Pain-receptor research peptide (CHEMBL1161419)
A tiny lab-made peptide used to study how opioid receptors, the same ones morphine acts on, recognize pain-relieving molecules; a research tool only, not a medicine.
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
CHEMBL1161419 is a synthetic four-residue research peptide designed to probe how the mu-opioid receptor — the main target of morphine and related analgesics — recognises its ligands. Built as a modified version of endomorphin-2, a naturally occurring brain opioid peptide, it was synthesised at Harvard as part of a structure–activity study examining what structural features are needed for high-affinity mu-receptor binding. The compound binds the mu-opioid receptor (OPRM1) with sub-nanomolar potency while showing essentially no affinity for the delta-opioid receptor (OPRD1), despite being catalogued in ChEMBL under OPRD1 because a delta-receptor assay was also conducted. It is not approved for any use and exists only as a biochemical tool. The stored raw sequence (FFF) represents only the three phenylalanine residues; the full compound is a tetrapeptide with D-proline at position 2 and a C-terminal amide, neither of which appears in the stored sequence field.
History
Endomorphin-2 (H-Tyr-Pro-Phe-Phe-NH₂) is an endogenous tetrapeptide first described in 1997 that shows unusually high selectivity for the mu-opioid receptor. Harrison and colleagues at Harvard (Verdine laboratory) used endomorphin-2 as the scaffold for an exhaustively stereodiversified ligand library to explore the chemical space around its core backbone. In a 2003 publication in the Journal of Medicinal Chemistry, they reported a series of analogues — including compounds with 2,6-dimethyltyrosine at position 1 and varied stereochemistry at other positions — that retained or exceeded endomorphin-2's potency at OPRM1 (Harrison and colleagues, J Med Chem 2003). CHEMBL1161419, with phenylalanine substituted at the N-terminal position in place of the canonical tyrosine and D-proline at position 2, was among the compounds characterised in that programme to establish how each structural departure from the natural sequence affects receptor selectivity and binding affinity.
What it does
The compound binds the mu-opioid receptor with high affinity and acts as a full agonist: in a [³⁵S]GTPγS functional assay, it stimulates G-protein coupling in OPRM1-expressing cell membranes with an EC50 of 31 nM and 100% maximal efficacy relative to a reference agonist (Harrison and colleagues, J Med Chem 2003). It shows negligible affinity for the delta-opioid receptor and low affinity for the kappa-opioid receptor at the concentrations studied. Its primary scientific value lies in the SAR insight it provides: by replacing the N-terminal tyrosine of endomorphin-2 with phenylalanine — thereby removing the phenolic hydroxyl that was traditionally considered essential for opioid activity — researchers could quantify the hydroxyl's contribution to mu selectivity and binding potency.
Evidence
- Human: No human studies. This is a research ligand only.
- Animal: No in vivo animal studies identified for this specific compound.
- In vitro: Radioligand displacement assays in transfected cell lines: OPRM1 Ki = 0.69 nM (displacement of [³H]DAMGO from human OPRM1-expressing CHO cells); OPRD1 Ki = 25,000 nM (displacement of [³H]diprenorphine from human OPRD1-expressing HEK293 cells); OPRK1 Ki = 10,400 nM (guinea pig cerebellar preparation). The μ/δ selectivity ratio is approximately 36,000-fold in favour of OPRM1. Full-agonist functional activity confirmed by [³⁵S]GTPγS incorporation. All data from Harrison and colleagues (J Med Chem 2003).
Known effects
- OPRM1 binding — High potency in vitro (Ki 0.69 nM); full agonist by [³⁵S]GTPγS assay (EC50 31 nM). Mechanistic only — no in vivo efficacy data for this compound.
- OPRD1 binding — Essentially inactive (Ki 25,000 nM). The ChEMBL record indexes this compound under OPRD1 because the delta-receptor displacement assay was run, but the measured affinity is negligible.
- OPRK1 binding — Weak (Ki 10,400 nM).
Mechanism
CHEMBL1161419 belongs to the endomorphin-2 analogue class. Endomorphin-2 (Tyr-Pro-Phe-Phe-NH₂) achieves its exceptional mu-selectivity through several structural features: the N-terminal tyrosine phenolic hydroxyl makes key contacts in the OPRM1 orthosteric binding pocket; the L-Pro² residue constrains backbone conformation; and the C-terminal amide protects against carboxypeptidase degradation. In CHEMBL1161419, Tyr¹ is replaced by Phe (removing the hydroxyl) and L-Pro² is replaced by D-Pro², inverting stereochemistry at that position. Despite removal of the phenolic hydroxyl — a modification that in other endomorphin-2 analogue series substantially reduces mu-receptor affinity — this compound retains sub-nanomolar potency at OPRM1. The D-Pro substitution additionally improves resistance to dipeptidyl peptidase IV, the principal enzyme that cleaves at the Pro² position of endomorphins. Upon mu receptor engagement, the compound couples to Gi/o proteins, inhibiting adenylyl cyclase, suppressing N- and P/Q-type calcium channel conductance, and activating inwardly rectifying potassium channels — the same downstream pathway as morphine and endogenous enkephalins.
Regulatory status
- US: Not approved. Research reagent only.
- EU: Not approved. Research reagent only.
- No registered trials on ClinicalTrials.gov for this compound.
Related peptides
- Endomorphin-2 analogue with cyclic scaffold — pep-10425: another research ligand built on the endomorphin-2 Tyr-Pro-Phe-Phe-NH₂ core, here constrained into a cyclic pseudo-tetrapeptide; studied in the same opioid receptor SAR context.
- CTAP-type mu-opioid research ligand — pep-10434: a five-residue OPRM1 binder from the somatostatin-template CTAP scaffold series; a structurally distinct approach to mu-receptor pharmacology studied in parallel SAR programmes.
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.
Does flipping one amino acid from its unusual mirror-image form back to normal collapse selectivity for the pain receptor?
If true, drug designers chasing non-addictive painkillers could focus on mimicking a geometric kink rather than endlessly varying bulky side groups, potentially speeding up the discovery of safer analgesics for the millions living with chronic pain.
Does the amide group at the end of this peptide actively trigger receptor activation, or just stabilise the molecule?
Understanding which chemical features flip a receptor from active to inactive could guide the rational design of opioid antagonists for overdose reversal or opioid-use disorder treatment, helping clinicians with more targeted options.
Would adding small methyl groups to the ring structures of the phenylalanine amino acids push binding to the pain receptor from nanomolar down to picomolar strength?
If true, an ultra-potent version of this scaffold could work at much lower doses, potentially reducing side-effect burden for patients requiring strong analgesics and giving chemists a cleaner tool to study opioid receptor biology.
Could this compound accidentally bind the anti-opioid receptor NPFFR2, which controls how quickly pain drugs lose their effect?
If this peptide hits both receptors, it could reduce the tolerance build-up that forces chronic pain patients onto ever-higher opioid doses, potentially offering a new strategy to maintain long-term pain relief without escalating drug exposure.
Is the gap between this compound's activity at the two opioid receptors large enough to separate pain relief from delta-receptor side effects?
If the potency gap is as large as the data suggest, this scaffold could inform analgesic designs that deliver pain relief with fewer delta-opioid complications, potentially benefiting patients who need long-term opioid therapy.
▸full evidence table1 metrics
| metric | value | tool |
|---|---|---|
| Ki | 25000 nM | GPCRDB/ChEMBL |
▸structural qualityopenfold3
| metric | value | note |
|---|---|---|
| gpde | 0.949 | 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{pep10415,
sequence = {FFF},
target = {oprd1},
author = {peptidemodel},
year = {2026},
status = {bioassayed}
}