Allosteric mode of action.

Escitalopram increases intrasynaptic levels of the

neurotransmitter serotonin by blocking the reuptake of the neurotransmitter
into the neuron. Of the SSRIs currently on the market escitalopram has the
highest affinity for the human serotonin transporter (SERT). Another
enantiomer of citalopram (R-citalopram) counteracts to a certain degree the
serotonin-enhancing action of escitalopram. As a result, escitalopram is a
more potent antidepressant than citalopram, which is a mixture of
escitalopram and R-citalopram. In order to explain this phenomenon,
researchers from Lundbeck proposed that escitalopram enhances its own
binding via an additional interaction with another allosteric site on the
transporter.[15] Further research by the same group showed that R-citalopram
also enhances binding of escitalopram,[16] and therefore the allosteric
interaction cannot explain the observed counteracting effect. In the most
recent paper, however, the same authors again reversed their findings and
reported that R-citalopram decreases binding of escitalopram to the
transporter.[17] Although allosteric binding of escitalopram to the serotonin
transporter is of unquestionable research interest, its clinical relevance is
unclear since the binding of escitalopram to the allosteric site is at least 1000
times weaker than to the primary binding site.

The serotonin transporter (SERT) is a monoamine transporter protein.

This protein is an integral membrane protein that transports the
neurotransmitter serotonin from synaptic spaces into presynaptic neurons.
This transport of serotonin by the SERT protein terminates the action of
serotonin and recycles it.

ALLOSTERIC SITES.

In vitro studies have revealed the existence of at least two binding

sites on SERT: (1) a primary high-affinity binding site or
orthosteric site that mediates the inhibition of 5-HT reuptake and
(2) an allosteric low-affinity binding site that modulates the binding
of ligands at the primary site. In presence of escitalopram alone,
both the primary and the allosteric sites are occupied. Thus,
escitalopram exerts a stabilizing effect on this association to
SERT, resulting in an effective inhibition of 5-HT reuptake activity.
On the other hand, in the presence of the two enantiomers, R-
citalopram binds to the allosteric site and decreases the
escitalopram action on SERT. Such an innovative mechanism of
action can constitute a basis for development of new allosteric
antidepressants that demonstrate higher efficacy and earlier
onset of therapeutic effect.