Opioid receptor research tool (Ac-YKWW-NH₂ / CHEMBL102690)
A synthetic four-amino-acid peptide that weakly binds opioid receptors; used only as a lab research tool to study how peptide structure affects opioid activity.
A researcher, an agent, or an algorithm wrote down the sequence and picked a target to hit.
An AI model like OpenFold3 or AlphaFold built a 3D structure and scored how well it fits the binding site.
A second contributor repeated the computation on their own hardware and the scores matched.
A chemistry service or a researcher ordered the sequence, it was manufactured, and mass spectrometry confirmed the right molecule was produced.
A binding or activity measurement confirmed that it actually does what the computer predicted — or didn't.
What this is
Ac-YKWW-NH₂ is a synthetic tetrapeptide — four amino acids long — studied as a research tool in opioid receptor pharmacology. It was synthesized and tested by Wan, Murray, and Aldrich (Journal of Medicinal Chemistry, 1999) as part of an effort to explore acetylated peptide analogues of dynorphin A, an endogenous opioid. The compound carries an N-terminal acetyl cap and a C-terminal amide group; the raw four-letter sequence YKWW does not reflect these modifications. It binds weakly and without selectivity to all three classical opioid receptor subtypes — delta (OPRD1), mu (OPRM1), and kappa — making it primarily a reference point in structure-activity relationship (SAR) research rather than a drug candidate.
What it does
At the delta opioid receptor (OPRD1), Ac-YKWW-NH₂ shows a Ki of 3,478 nM — roughly 3.5 micromolar — indicating very weak binding affinity. The compound also binds the mu (OPRM1) and kappa opioid receptors with similarly low affinity (Ki 3,590 nM and 1,367 nM respectively), with no meaningful selectivity across the three subtypes. All three values were measured by radioligand displacement: [³H]-DPDPE for delta, [³H]-DAMGO for mu, and [³H]-diprenorphine for kappa (Wan, Murray, and Aldrich, 1999).
Evidence
- Human: No human data. This compound has not been evaluated in human subjects.
- Animal: No animal data. All reported data are from cell-membrane binding assays.
- In vitro: Radioligand binding assays against opioid receptors: Ki (OPRD1, delta) = 3,478 nM; Ki (OPRM1, mu) = 3,590 nM; Ki (OPRK1, kappa) = 1,367 nM (Wan, Murray, and Aldrich, Journal of Medicinal Chemistry, 1999).
Mechanism
Opioid receptors are G protein-coupled receptors (GPCRs) expressed throughout the central and peripheral nervous system. Their endogenous peptide ligands — enkephalins (delta-preferring), endorphins (mu-preferring), and dynorphins (kappa-preferring) — all share the N-terminal motif Tyr-Gly-Gly-Phe, which acts as the receptor-activating "message sequence." Ac-YKWW-NH₂ retains the N-terminal tyrosine but replaces the Gly-Gly-Phe core with Lys-Trp-Trp, and blocks the free N-terminus with an acetyl group — a departure from the canonical pharmacophore that likely accounts for its weak, non-selective receptor engagement. The compound was part of an early SAR exploration by the Aldrich group into acetylated dynorphin A analogues, a programme that subsequently identified more potent and selective kappa-targeted peptides.
Related peptides
- Arodyn (Ac[Phe¹,²,³,Arg⁴,D-Ala⁸]Dyn A-(1–11)-NH₂) is an 11-residue acetylated dynorphin A analogue from the same research programme, later identified as a selective kappa opioid receptor antagonist (Bennett, Murray, and Aldrich, 2002).
- Met-enkephalin (Tyr-Gly-Gly-Phe-Met) and Leu-enkephalin (Tyr-Gly-Gly-Phe-Leu) are endogenous delta-preferring opioid pentapeptides whose Tyr-Gly-Gly-Phe message sequence Ac-YKWW-NH₂ structurally departs from.
Research directions for this peptide, selected from the current sources — hypotheses you can explore and model. None of it is proven yet; tap any one to see the full thinking.
If a short positively charged sequence is attached to YKWW, will the resulting peptide bind only the kappa opioid receptor?
A kappa-selective peptide could potentially treat chronic pain and severe itch without triggering the euphoria and dependence associated with mu-receptor drugs like morphine, offering a safer option for patients with conditions poorly served by current opioids.
Do the two tryptophan amino acids at the end of YKWW grip the opioid receptor in a way that is shared by all three receptor types?
If confirmed, chemists would know exactly which part of the molecule to keep untouched and which part to modify when designing new, more targeted opioid drugs, shortening the drug discovery process.
Is the single positively charged amino acid in YKWW preventing the peptide from binding one opioid receptor much more strongly than the others?
If removing that one amino acid reveals selectivity, it would accelerate the design of opioid drugs that hit only the desired receptor, reducing side effects for pain and mood disorder patients.
Does the YKWW tetrapeptide bind the kappa opioid receptor for a structural reason that could be exploited to build a selective kappa drug?
If true, researchers would have a tiny, chemically simple starting point for kappa-selective painkillers, which could relieve pain and itch without the dependence risk of drugs like morphine, benefiting patients and prescribers alike.
Does YKWW actually switch on opioid receptors, or does it sit in the binding site without triggering a signal?
If YKWW turns out to partially block opioid receptors, it could be developed as a template for drugs that dampen opioid signalling, potentially useful in treating opioid overdose or addiction with fewer withdrawal side effects than existing blockers like naloxone.
▸full evidence table1 metrics
| metric | value | tool |
|---|---|---|
| Ki | 3478 nM | GPCRDB/ChEMBL |
▸structural qualityopenfold3
| metric | value | note |
|---|---|---|
| gpde | 0.990 | global PDE — lower = better |
| disorder | NaN | fraction disordered |
▸3-letter notation
▸recipeboltz-2 1.0
| parameter | value |
|---|---|
| model | boltz-2 1.0 |
| weights | — |
| hardware | nvidia_nim_api |
| mlx version | — |
| python | — |
| random seed | — |
| msa strategy | none |
| diffusion samples | 1 |
| runtime | — |
| predicted by | mlx@peptide |
| predicted at | 2026-04-24 |
▸citationbibtex
@peptide{pep10413,
sequence = {YKWW},
target = {oprd1},
author = {peptidemodel},
year = {2026},
status = {bioassayed}
}