<i>De Novo</i> Conception of Small Molecule Modulators Based on Endogenous Peptide Ligands: Pyrrolodiazepin-2-one γ-Turn Mimics That Differentially Modulate Urotensin II Receptor-Mediated Vasoconstriction <i>ex Vivo</i>
Bibliographic record
Abstract
A proof-of-concept library of pyrrolodiazepinone small molecules was designed based on the Bip-Lys-Tyr motif found in a recently described modulator of the urotensinergic system. Solid-phase synthesis provided 13 analogues, which were tested for their ability to modulate selectively and differentially the potency (EC50) and efficacy (E(max)) of hUII and URP ex vivo in a rat aortic ring bioassay. Notably, at 14 μM, pyrrolodiazepinone R-4a inhibited completely hUII-induced contractions and increased URP-associated vasoconstriction. Pyrrolodiazepinone R-4a represents, to the best of our knowledge, a first-in-class small molecule that exerts a probe-dependent effect on hUII and URP biological activities and proves that UT modulators of the urotensin II receptor (UT) can be rationally designed. The importance of the UT system in the pathogenesis and progression of cardiovascular diseases highlights the utility of pyrrolodiazepinones such as R-4a, which exhibit promising potential as tools for differentiating the respective roles, signaling pathways, and phenotypic outcomes of UII and URP in the UT system.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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) | 0.001 | 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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
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".