Design, Synthesis, and In Vitro Characterization of a Tryptamine-Based Visible-Light Photoswitchable 5-HT_2AR Ligand Showing Efficacy Preference for β-Arrestin over Mini-Gq

The serotonin 2A receptor (5-HT_2AR) modulates various neurotransmitter systems and is implicated in psychiatric disorders, including depression and schizophrenia. Despite progress, the detailed mechanisms of signaling at the 5-HT_2AR and its therapeutic implications remain unclear, warranting further exploration. Overcoming the limitations of conventional pharmacology, photopharmacology addresses issues such as spatial selectivity and spatiotemporal resolution by incorporating light as an additional external control element. To study the roles of G protein- and β-arrestin2-dependent signaling pathways independently, we designed a photoswitchable, pathway-selective 5-HT_2AR ligand. In radioligand binding studies, the <i>cis</i>-photoisomer has a greater affinity than the <i>trans-</i>isomer at the 5-HT_2AR and binds at nanomolar concentrations. In two highly analogous functional assays, the photoswitchable ligand showed a preference for β-arrestin2 recruitment over mini-Gα_q recruitment relative to LSD, providing a compelling tool for investigating the role of β-arrestin2 recruitment in 5-HT_2AR signaling and elucidating its potential role in psychedelic effects.