Nucleoligands-repurposing G Protein–coupled Receptor Ligands to Modulate Nuclear-localized G Protein–coupled Receptors in the Cardiovascular System
Bibliographic record
Abstract
There is significant evidence that internal pools of G protein-coupled receptors (GPCRs) exist and may be affected by both endogenous signaling molecules and hydrophobic pharmaceutical ligands, once assumed to only affect cell surface versions of these receptors. Here, we discuss evidence that the biology of nuclear GPCRs in particular is complex, rich, and highly interactive with GPCR signaling from the cell surface. Caging existing GPCR ligands may be an excellent means of further stratifying the phenotypic effects of known pharmacophores such as β-adrenergic, angiotensin II, and type B endothelin receptor ligands in the cardiovascular system. We describe some synthetic strategies we have used to design ligands to go from in cellulo to in vivo experiments. We also consider how surface and intracellular GPCR signaling might be integrated and ways to dissect this. If they could be selectively targeted, nuclear GPCRs and their associated nucleoligands would represent a completely novel area for exploration by Pharma.
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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 | 0.009 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.006 | 0.010 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.003 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.000 | 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".