Discovery of a Novel Template, <i>N</i> 3-1′-Homologated 4′-Truncated Thiosugar-Substituted Xanthine as an A <sub>3</sub> AR Antagonist via Conversion of an A <sub>1</sub> AR Antagonist
Bibliographic record
Abstract
Adenosine receptors (ARs) are G protein-coupled receptors involved in diverse physiological and pathological processes. Among them, the A 3 subtype (A 3 AR) is an attractive therapeutic target due to its low basal expression and strong upregulation in inflamed or tumor tissues. Here, an A 1 AR-derived xanthine scaffold was repurposed toward A 3 AR antagonism by introducing a 1′-homologated 4′-truncated thiosugar at the N3 position. Structure–activity studies identified C8 substitution as the key determinant of subtype selectivity, while N1 groups modulated binding cooperatively. The optimized analogue 5p exhibited potent and selective A 3 AR binding ( K i = 6.8 nM) with functional antagonism, showing an enhanced A 1 /A 3 selectivity index (72) compared with that of the known xanthine-based A 3 AR antagonist I-ABOPX (4.5). These findings demonstrate that thiosugar homologation effectively redirects xanthine scaffolds toward selective A 3 AR antagonists and identify 5p as a promising lead compound.
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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) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.000 |
| 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".