Bifunctional μ/δ Opioid Peptides: Variation of the Type and Length of the Linker Connecting the Two Components
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Bibliographic record
Abstract
On the basis of evidence that opioid compounds with a mixed μ agonist/δ antagonist profile may produce an antinociceptive effect with low propensity to induce side effects, bifunctional opioid peptides containing the μ agonist H-Dmt-d-Arg-Phe-Lys-NH(2) ([Dmt(1) ]DALDA; Dmt = 2',6'-dimethyltyrosine) connected tail-to-tail via various α,ω-diaminoalkyl- or diaminocyclohexane linkers to the δ antagonists H-Tyr-TicΨ[CH(2) -NH]Cha-Phe-OH (TICP[Ψ]; Cha = cyclohexylalanine, Tic = 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid), H-Dmt-Tic-OH or H-Bcp-Tic-OH (Bcp = 4'-[N-((4'-phenyl)phenethyl)carboxamido]phenylalanine) were synthesized and pharmacologically characterized in vitro. Bifunctional [Dmt(1) ]DALDA→NH-(CH(2) )(n) -NH←TICP[Ψ] compounds (n = -12) showed decreasing μ and δ receptor binding affinities with increasing linker length. As expected, several of the bifunctional peptides were μ agonist/δ antagonists with low nanomolar μ and δ receptor binding affinities. However, compounds with unexpected opioid activity profiles, including a μ partial agonist/δ partial agonist, μ antagonist/δ antagonists and μ agonist/δ agonists, were also identified. These results indicate that the binding affinities and intrinsic efficacies of these bifunctional compounds at both receptors depend on the length and type of the linker connecting the μ and δ components. An important recommendation emerging from this study is that the in vitro activity profiles of bifunctional compounds containing an agonist and an antagonist component connected via a linker need to be determined prior to their pharmacological evaluation in vivo.
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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 | 0.001 |
| 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 | 0.000 |
| 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 it