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
Source: PubMed
Summary
Imagine controlling brain signals with light to understand complex brain functions. Scientists designed a unique light-activated molecule targeting the serotonin 2A receptor. This molecule precisely activates one specific pathway, β-arrestin2, over others, even at very low concentrations. This offers a powerful new tool to unravel the receptor's role in conditions like depression and its connection to psychedelic effects.
Abstract
The serotonin 2A receptor (5-HT2AR) modulates various neurotransmitter systems and is implicated in psychiatric disorders, including depression and schizophrenia. Despite progress, the detailed mechanisms of signaling at the 5-HT2AR 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-HT2AR ligand. In radioligand binding studies, the cis-photoisomer has a greater affinity than the trans-isomer at the 5-HT2AR and binds at nanomolar concentrations. In two highly analogous functional assays, the photoswitchable ligand showed a preference for β-arrestin2 recruitment over mini-Gαq recruitment relative to LSD, providing a compelling tool for investigating the role of β-arrestin2 recruitment in 5-HT2AR signaling and elucidating its potential role in psychedelic effects.