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