The Power of Visual Imagery in Drug Design. Isopavines as a New Class of Morphinomimetics and Their Human Opioid Receptor Binding Activity
Bibliographic record
Abstract
The importance of visual imagery and relational thinking manifests itself in a heuristic approach to the design and synthesis of potential morphinomimetics as agonists of the human mu receptor. The well-known class of alkaloids represented by the isopavine nucleus has a topological resemblance to the morphine skeleton, especially when viewed in a particular way. Enantiopure isopavines can be readily obtained from a 1,2 Stevens rearrangement of 13-substituted dihydromethanodibenzoazocines, prepared in four steps from d- and l-amino acids. Consideration of the topology and the expected orientation of the nitrogen lone pair for a better overlap with morphine necessitates the utilization of d-amino acids. By variation of the substituents on the aromatic rings and a judicious choice of ring substituents, it is possible to obtain low nanomolar binding to the human mu receptor while maintaining good to excellent mu/delta selectivity. Agonist-like activity is indicated in a functional assay for one of the analogues originally derived from d-alanine as a precursor. X-ray crystal structures of several compounds corroborate stereochemistries and overall topologies.
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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 | 0.002 |
| 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 | 0.001 |
| 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".