Nausea & pain signal blocker (CHEMBL2369600)
A lab-made ring-shaped peptide that blocks the docking site (called NK-1) that the brain chemical substance P uses to send pain and nausea signals; 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
CHEMBL2369600 is a synthetic cyclic hexapeptide that binds to the NK-1 receptor — the protein that the brain chemical substance P uses to transmit pain signals and trigger nausea. It was created as a research tool in the 1990s to explore how the same peptide scaffold could be used to interact with multiple receptor families, including both substance P (NK-1) and somatostatin receptors. It has not been developed as a drug.
The stored sequence PFYTF is a five-residue shorthand. The actual compound is a head-to-tail cyclic hexapeptide, c[-Pro-Phe-D-Trp-Tyr-Thr-Phe-], containing a D-tryptophan at position 3 and a backbone cyclization that are absent from the raw sequence display; these structural features are central to its receptor-binding activity (Hirschmann et al. 1996; Schiller and colleagues 2000).
History
This compound emerged from a research programme led by Ralph Hirschmann and Amos B. Smith III at the University of Pennsylvania, focused on designing "polyvalent peptidomimetics" — compact cyclic scaffolds that could be tuned to act at structurally distinct receptors. In 1996, Hirschmann and colleagues reported in the Journal of Medicinal Chemistry that systematic substitution of residues in the somatostatin agonist L-363,301 — using a small combinatorial minilibrary — converted the scaffold into potent NK-1 receptor antagonists, demonstrating that a single cyclic peptide framework could be redirected across receptor families by residue-level changes (Hirschmann et al. 1996).
CHEMBL2369600 (c[-Pro-Phe-D-Trp-Tyr-Thr-Phe-]) later appeared as a named compound in a 2000 follow-up study by Schiller and colleagues, which extended the work into opioid receptor pharmacology, showing that closely related cyclic hexapeptides could acquire delta- and mu-opioid receptor activity while retaining the NK-1 scaffold (Schiller and colleagues 2000).
What it does
CHEMBL2369600 antagonises the NK-1 receptor, the primary receptor for substance P. Substance P is a neuropeptide released during pain and stress; when it binds NK-1R it activates signalling pathways involved in pain transmission, neurogenic inflammation, and the vomiting reflex. An antagonist blocks this binding without activating the receptor. At concentrations in the low-micromolar range (IC50 = 1045 nM at human NK-1R), this compound competes with substance P for receptor occupancy (Hirschmann et al. 1996).
The same cyclic scaffold also shows affinity for opioid receptors. Schiller and colleagues (2000) reported delta-opioid antagonist activity for the compound in a mouse vas deferens bioassay (Ke = 128 nM) and binding affinity at the delta-opioid receptor (Ki = 152 nM), alongside mu-opioid receptor affinity (Ki = 759 nM, rat brain membrane). This dual NK-1/opioid activity made the compound pharmacologically interesting as evidence that a single cyclic peptide backbone can span structurally distinct receptor families.
Evidence
- Human: No clinical data. This is a research ligand characterised in biochemical and isolated-tissue assays only.
- Animal: Bioassay data in isolated mouse vas deferens (delta-opioid antagonism, Ke = 128 nM) and guinea pig ileum (Schiller and colleagues 2000). No in vivo animal studies identified.
- In vitro: IC50 = 1045 nM at human NK-1R (radioligand binding, Hirschmann et al. 1996). Ki = 152 nM (delta-opioid receptor, rat brain membrane); Ki = 759 nM (mu-opioid receptor, rat brain membrane) (Schiller and colleagues 2000).
Mechanism
NK-1R (gene name TACR1) is a seven-transmembrane G protein-coupled receptor of 407 amino acids. It couples to multiple G proteins: Gq/11 activates phospholipase C-β, elevating intracellular calcium; Gs stimulates adenylate cyclase and cAMP production; Gi inhibits adenylate cyclase; G12/13 mediates Rho-dependent cytoskeletal effects. Downstream, SP binding triggers MAPK/ERK activation and NF-κB-dependent transcription, contributing to neurogenic inflammation and cell proliferation (Garcia-Recio & Gascón 2015). The endogenous affinity hierarchy at NK-1R is SP > neurokinin A > neurokinin B.
CHEMBL2369600 acts as an antagonist at this receptor. The Phe-Trp-Tyr triad of the cyclic hexapeptide contributes to binding in a manner analogous to the pharmacophore found in substance P's C-terminal region, which carries the conserved Phe-X-Gly-Leu-Met-NH₂ motif responsible for receptor engagement. By incorporating a D-Trp residue and constraining the backbone through cyclization, the scaffold achieves conformational preorganisation that allows it to occupy the receptor binding pocket without triggering signal transduction (Hirschmann et al. 1996).
The compound's dual NK-1/opioid activity reflects a principle articulated by Hirschmann's group: that constrained cyclic peptide scaffolds can present side-chain arrays that mimic the binding epitopes of structurally unrelated receptor classes, provided the spatial orientation of key aromatic residues is preserved (Schiller and colleagues 2000).
Known effects
- NK-1 receptor antagonism — Mechanistic only. IC50 = 1045 nM at human NK-1R in vitro (Hirschmann et al. 1996).
- Delta-opioid receptor antagonism — Preclinical (isolated tissue). Ke = 128 nM, Ki = 152 nM (Schiller and colleagues 2000).
- Mu-opioid receptor binding — Preclinical (in vitro). Ki = 759 nM (Schiller and colleagues 2000).
Regulatory status
- US / EU: Not approved. Research compound with no IND or clinical development record.
- ClinicalTrials.gov: No registered trials identified for CHEMBL2369600 or its scaffold class.
Related peptides
The NK-1 antagonist class that reached clinical use is structurally distinct — approved non-peptide NK-1 antagonists include aprepitant (EMEND), which blocks the same TACR1 receptor. For tachykinin receptor biology more broadly, see also substance P and its receptor family members neurokinin A and neurokinin B, which share partial activity at NK-1R.
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.
Could the rigid ring shape of this synthetic peptide engage the brain's substance P receptor by positioning its phenylalanine side chains like the natural signal does, even though the two molecules share no sequence?
If true, this would support designing smaller, more stable receptor blockers that do not need to copy the exact chemical sequence of natural pain molecules, pointing toward anti-nausea and pain medicines that could work by mouth and last longer than today's peptide options.
▸full evidence table1 metrics
| metric | value | tool |
|---|---|---|
| IC50 | 1045 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{pep10449,
sequence = {PFYTF},
target = {tacr1},
author = {peptidemodel},
year = {2026},
status = {bioassayed}
}