Clickable photoaffinity ligands for the human serotonin transporter based on the selective serotonin reuptake inhibitor (S)-citalopram.
Bioorg Med Chem Lett
; 28(21): 3431-3435, 2018 11 15.
Article
in En
| MEDLINE
| ID: mdl-30266542
ABSTRACT
To date, the development of photoaffinity ligands targeting the human serotonin transporter (hSERT), a key protein involved in disease states such as depression and anxiety, have been radioisotope-based (i.e., 3H or 125I). This letter instead highlights three derivatives of the selective serotonin reuptake inhibitor (SSRI) (S)-citalopram that were rationally designed and synthesized to contain a photoreactive benzophenone or an aryl azide for protein target capture via photoaffinity labeling and a terminal alkyne or an aliphatic azide for click chemistry-based proteomics. Specifically, clickable benzophenone-based (S)-citalopram photoprobe 6 (hSERT Kiâ¯=â¯0.16â¯nM) displayed 11-fold higher binding affinity at hSERT when compared to (S)-citalopram (hSERT Kiâ¯=â¯1.77â¯nM), and was subsequently shown to successfully undergo tandem photoaffinity labeling-biorthogonal conjugation using purified hSERT. Given clickable photoprobes can be used for various applications depending on which reporter is attached by click chemistry subsequent to photoaffinity labeling, photoprobe 6 is expected to find value in structure-function studies and other research applications involving hSERT (e.g., imaging).
Key words
Full text:
1
Database:
MEDLINE
Main subject:
Azides
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Benzophenones
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Citalopram
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Photoaffinity Labels
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Serotonin Plasma Membrane Transport Proteins
Limits:
Humans
Language:
En
Year:
2018
Type:
Article