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Cited by 213Psychedelics and Drug StudiesReceptor Mechanisms and SignalingNeurotransmitter Receptor Influence on Behavior

Psychedelic-inspired drug discovery using an engineered biosensor

Open access
Dong, Chunyang, Ly, Calvin, Dunlap, Lee E., Vargas, Maxemiliano V., Sun, Junqing, Hwang, In-Wook, Azinfar, Arya, Oh, Won Chan +3 more·2021·Cell
DOI 10.1016/j.cell.2021.03.043PMC PMC8122087
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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.

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  • We engineered several non-hallucinogenic analogs of psychedelics with beneficial properties.

    “we were able to engineer several non-hallucinogenic analogs of psychedelics with beneficial properties”

    From Psychedelics and Other Psychoplastogens for Treating Mental Illness. (2021) · cites this paper as [251]

    The Discussion identifies AAZ-A-154 as a non-hallucinogenic psychedelic analog with neuronal-growth and lasting beneficial behavioral effects in rodents. It does not establish that the authors developed several such analogs with beneficial properties; the Results describe testing several known non-hallucinogenic congeners, not demonstrating those benefits for each. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • The psychoplastogenic effects of TBG and AAZ may involve activation of 5-HT2 receptors.

    “The psychoplastogenic effects of TBG and AAZ may involve activation of 5-HT2 receptors”

    From Psychedelics and Other Psychoplastogens for Treating Mental Illness. (2021) · cites this paper as [251]

    The Results section ('Characterizing the antidepressant-like effects of AAZ-A-154'; page not available) says ketanserin abolished AAZ-A-154-induced dendritic growth, suggesting activation of 5-HT2 receptors. The Discussion (page not available) identifies TBG as a psychoplastogen and a 5-HT2AR ligand, but does not establish that receptor activation contributes to TBG’s psychoplastogenic effect. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • AAZ and TBG produce sustained (>1 week) antidepressant-like effects following a single administration in both environmental (chronic unpredictable stress) and genetic (VMAT2 heterozygous mice) models of depression as measured via behavioral tests relevant to motivation, anhedonia, anxiety, and cognitive flexibility.

    “produce sustained (>1 week) antidepressant-like effects following a single administration in both environmental (chronic unpredictable stress) and genetic (VMAT2 heterozygous mice) models of depression as measured via behavioral tests relevant to motivation, anhedonia, anxiety, and cognitive flexibility”

    From Psychedelics and Other Psychoplastogens for Treating Mental Illness. (2021) · cites this paper as [251]

    Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

    Experimental — accuracy not yet measured

  • AAZ and TBG have demonstrated robust plasticity-promoting properties.

    “Our two most advanced compounds—AAZ and TBG—have demonstrated robust plasticity-promoting properties”

    From Psychedelics and Other Psychoplastogens for Treating Mental Illness. (2021) · cites this paper as [251]

  • Non-hallucinogenic psychoplastogens, like their hallucinogenic counterparts, produce sustained therapeutic behavioral responses in preclinical animal models after a single administration.

    “non-hallucinogenic psychoplastogens, like their hallucinogenic counterparts, produce sustained therapeutic behavioral responses in preclinical animal models after a single administration”

    From Psychedelics and Other Psychoplastogens for Treating Mental Illness. (2021) · cites this paper as [251]

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Authors
Dong, C., Ly, C., Dunlap, L. E., Vargas, M. V., Sun, J., Hwang, I.-W., Azinfar, A., Oh, W. C., Wetsel, W. C., Olson, D. E., & Tian, L.
Affiliations
  • University of California, Davis (US)
  • University of Colorado Anschutz (US)
  • Duke University (US)
Corresponding author
  • Olson, David E.
  • Tian, Lin
ORCID
Venue
Cell
Publisher
Elsevier BV
Published
2021-05
Volume
184
Issue
10
Pages
2779-2792.e18
ISSN
0092-8674 (ISSN-L)
DOI
10.1016/j.cell.2021.03.043
PMC
PMC8122087
OpenAlex
W3157088173
Cited by
213
References
68
Citations by year
2026: 35 · 2025: 51 · 2024: 51 · 2023: 30 · 2022: 30 · 2021: 16
FWCI
7.61
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell (publishedVersion)
  • SSRN Electronic Journal (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • National Institutes of Health (DP2MH107056, U01NS013522, U01NS090604, R01MH101214, U01NS103571, R21MH126073, R01GM128997, R01MH12478)
  • Denali Therapeutics
  • University of California, Davis (T32GM113770, 5T32GM099608)
  • University of Washington
  • Brain and Behavior Research Foundation (AAZ-A-154)
Topics
  • Social Sciences › Psychology › Clinical Psychology › Psychedelics and Drug Studies
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
Keywords
5-HT2A receptor, genetically encoded fluorescent sensors, serotonin release, hallucinogens, antidepressant-like effects, psychoplastogens
MeSH terms
Animals, Drug Evaluation, Preclinical, Female, Fluorescence, Fluorescent Dyes, Hallucinogens, Humans, Male, Mice, Inbred C57BL, Photometry, Protein Conformation, Serotonin, Designer Drugs, Protein Engineering, Biosensing Techniques, Receptor, Serotonin, 5-HT2A, Mice, Small Molecule Libraries, Drug Discovery, HEK293 Cells

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