Selective Serotonin Uptake Inhibitors (SSRIs) are drugs (bullets) that are targeting the serotonin transporter in order to block the reuptake of the neurotransmitter serotonin. Escitalopram has, in contrast to other SSRI drugs been shown to interact with the serotonin transporter at two different sites: the primary binding site shared with other SSRIs and a separate allosteric binding site. A consequence of this unique allosteric interaction is a prolonged dissociation half-life from the primary binding site resulting in very efficient inhibition of the serotonin uptake. Escitalopram is therefore due to this self-enhancing effect a Magic Bullet which has been termed Allosteric Serotonin Uptake Inhibitor (ASRI). Escitalopram is the active enantiomer of the racemic drug citalopram. While the R-enantiomer originally was believed to be inactive, recent investigations have surprisingly show that the R-enantiomer inhibit the effect of the S-enantiomer. Pharmacological and clinical studies have shown a clear tendency for faster onset of antidepressant action and more than two-fold higher potency of escitalopram compared with citalopram. The presentation will focus on comparing the profile of escitalopram/ASRI with SSRIs and discuss the mechanism behind and the consequences of the inhibition of S-citalopram by its R-enantiomer. A molecular model of the serotonin transporter will be presented as well as possible mechanisms involved in the allosteric interaction.

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