Substance P receptor blocker (CHEMBL2369630)
A lab-made ring-shaped peptide that blocks the substance P receptor, which helps carry pain and nausea signals; used only as a research tool.
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
CHEMBL2369630 is a synthetic cyclic peptide designed as an antagonist of the NK1 receptor (also called the substance P receptor, encoded by TACR1). It belongs to a line of research that asked whether the backbone scaffold of somatostatin — a naturally cyclic, disulfide-bridged peptide — could be repurposed to block substance P rather than mimic it. The result is a 14-residue ring that competes with substance P for the NK1 receptor binding site with an IC50 of 44 nM in cell-based radioligand displacement assays, as reported by Liu and colleagues (Journal of Medicinal Chemistry, 2000).
The stored sequence GACKNFFWTFTS is a simplified 12-residue representation. The actual compound is a 14-residue cyclic peptide in which Cys at position 3 forms a disulfide bridge with a D-Cys residue at position 14, and position 9 carries a fluorinated non-canonical amino acid — neither the ring closure nor the modified residue is visible in the stored sequence.
History
The conceptual lineage of CHEMBL2369630 runs through two converging threads. The first is the tachykinin field itself: substance P was identified in 1931 by von Euler and Gaddum as an intestinal-contracting extract, its eleven-amino-acid sequence was determined in 1971, and by 1984 the community had agreed to name its three receptor subtypes NK1, NK2, and NK3 (Garcia-Recio and Gascón, BioMed Research International, 2015; Hökfelt and colleagues, Journal of Internal Medicine, 2001). Peptide antagonists derived directly from substance P's sequence emerged in the 1980s, but they suffered from poor selectivity, limited potency, and unfavorable pharmacokinetics.
The second thread is the somatostatin scaffold program. Somatostatin is itself a disulfide-cyclized peptide, and researchers including Hirschmann and Smith at the University of Pennsylvania, in collaboration with Merck Research Laboratories, had spent the preceding decade exploring whether its ring structure could serve as a geometry-fixing scaffold for diverse pharmacological activities. Liu and colleagues (Journal of Medicinal Chemistry, 2000) reported the culmination of that effort as applied to NK1 antagonism: by grafting substance P pharmacophore elements onto the somatostatin backbone they obtained a compound — CHEMBL2369630 — whose agonist-vs-antagonist behavior and receptor subtype selectivity they analyzed in terms of pseudosymmetry within the scaffold.
What it does
CHEMBL2369630 competes with substance P for binding to the NK1 receptor, displacing the radioligand [¹²⁵I]substance P from cells expressing TACR1 with IC50 = 44 nM. It also shows measurable, weaker affinity at the NK2 receptor (TACR2; IC50 = 730 nM in the same cell-based format), making it roughly 17-fold selective for NK1 over NK2 (Liu and colleagues, 2000, via ChEMBL bioactivity records).
The NK1 receptor is a G protein-coupled receptor expressed widely in the central and peripheral nervous system. Substance P binding to NK1 contributes to nociceptive signaling, the vomiting reflex, and neuromodulation; receptor antagonism at NK1 is the mechanism exploited by aprepitant, the FDA-approved antiemetic for chemotherapy-induced nausea (Garcia-Recio and Gascón, BioMed Research International, 2015).
Evidence
- Human: No human trials. CHEMBL2369630 is a research ligand characterised exclusively in biochemical and cell-based assays; no in vivo studies are recorded in the source publication or ChEMBL bioactivity database.
- Animal: None reported for this compound.
- In vitro: Radioligand displacement assays in CHO cells expressing human TACR1 or TACR2 yielded IC50 = 44 nM (NK1) and IC50 = 730 nM (NK2). Extended mutagenesis assays in COS cells with the same radioligand showed that substituting histidine residues in the NK1 receptor substantially reduced binding (IC50 shifted to 2700–8200 nM for H197A and H265A mutants), and the Q165A mutation also reduced affinity (IC50 = 3600 nM), indicating that these extracellular positions contribute to the peptide-binding site (Liu and colleagues, Journal of Medicinal Chemistry, 2000, via ChEMBL bioactivity records).
Mechanism
CHEMBL2369630 acts as a competitive antagonist at TACR1, the primary substance P receptor. Substance P makes key contacts at the extracellular loops and outer transmembrane helices of NK1; the conserved C-terminal Phe-X-Gly-Leu-Met-NH₂ motif of tachykinins drives receptor engagement, while the N-terminal sequence provides selectivity between NK1 and NK2 (Madsen and colleagues, Journal of Biological Chemistry, 2023). Peptide antagonists of NK1 compete at this same extracellular binding surface — a different pocket from the transmembrane cavity occupied by small-molecule antagonists such as aprepitant.
The somatostatin scaffold constrains the backbone into a geometry that presents the substance P pharmacophore elements without triggering full agonism. Liu and colleagues (2000) analyzed the agonism-vs-antagonism outcome in terms of pseudosymmetry: the disulfide-bridged ring of somatostatin has approximate twofold symmetry, and the orientation of grafted pharmacophore groups relative to that axis determines whether the resulting compound activates or blocks the receptor. The mutagenesis data (Q165A, H197A, H265A NK1 mutants losing 30- to 190-fold in affinity) localise the compound's contact surface to the outer receptor face.
Known effects
- NK1 (TACR1) antagonism — In vitro; IC50 = 44 nM (CHO cell radioligand displacement assay, Liu and colleagues, 2000)
- NK2 (TACR2) binding — In vitro, weaker; IC50 = 730 nM (same format)
- Receptor contact-site mapping — Mutagenesis assays identify Q165, H197, H265 on NK1 as binding determinants
Regulatory status
- Research compound only. No regulatory submissions; no IND, NDA, or EMA filing on record.
- Not approved for any human use.
Related peptides
The somatostatin scaffold program that produced this compound intersects with several other NK1-active and GPCR-active cyclic peptides on the platform. Substance P itself (the endogenous NK1 agonist whose binding this compound blocks) is the direct pharmacological counterpart. The clinically approved NK1 antagonist aprepitant (MK-869) works by the same receptor-blocking mechanism but uses a small-molecule rather than a peptide scaffold.
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 this cyclic peptide work as a pain treatment by blocking substance P signals in peripheral tissues while staying outside the brain?
Existing NK1-blocking drugs that enter the brain failed for depression and had mixed results in pain. A peptide version that stays out of the brain might deliver pain relief for conditions like migraines or IBS while avoiding those earlier pitfalls, giving patients a safer option.
Could grafting a somatostatin signal onto the free end of this peptide create a single drug that blocks pain-driving inflammation and slows neuroendocrine tumor growth?
If this design works, patients with neuroendocrine tumors could receive a single peptide drug addressing both the tumor and the pain, replacing a two-drug regimen with one more manageable treatment.
Does this cyclic peptide bind the NK1 receptor deep in the transmembrane pocket, like small-molecule drugs do?
Mutating three pocket residues (Gln165, His197, His265) already weakens this peptide's binding, the same residues that small-molecule NK1 blockers need. Confirming a shared pocket would help explain why oral NK1 blockers work and guide peptide-based treatments for nausea or pain.
Is the N-terminal segment outside the disulfide ring required to mold itself around the receptor's outer loop?
A moderate model-confidence score hints (but does not prove) the tail is flexible. If experiments show that flexibility is load-bearing for binding, designers would know not to rigidify it in next-generation analogs, avoiding failed optimization.
▸full evidence table1 metrics
| metric | value | tool |
|---|---|---|
| IC50 | 44 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{pep10450,
sequence = {GACKNFFWTFTS},
target = {tacr1},
author = {peptidemodel},
year = {2026},
status = {bioassayed}
}