Psychedelic-inspired drug discovery using an engineered biosensor

  • Cell. 2021 May 13;184(10):2779-2792.e18. doi: 10.1016/j.cell.2021.03.043.
Chunyang Dong  1 ,  Calvin Ly  2 ,  Lee E Dunlap  2 ,  Maxemiliano V Vargas  3 ,  Junqing Sun  4 ,  In-Wook Hwang  5 ,  Arya Azinfar  2 ,  Won Chan Oh  5 ,  William C Wetsel  6 ,  David E Olson  7 ,  Lin Tian  8
Affiliations
  • 1. Graduate Program in Biochemistry, Molecular, Cellular, Developmental Biology, University of California, Davis, Davis, CA 95616, USA; Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, Davis, CA, USA.
  • 2. Department of Chemistry, University of California, Davis, One Shields Avenue, Davis, CA 95616, USA.
  • 3. Neuroscience Graduate Program, University of California, Davis, Davis, CA 95618, USA.
  • 4. Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, Davis, CA, USA.
  • 5. Department of Pharmacology, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO 80045, USA.
  • 6. Departments of Psychiatry and Behavioral Sciences, Cell Biology, and Neurobiology, Mouse Behavioral and Neuroendocrine Analysis Core Facility, Duke University Medical Center, Durham, NC 27710, USA.
  • 7. Department of Chemistry, University of California, Davis, One Shields Avenue, Davis, CA 95616, USA; Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, Davis, CA, USA; Center for Neuroscience, University of California, Davis, 1544 Newton Court, Davis, CA 95618, USA. Electronic address: [email protected].
  • 8. Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, Davis, CA, USA; Center for Neuroscience, University of California, Davis, 1544 Newton Court, Davis, CA 95618, USA. Electronic address: [email protected].
PMID: 33915107 DOI: 10.1016/j.cell.2021.03.043
Abstract

Ligands can induce G protein-coupled receptors (GPCRs) to adopt a myriad of conformations, many of which play critical roles in determining the activation of specific signaling cascades associated with distinct functional and behavioral consequences. For example, the 5-hydroxytryptamine 2A receptor (5-HT2AR) is the target of classic hallucinogens, atypical antipsychotics, and psychoplastogens. However, currently available methods are inadequate for directly assessing 5-HT2AR conformation both in vitro and in vivo. Here, we developed psychLight, a genetically encoded fluorescent sensor based on the 5-HT2AR structure. PsychLight detects behaviorally relevant serotonin release and correctly predicts the hallucinogenic behavioral effects of structurally similar 5-HT2AR ligands. We further used psychLight to identify a non-hallucinogenic psychedelic analog, which produced rapid-onset and long-lasting antidepressant-like effects after a single administration. The advent of psychLight will enable in vivo detection of serotonin dynamics, early identification of designer drugs of abuse, and the development of 5-HT2AR-dependent non-hallucinogenic therapeutics.

Keywords
depression; genetically encoded indicators; hallucinogen; psychedelic; serotonin; serotonin receptors.
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