Photoswitchable Serotonins for Optical Control of the 5-HT2A Receptor
Bibliographic record
Abstract
The serotonin receptor family of G protein-coupled receptors (GPCRs) and ligand-gated ion channels play central roles in neuromodulation and are critical drug targets for the treatment of psychiatric disorders. Optical control of serotonin receptor subtypes has the potential to greatly enhance our understanding of the spatiotemporal dynamics of receptor function both at the cellular level and within neural circuits. While other neuromodulatory receptors have been successfully rendered photoswitchable, reversible photocontrol of serotonin receptors has not been achieved, representing a major gap in GPCR photopharmacology. Herein, by designing and screening a family of azobenzene-conjugated serotonin analogues, we developed the first photopharmacological tools that allow for such control. Azo5HT-2 shows light-dependent 5-HT2AR agonism, inducing receptor-mediated calcium signaling in the light-activated cis-form. Based on computational docking and test compound analysis, we also synthesize and test photoswitchable orthogonal, remotely-tethered ligands (PORTLs). BG-Azo5HTn PORTLs provide rapid, reversible and repeatable optical control following conjugation to SNAP-tagged 5-HT2AR. Overall, this study both introduces new tools for the optical control of 5-HT2ARs and provides a foundation for the broad extension of photopharmacology to the serotonin receptor family.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".