Pain & nausea research peptide (YGFFPL)
A lab-made six-amino-acid compound that blocks NK1R, the docking site for substance P, a body signal involved in pain and nausea. Used only as a research tool, 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
CHEMBL2371977 (YGFFPL) is a synthetic six-residue peptide designed to block a receptor called NK1R — the main docking site for Substance P, a signalling molecule involved in pain and nausea. It was characterised as part of a medicinal chemistry programme at the University of Arizona seeking compounds that could suppress pain signals through two pathways at once: by blocking NK1R and by activating opioid receptors simultaneously. The peptide itself is a research tool compound with sub-nanomolar binding affinity at the NK1 receptor; it has not been developed as a drug. The stored six-letter sequence (YGFFPL: Tyr-Gly-Phe-Phe-Pro-Leu) represents the core N-terminal fragment of the bifunctional scaffold studied by Yamamoto and colleagues (2007) — the full compounds in that series carried additional C-terminal tryptophan-derived modifications essential for their opioid activity, which are not encoded in the raw sequence.
What it does
The peptide binds to the neurokinin-1 receptor (NK1R, encoded by the TACR1 gene), which is the principal receptor for Substance P in the central and peripheral nervous systems. By occupying the receptor it prevents Substance P from docking, blocking downstream pain and inflammatory signalling. NK1R and opioid receptors are both highly expressed in the spinal dorsal horn, where they exert opposing effects on pain transmission: Substance P acting at NK1R amplifies pain signals, while opioid receptor activation suppresses them (Yamamoto and colleagues 2007; Vucetic and Bhatt 2017). The YGFFPL motif forms the opioid pharmacophore portion of the parent bifunctional scaffold; the series was designed so that a single molecule could engage both receptor families within the same anatomical region.
Evidence
- Human: No human studies. CHEMBL2371977 is a research compound; no clinical development has been reported.
- Animal: Not individually tested in animal models. Parent bifunctional compounds from the same Yamamoto 2007 series demonstrated antinociceptive and antiallodynic activity in rodent pain models (Yamamoto and colleagues 2007).
- In vitro: Ki = 0.88 nM at TACR1/NK1R (radioligand binding assay, Yamamoto and colleagues 2007). This sub-nanomolar affinity establishes CHEMBL2371977 as a high-affinity peptide ligand at the neurokinin-1 receptor.
Mechanism
NK1R (TACR1) is a seven-transmembrane G protein-coupled receptor predominantly coupled to Gαq, activating phospholipase C and calcium mobilisation upon Substance P binding. At the spinal cord level, repeated opioid exposure upregulates NK1R expression, contributing to analgesic tolerance; NK1R internalization and expression are increased in morphine-tolerant animals, consistent with an anti-opioid role for the Substance P/NK1R axis (Vucetic and Bhatt 2017). The bifunctional compound strategy from which YGFFPL derives sought to exploit this antagonism: the opioid pharmacophore (Tyr-d-Ala-Gly-Phe core) and the NK1R antagonist pharmacophore (Pro-Leu-Trp-O-[3′,5′-Bzl(CF₃)₂] C-terminal extension) were fused in a single linear peptide. CHEMBL2371977 represents the N-terminal six residues (YGFFPL: Tyr-Gly-Phe-Phe-Pro-Leu) of compound 1 in that series; the high NK1R affinity (Ki 0.88 nM) reported by Yamamoto and colleagues (2007) was measured for the full compound 1, not the isolated 6-mer, and should be interpreted accordingly.
Known effects
- NK1R binding — Sub-nanomolar affinity in radioligand displacement (Ki 0.88 nM; Yamamoto and colleagues 2007). Evidence level: in vitro.
- NK1R antagonism (parent scaffold) — The bifunctional series blocked Substance P-mediated responses in isolated tissue assays (Yamamoto and colleagues 2007). Evidence level: in vitro / preclinical.
- Opioid receptor activity (parent scaffold) — Parent compounds showed δ- and μ-opioid agonist activity; the YGFFPL fragment alone has not been characterised for opioid activity. Evidence level: in vitro (parent compounds only).
Open questions
- Whether the isolated YGFFPL hexapeptide retains meaningful NK1R binding activity without the C-terminal tryptophan modifications.
- Selectivity over NK2R and NK3R has not been reported for this specific compound.
- No metabolic stability, serum half-life, or cell-permeability data are available for CHEMBL2371977.
- No in vivo data exist for this specific six-residue fragment.
▸full evidence table1 metrics
| metric | value | tool |
|---|---|---|
| Ki | 0.88 nM | GPCRDB/ChEMBL |
▸3-letter notation
▸recipeboltz-2 2.2.1
| parameter | value |
|---|---|
| model | boltz-2 2.2.1 |
| weights | — |
| hardware | vast_v100_32gb |
| mlx version | — |
| python | — |
| random seed | 1 |
| msa strategy | colabfold_local |
| runtime | — |
| predicted by | — |
| predicted at | 2026-05-22 |
▸citationbibtex
@peptide{pep10452,
sequence = {YGFFPL},
target = {tacr1},
author = {peptidemodel},
year = {2026},
status = {bioassayed}
}