Plenge P, Mellerup ET, Laursen H. Affinity modulation of [3H]imipramine, [3H]paroxetine and [3H]citalopram binding to the 5-HT transporter from brain and platelets. Eur J Pharmacol 206: 243-250

IT University of Copenhagen, København, Capital Region, Denmark
European Journal of Pharmacology (Impact Factor: 2.53). 04/1991; 206(3):243-250. DOI: 10.1016/S0922-4106(05)80025-2


The dissociations of [3H]imipramine, [3H]paroxetine and [3H]citalopram from the 5-HT (serotonin 5-hydroxytryptamine) transporter were found to be markedly influenced by several drugs, although concentrations in the μM range were needed. Most of these drugs attenuated the dissociation rate, i.e. increased the affinity between the ligand and the binding site. A few increased the dissociation rate however. The binding of drugs to the affinity-modulating site was specific, although of low affinity and probably changing the conformation of the high-affinity binding site, thereby changing the fit between the ligand and the interacting amino acid side-chains.Although the drugs usually affected the dissociation rates of the three ligands in the same manner, there were some which had different effects on [3H]imipramine, [3H]paroxetine and [3H]citalopram. For example, 5-HT markedly attenuated the dissociation of [3H]imipramine, had a moderate effect on [3H]paroxetine and very little effect on [3H]citalopram dissociation. This indicates that the three ligands are bound to different domains on the 5-HT transporter.[3H]Citalopram dissociation from human brain and rat brain were differently affected by several drugs. Indalpine augmented the dissociation rate of the [3H]citalopram 5-HT transport complex in human brain but attenuated it in rat brain, thus revealing a species difference of the 5-HT transporter.

4 Reads
  • Source
    • "However, previously published studies of in vitro binding kinetics of 3 H-citalopram in rat brain homogenates and human platelets have shown that higher concentrations of escitalopram or R-citalopram stabilize [ 3 H]citalopram binding, resulting in a low dissociation rate (Plenge and Mellerup, 1985). This is suggested to be due to an allosteric effect on the 5-HT transporter protein via binding to a low-affinity site (Plenge et al., 1991). Recent studies with membrane preparations of COS-1 cells expressing the human 5-HT transporter protein have compared effects of escitalopram and R-citalopram on dissociation rates of [ 3 H]escitalopram , [ 3 H]MADAM and [ 125 I]RTI, and have demonstrated differences between escitalopram and Rcitalopram (Wiborg and Sánchez, 2002). "

    European Neuropsychopharmacology 10/2003; Suppl 4(13):204-205. DOI:10.1016/S0924-977X(03)91781-0 · 4.37 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Tricyclic antidepressants (TCAs) affect a series of neurotransmitter functions. The uptake of noradrenaline (NA) and serotonin (5-HT) is inhibited to a varying degree. Many of the TCAs potently inhibit a series of neurotransmitter receptors. A series of newer antidepressants preferentially increases 5-HT transmission by inhibiting 5-HT uptake. Selective serotonin re-uptake inhibitors (SSRIs) are those which have a high potency ratio of 5-HT-uptake inhibition as compared to NA-uptake inhibition, together with slight or no effect on other uptake mechanisms, neurotransmitter receptors, enzymes, etc. The marketed SSRIs, citalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline all fulfil the above-mentioned criteria. Paroxetine is the most potent 5-HT-uptake inhibitor, whereas citalopram is the most selective. In general, the rank order of selectivity is equal in in vitro studies, in biochemical in vivo studies and in behavioural studies. Potency and selectivity for 5-HT uptake do not coincide. In contrast to TCAs, most of which inhibit receptors for acetylcholine, histamine, NA, 5-HT or DA, most SSRIs neither bind to nor inhibit these receptors. Likewise, monoamine oxidase (MAO) is not inhibited by these drugs. Citalopram, fluoxetine and sertraline are metabolized to compounds possessing similar properties as the parent drugs, whereas this is not the case with the metabolites of fluvoxamine and paroxetine. Upon repeated administration the potency and selectivity of SSRIs are maintained. Although repeated treatment with TCAs and electroconvulsive shocks leads to changes in receptor number and pharmacological responsiveness, e.g. down-regulation of β-adrenoceptors and down-regulation of 5-HT2-mediated function, no consistent changes are seen after prolonged treatment with SSRIs. Since SSRIs show antidepressant effect, this receptor regulation seems not to be a prerequisite for clinical antidepressant activity.
    Nordic Journal of Psychiatry 01/1993; 47(s30):5-12. DOI:10.3109/08039489309104119 · 1.34 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The pathogenesis of eating disorders is still unclear. However, there is evidence that neurotransmitters may be involved in the control of satiety/appetite. Investigating these disorders could be facilitated if a readily available human cell model were to reflect central nervous system (CNS) function. Platelets may satisfy, at least partially, this requirement. We discuss here the use of platelets as neuronal models with an emphasis on eating disorders.
    Biomedecine [?] Pharmacotherapy 02/1993; 47(1):11-8. DOI:10.1016/0753-3322(93)90031-F · 2.02 Impact Factor
Show more