Development of agonists of endothelin‐1 exhibiting selectivity towards ET<sub>A</sub> receptors
Bibliographic record
Abstract
(1) Endothelin-1 (ET-1) is a bicyclic 21-amino-acid peptide causing a potent and sustained vasoconstriction, mainly through the ET(A) receptor subtype. So far, no selective ET(A) agonists are described in the literature. (2) A series of truncated and chemically modified ET-1 analogues were obtained through solid-phase peptide synthesis and their biological activity was assessed on rat thoracic aorta rings (ET(A) receptors) and guinea-pig lung parenchyma strips (ET(B) receptors). (3) Structure-activity studies led to the identification of ET-1 fragments exhibiting an ET(A) selective agonistic activity. (4) In particular, [D-Lys(9)]cyclo(11-15) ET-1(9-21) was the most potent peptide. It appeared as a full agonist of ET(A) receptors, being under two orders of magnitude less potent than ET-1 (EC(50): 2.3 x 10(-7) vs 6.8 x 10(-9) M). Interestingly, even a linear formylated analogue, [Ala(11,15), Trp(For)(21)]ET-1(9-21), showed a selective ET(A) activity (EC(50): 3.0 x 10(-6) M). None of the numerous analogues of the series exhibited substantial effects in the guinea-pig lung parenchyma bioassay. (5) Thus, this study describes the first compounds showing a significant bioactivity in an ET(A) pharmacological preparation while being inactive in an ET(B) paradigm. They show that the ET-1 pharmacophores, responsible for the ET(A)-mediated actions, are located within the 9-21 segment of the molecule. Moreover, the bicyclic structure of ET-1 does not appear as essential for the ET(A)-related vasoconstriction. Results also suggest that the positive charge of the Lys(9) side chain participates in an intramolecular ionic bond with the carboxylate function of Asp(18).
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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 | 0.001 |
| 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".