Clickable photoaffinity ligands for the human serotonin transporter based on the selective serotonin reuptake inhibitor (S)-citalopram |
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Authors: | Nageswari Yarravarapu Laura Geffert Christopher K Surratt Michael Cascio David J Lapinsky |
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Institution: | 1. Graduate School of Pharmaceutical Sciences, Duquesne University, 600 Forbes Avenue, Pittsburgh, PA 15282, United States;2. Bayer School of Natural and Environmental Sciences, Department of Chemistry and Biochemistry, Duquesne University, 600 Forbes Avenue, Pittsburgh, PA 15282, United States |
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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 Ki?=?0.16?nM) displayed 11-fold higher binding affinity at hSERT when compared to (S)-citalopram (hSERT Ki?=?1.77?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). |
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Keywords: | Citalopram Selective serotonin reuptake inhibitor Serotonin transporter Photoaffinity labeling Click chemistry |
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