Dreier, D., Belleza, O.J.V., Schlögl, K., Kickinger, S., Hellsberg, E., Mayer, F.P., Sandtner, W., Mikšovsky, P., Schittmayer, M., Hu, Y., Jäntsch, K., Holy, M., Ecker, G.F., Sitte, H.H. and Mihovilovic, M.D. (2025), Careful Examination of a Novel Azobenzene Paroxetine Derivative and Its Interactions With Biogenic Amine Transporters. J Neurochem, 169: e70068.

DOI

https://doi.org/10.1111/jnc.70068

Abstract

The serotonin transporter (SERT) belongs to the family of neurotransmitter sodium symporters (NSS), together with other neurotransmitter transporters for norepinephrine, dopamine, glycine, and GABA. The main physiological role of SERT is the retrieval of previously released serotonin from the synaptic cleft. Thereby, SERT plays an important role in regulating the extracellular serotonin concentration and maintaining serotonergic neurotransmission. This process can be influenced by molecules acting as serotonin uptake inhibitors, like paroxetine. Here, we report the development of a novel photoswitchable paroxetine derivative and its pharmacological interaction profile with SERT as a tool compound for the light-induced control of SERT. Based on the azo-extension strategy, the photoswitchable moiety was formed at the former position of the fluoro substituent in paroxetine. The resulting azo-paroxetine (9) was easily and reversibly switched between active (Z) and inactive (E) configurations and remained stable between these configurations: serotonin uptake was inhibited more than 12 times more potently by the active (Z)-configuration having a sub μM IC50 value. This was supported by electrophysiological patch-clamp recordings in the whole-cell configuration and docking studies. No significant toxic impact of azo-paroxetine (9) and no off-target activity at the norepinephrine transporter (NET), human GABA transporter subtypes 1 and 3, and rat GAT1 were observed. Our results demonstrate that the activity of SERT can be reversibly manipulated by the optopharmacological agent azo-paroxetine (9). This compound can thus be applied as a tool for the selective manipulation of SERT in central or peripheral investigations, further benefiting from its low probability for compound-related off-target effects.

Funding

We thank Petrine Wellendorph for the generous donation of the human isoforms of the GABA transporter. This work was supported by the Austrian Science Fund/FWF: MolTag W1232 to G.F.E., H.H.S., and M.D.M. Open access funding provided by Technische Universitat Wien/KEMÖ.

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© 2025 The Author(s). Journal of Neurochemistry published by John Wiley & Sons Ltd on behalf of International Society for Neurochemistry.

Keywords

azobenzene, GABA, neurotransmitter transporters, norepinephrine, off-target effect, serotonin