Structure-activity relationships of contulakin-G: Design, synthesis, and characterization of Thr10 analogs for pain modulation
Bibliographic record
Abstract
Contulakins are a subclass of conopeptides derived from cone snail venom, known for their analgesic properties mediated through activation of neurotensin receptors NTS1 and NTS2. Among them, contulakin-G, isolated from Conus geographus , exhibits a favorable pharmacokinetic profile, including a 24-hour plasma half-life, and produces potent opioid-independent antinociceptive effects. To facilitate synthesis while preserving analgesic efficacy, we investigated the structure-activity relationships of contulakin-G, focusing on modifications to the glycosylated Thr 10 residue. In the first series, Thr 10 was substituted by natural and non-natural amino acids encompassing diverse physiochemical and steric properties. Most substitutions had minimal impact on receptor affinity, though some increased the NTS2/NTS1 selectivity ratio. Of these, only the Tyr 10 analog retained antinociceptive efficacy comparable to native contulakin-G. Building on tyrosine's hydrophobicity, a second series introduced non-natural hydrophobic residues at position 10, including Gln-cycloheptyl, Gln-biphenylmethyl, and Gln-dimethyladamantyl, along with a non-glycosylated form. In both tonic and postoperative pain models, the non-glycosylated and Gln-cycloheptyl analogs demonstrated potent analgesic activity, comparable to contulakin-G and reversed mechanical allodynia in a neuropathic pain model. In contrast, a third series involving N -terminal truncations led to reduced plasma half-life and loss of antinociceptive efficacy, underscoring the importance of the N -terminal region. Molecular modeling further revealed that full-length analogs engage a broader NTS2 binding interface than truncated derivatives. These findings support the development of synthetically accessible contulakin-G analogs as promising non-opioid analgesics.
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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 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 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 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".