Psychedelic-inspired drug discovery using an engineered biosensor
This study describes the development and use of an engineered biosensor (PsychLight) that detects relevant serotonin release to predict the hallucinogenic behavioral effects of psychedelics. This tool is used to identify non-hallucinogenic psychedelic compounds that still elicit antidepressant-like effects.
Authors
- Maxemiliano Vargas
- Lee Edmunds Dunlap
Published
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.
Research Summary of 'Psychedelic-inspired drug discovery using an engineered biosensor'
Introduction
G protein-coupled receptors (GPCRs) are major drug targets, and ligands that stabilise particular receptor conformations can bias signalling toward therapeutically desirable pathways while avoiding side effects. Ligands at the serotonin 2A receptor (5-HT2AR) exemplify biased agonism and include clinically important compounds such as atypical antipsychotics, classical psychedelics (for example LSD), and so-called psychoplastogens that promote neural plasticity. Recent preclinical work suggests that neural plasticity and therapeutic benefit can be elicited by some 5-HT2AR-targeting compounds without necessarily producing overt hallucinatory effects, creating a need for assays that can predict whether a novel ligand will induce hallucinogen-associated receptor conformations. Dong and colleagues set out to build a genetically encoded fluorescent biosensor based on the human 5-HT2AR that reports ligand-induced receptor conformations and endogenous serotonin (5-HT) release in real time. Their goals were to: (1) create a sensor able to detect physiologically relevant 5-HT dynamics in vitro and in vivo, (2) determine whether sensor readouts distinguish hallucinogenic from non-hallucinogenic 5-HT2AR ligands, and (3) apply the sensor in a medium-throughput cellular assay to discover novel ligands, including non-hallucinogenic psychoplastogens with antidepressant-like properties.
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Study Details
- Study Typeindividual
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- APA Citation
Dong, C., Ly, C., Dunlap, L. E., Vargas, M. V., Sun, J., Hwang, I., Azinfar, A., Oh, W. C., Wetsel, W. C., Olson, D. E., & Tian, L. (2021). Psychedelic-inspired drug discovery using an engineered biosensor. Cell, 184(10), 2779-2792.e18. https://doi.org/10.1016/j.cell.2021.03.043
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