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Psychedelic-inspired drug discovery using an engineered biosensor.

Chunyang Dong1, Calvin Ly2, Lee E Dunlap2

  • 1Graduate 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.

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|April 29, 2021
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Summary
This summary is machine-generated.

Researchers developed psychLight, a novel fluorescent sensor for the 5-hydroxytryptamine 2A receptor (5-HT2AR). This tool enables in vivo detection of serotonin dynamics and aids in developing non-hallucinogenic therapeutics.

Keywords:
depressiongenetically encoded indicatorshallucinogenpsychedelicserotoninserotonin receptors

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Area of Science:

  • Neuroscience
  • Pharmacology
  • Biochemistry

Background:

  • G protein-coupled receptors (GPCRs) adopt various conformations influencing signaling pathways.
  • The 5-hydroxytryptamine 2A receptor (5-HT2AR) is a key target for psychoactive drugs, including hallucinogens.
  • Current methods for assessing 5-HT2AR conformation in vitro and in vivo are insufficient.

Purpose of the Study:

  • To develop a novel tool for assessing 5-HT2AR conformation and serotonin dynamics.
  • To enable in vivo detection of receptor activity and ligand effects.
  • To facilitate the discovery of novel therapeutics targeting the 5-HT2AR.

Main Methods:

  • Development of psychLight, a genetically encoded fluorescent sensor based on the 5-HT2AR structure.
  • Utilizing psychLight to detect behaviorally relevant serotonin release.
  • Correlating psychLight sensor output with the hallucinogenic effects of 5-HT2AR ligands.

Main Results:

  • PsychLight accurately detects serotonin release and predicts hallucinogenic potential of 5-HT2AR ligands.
  • PsychLight was used to identify a non-hallucinogenic psychedelic analog with antidepressant-like effects.
  • The sensor enables real-time monitoring of 5-HT2AR activity.

Conclusions:

  • PsychLight is a valuable tool for in vivo serotonin dynamics detection.
  • This sensor can aid in the early identification of designer drugs of abuse.
  • PsychLight facilitates the development of 5-HT2AR-dependent non-hallucinogenic therapeutics.