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Abstract:
The aim of this study was to design, synthesize and validate a
multifunctional antidepressant probe that is modified at two distinct
positions. The purpose of these modifications was to allow covalent
linkage of the probe to interaction partners, and decoration of
probe-target complexes with fluorescent reporter molecules. The strategy
for the design of such a probe (i.e., azidobupramine) was guided by the
need for the introduction of additional functional groups, conveying the
required properties while keeping the additional moieties as small as
possible. This should minimize the risk of changing antidepressant-like
properties of the new probe azidobupramine. To control for this, we
evaluated the binding parameters of azidobupramine to known target sites
such as the transporters for serotonin (SERT), norepinephrine (NET), and
dopamine (DAT). The binding affinities of azidobupramine to SERT, NET,
and DAT were in the range of structurally related and clinically active
antidepressants. Furthermore, we successfully visualized
azidobupramine-SERT complexes not only in SERT-enriched protein material
but also in living cells stably overexpressing SERT. To our knowledge,
azidobupramine is the first structural analogue of a tricyclic
antidepressant that can be covalently linked to target structures and
further attached to reporter molecules while preserving
antidepressant-like properties and avoiding radioactive isotopes.
