide ranges and higher concentrations evident from preliminary results. Expand