2. Academic Validation
  3. 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

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

  • J Med Chem. 2025 Jul 10;68(13):13628-13639. doi: 10.1021/acs.jmedchem.5c00442.
Alexandra Sink 1,  Eline Pottie 2,  Samuel J Carter 3 4,  Robert J Tombari 5,  Verena Weber 6 7,  Paolo Carloni 6 8,  Giulia Rossetti 6 9 10,  David E Olson 3 4 11 12,  Christophe P Stove 2,  Michael Decker 1
Affiliations

Affiliations

  • 1 Institut für Pharmazie und Lebensmittelchemie, Pharmazeutische und Medizinische Chemie, Julius-Maximilians-Universität Würzburg (JMU), Am Hubland, Würzburg 97074 Germany.
  • 2 Laboratory of Toxicology, Department of Bioanalysis, Faculty of Pharmaceutical Sciences, Ghent University, Ghent B-9000, Belgium.
  • 3 Department of Chemistry, University of California, Davis, One Shields Avenue, Davis, California 95616, United States.
  • 4 Institute for Psychedelics and Neurotherapeutics, University of California, Davis, Davis, California 95616, United States.
  • 5 Chemistry and Chemical Biology Graduate Program, University of California, Davis, Davis, California 95616, United States.
  • 6 Institute for Neuroscience and Medicine (INM-9), Computational Biomedicine, Forschungszentrum Jülich, Wilhelm-Johnen-Straße, Jülich 52425, Germany.
  • 7 Department of Chemistry, Faculty of Mathematics, Computer Science and Natural Sciences, RWTH Aachen University institution, Aachen 52062, Germany.
  • 8 Department of Physics, Faculty of Mathematics, Computer Science and Natural Sciences, RWTH Aachen University, Aachen 52062, Germany.
  • 9 Jülich Supercomputing Center, Forschungszentrum Jülich, Wilhelm-Johnen-Straße, Jülich 52425, Germany.
  • 10 Department of Neurology, University Hospital Aachen, RWTH Aachen University, Pauwelsstraße 30, Aachen 52074, Germany.
  • 11 Department of Biochemistry & Molecular Medicine, School of Medicine, University of California, Davis, 2700 Stockton Blvd, Suite 2102, Sacramento, California 95817, United States.
  • 12 Center for Neuroscience, University of California, Davis, 1544 Newton Ct, Davis, California 95618, United States.
PMID: 40532050 DOI: 10.1021/acs.jmedchem.5c00442
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.

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