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 machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| 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 source (direct Gemma or distilled Codex), 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".