Design, Synthesis, and In Vitro Characterization of a Tryptamine-Based Visible-Light Photoswitchable 5-HT2AR Ligand Showing Efficacy Preference for β-Arrestin over Mini-Gq.
Journal of medicinal chemistry June 18, 2025 Alexandra Sink, Eline Pottie, Samuel J Carter et al. 2 citations
A photoswitchable ligand for the serotonin 2A receptor (5-HT2AR) was designed to independently study G protein- and β-arrestin2-dependent signaling pathways. The cis-photoisomer binds the receptor with greater affinity than the trans-isomer, at nanomolar concentrations. In functional assays, this ligand showed a preference for recruiting β-arrestin2 over mini-Gαq relative to LSD, offering a tool to investigate β-arrestin2's role in 5-HT2AR signaling and its potential involvement in psychedelic effects.