A Study of the Relationship between Biological Activity and Prolyl Amide Isomer Geometry in Oxytocin Using 5-<i>tert</i>-Butylproline To Augment the Cys<sup>6</sup>-Pro<sup>7</sup>Amide<i>Cis</i>-Isomer Population
Bibliographic record
Abstract
Three [5-t-BuPro(7)]oxytocin analogues were synthesized by substituting (2S,5R)-5-tert-butylproline for proline in oxytocin, [Mpa(1)]oxytocin, and [dPen(1)]oxytocin. Relative to oxytocin, [5-t-BuPro(7)]oxytocin and [Mpa(1),5-t-BuPro(7)]oxytocin exhibited strongly reduced binding affinity to the receptor; however, both peptides maintained the pharmacophore characteristics responsible for signal transfer evoking the same maximal response as oxytocin in the single-dose procedure and exhibiting partial agonistic activity in the cumulative dose-response procedure. Although [dPen(1)]oxytocin exhibited inhibitory as well as partial agonistic activity, [dPen(1),5-t-BuPro(7)]oxytocin exhibited only inhibitory potency with a similar in vitro pA(2) value of 7.50 in the absence of magnesium. In the presence of magnesium, [dPen(1), 5-t-BuPro(7)]oxytocin exhibited stronger inhibitory potency than [dPen(1)]oxytocin and no partial agonism. Assignment of the proton signals for the 5-tert-butylprolyl amide cis- and trans-isomers by two-dimensional NMR experiments in water indicated that the Cys(6)-Pro(7) peptide bond cis-isomer population was augmented relative to the prolyl peptides and measured respectively at 35%, 33%, and 20% in the 5-tert-butylproline(7) analogues of oxytocin, [Mpa(1)]oxytocin and [dPen(1)]oxytocin. Although caution must be taken when relating the increase in cis-isomer population with an influence on biological activity in [5-t-BuPro(7)]oxytocin analogues, the synthesis and evaluation of analogues 1-3 have provided additional evidence that can be used to support the hypothesis that the prolyl amide cis-isomer may favor antagonism and the trans-isomer is necessary for agonist activity.
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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 | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 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) | 0.000 | 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".