5-HT2A Receptor Pathways And Psychedelic Potential (Wallach et al., 2023)

Описание: I. Introduction to Psychedelic Therapeutics
Serotonergic psychedelics show therapeutic potential for mental health.
Hallucinogenic effects can limit their clinical application.
This study explores separating therapeutic from psychedelic effects.
Researchers focused on the 5-HT2A receptor signaling pathways.
The goal was to guide the rational design of new non-psychedelic drugs.

II. Investigating Receptor Signaling
Classical psychedelics activate two main intracellular pathways.
These pathways are Gq signaling and beta-arrestin2 recruitment.
Previous research had not clarified which pathway drives hallucinations.
The team developed selective ligands to test these specific pathways.
Bioluminescence resonance energy transfer was used to measure activity.

III. The Role of Gq Signaling
The study used the head-twitch response in mice as a psychedelic proxy.
5-HT2A-Gq activation efficacy predicts psychedelic potential in vivo.
A threshold level of Gq activation is required for these effects.
Compounds below this Gq threshold do not cause head twitches.
Lisuride is non-psychedelic because it does not meet this threshold.

IV. Beta-Arrestin Biased Agonists
The team engineered beta-arrestin-biased 5-HT2A agonists.
These compounds recruit beta-arrestin but have weak Gq efficacy.
These biased agonists did not induce a psychedelic head-twitch response.
Interestingly, they blocked the effects of standard psychedelics.
This confirms beta-arrestin recruitment alone does not cause hallucinations.

V. Structural Mechanisms & Design
Molecular dynamics showed unique receptor binding conformations.
The residue W336 acts as a toggle switch for biased signaling.
Steric bulk on the ligand influences the signaling pathway choice.
Larger substituents can prevent the Gq-active conformation.
This structural insight aids in designing specific therapeutic agents.

VI. Therapeutic Implications
Findings suggest distinct pathways for different behavioral effects.
Beta-arrestin-biased ligands promoted receptor downregulation.
These ligands also blocked hyperactivity in schizophrenia models.
This mimics the effects of antipsychotics with potentially fewer side effects.
Novel compounds could treat neuropsychiatric disorders without trips.

VII. Additional Resource Support
See NourishED RFI's NotebookLM Resource Support Page.
https://notebooklm.google.com/noteboo...

VIII. Source
Wallach, J., Cao, A. B., Calkins, M. M., Heim, A. J., Lanham, J. K., Bonniwell, E. M., Hennessey, J. J., Bock, H. A., Anderson, E. I., Sherwood, A. M., Morris, H., de Klein, R., Klein, A. K., Cuccurazzu, B., Gamrat, J., Fannana, T., Zauhar, R., Halberstadt, A. L., & McCorvy, J. D. (2023). Identification of 5-HT2A receptor signaling pathways associated with psychedelic potential. Nature Communications, 14(1). https://doi.org/10.1038/s41467-023-44...

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