Psychedelic-inspired drug discovery using an engineered biosensor.
Cell
; 184(10): 2779-2792.e18, 2021 05 13.
Article
en En
| MEDLINE
| ID: mdl-33915107
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.
Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Técnicas Biosensibles
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Drogas de Diseño
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Receptor de Serotonina 5-HT2A
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Descubrimiento de Drogas
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Alucinógenos
Límite:
Animals
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Female
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Humans
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Male
Idioma:
En
Año:
2021
Tipo del documento:
Article