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  Azidobupramine, an Antidepressant-Derived Bifunctional Neurotransmitter Transporter Ligand Allowing Covalent Labeling and Attachment of Fluorophores

Kirmeier, T., Gopalakrishnan, R., Ganal, V., Werner, A. M., Cuboni, S., Rudolf, G. C., et al. (2016). Azidobupramine, an Antidepressant-Derived Bifunctional Neurotransmitter Transporter Ligand Allowing Covalent Labeling and Attachment of Fluorophores. PLOS ONE, 11(2): e0148608. doi:10.1371/journal.pone.0148608.

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Kirmeier, Thomas1, Author           
Gopalakrishnan, Ranganath2, Author           
Ganal, Vanessa2, Author           
Werner, Anna Maria2, Author           
Cuboni, Serena2, Author           
Rudolf, Georg C.3, Author
Hoefner, Georg3, Author
Wanner, Klaus T.3, Author
Sieber, Stephan A.3, Author
Schmidt, Ulrike1, Author           
Holsboer, Florian4, Author           
Rein, Theo2, Author           
Hausch, Felix2, Author           
Affiliations:
1Clinical Research, Max Planck Institute of Psychiatry, Max Planck Society, ou_2035296              
2Dept. Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Max Planck Society, ou_2035295              
3external, ou_persistent22              
4Emeritiertes wissenschaftliches Mitglied, Max Planck Institute of Psychiatry, Max Planck Society, ou_2074301              

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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.

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Language(s): eng - English
 Dates: 2016-02-10
 Publication Status: Published online
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Title: PLOS ONE
Source Genre: Journal
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Publ. Info: PLOS Public Library of Science
Pages: - Volume / Issue: 11 (2) Sequence Number: e0148608 Start / End Page: - Identifier: ISSN: 1932-6203