Psychedelic-inspired drug discovery using an engineered biosensor.

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Dong, C; Ly, C; Dunlap, LE; Vargas, MV; Sun, J; Hwang, I-W; Azinfar, A; Oh, WC; Wetsel, WC; Olson, DE; Tian, L

Published Date

  • May 13, 2021

Published In

Volume / Issue

  • 184 / 10

Start / End Page

  • 2779 - 2792.e18

PubMed ID

  • 33915107

Pubmed Central ID

  • PMC8122087

Electronic International Standard Serial Number (EISSN)

  • 1097-4172

Digital Object Identifier (DOI)

  • 10.1016/j.cell.2021.03.043

Language

  • eng

Conference Location

  • United States