A Structure–Activity Relationship Study of Novel Positive Allosteric Modulators for the δ-Opioid Receptor
Bibliographic record
Abstract
Chronic pain and depression are widely prevalent comorbid conditions with limited safe, yet effective treatments. While μ-opioid receptor (MOR) agonists are effective for treating pain, they are plagued with significant drawbacks, including dependence, addiction, and respiratory depression. The δ-opioid receptor (DOR) offers a promising alternative due to its potential ability to reduce pain but with a reduced side effect profile. Previous studies have identified potent DOR positive allosteric modulators (PAMs) capable of eliciting bias through allostery. Our research has focused on developing the structure-activity relationship (SAR) around these PAMs, investigating DOR vs MOR/KOR selectivity, and lowering lipophilicity. We have developed a novel tetrazoloquinazolinone scaffold, which exhibits G protein-pathway favorability over β-arrestin2 recruitment. This scaffold offers a promising avenue for designing drug-like, DOR-targeted therapeutics with specific signaling profiles, potentially leading to new treatment options for chronic pain and depression, as well as providing an avenue for utilization in further structural studies.
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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 | 0.000 | 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) | 0.000 | 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".