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.

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    • "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). "

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