A Photoswitchable Inhibitor of the Human Serotonin Transporter

Creators: Cheng, Bichu; Morstein, Johannes^{1, 2}; Ladefoged, Lucy Kate; Maesen, Jannick Bang; Schiøtt, Birgit; Sinning, Steffen; Trauner, Dirk

1. New York University
2. California Institute of Technology

Abstract

The human serotonin transporter (hSERT) terminates serotonergic signaling through reuptake of neurotransmitter into presynaptic neurons and is a target for many antidepressant drugs. We describe here the development of a photoswitchable hSERT inhibitor, termed azo-escitalopram, that can be reversibly switched between trans and cis configurations using light of different wavelengths. The dark-adapted trans isomer was found to be significantly less active than the cis isomer, formed upon irradiation.

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Acknowledgement

We are grateful to Simon Ravnkilde Sinning for designing and producing custom 3D-printed plastic polymer masks enabling controlled illumination of desired wells in microplates. We thank Grace Pan for assistance with the glutathione assay.

Funding

J.M. thanks the German Academic Scholarship Foundation for a fellowship and New York University for a MacCracken fellowship and a Margaret and Herman Sokol fellowship. This work was supported by the National Institutes of Health (Grant R01NS108151-01).

Additional Information

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acschemneuro.9b00521.

Synthetic procedures and analytical data for new compounds; GSH reduction assay results; molecular docking results (PDF)

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