Substance P receptor-binding peptide (CHEMBL2370435)
A synthetic peptide closely related to Substance P, a natural pain-and-inflammation signaler, that binds tightly to its receptor; used only as a lab 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
CHEMBL2370435 is a 10-residue synthetic peptide that binds to the tachykinin NK1 receptor (TACR1, also called the substance P receptor or NK1R) with sub-nanomolar affinity. It is structurally derived from Substance P, the archetypal endogenous NK1R ligand, and carries the N-terminal sequence Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe shared with that neuropeptide. The stored sequence (RPKPQQFFAL) differs from full-length Substance P (RPKPQQFFGLM-NH₂) at position 9 — an alanine replaces glycine — and lacks the C-terminal Met-NH₂ that is present on all naturally occurring tachykinins; this modification context matters for interpreting the binding data.
What it does
This compound binds to TACR1 with a Ki of 0.41 nM (ChEMBL assay CHEMBL2370435). TACR1 is the principal receptor for the endogenous neuropeptide Substance P: its activation couples to Gq/11 proteins, triggering phospholipase Cβ to hydrolyse PIP₂ into inositol trisphosphate (IP3) and diacylglycerol (DAG), which mobilise intracellular calcium and activate protein kinase C. Through this pathway, Substance P and related tachykinin ligands modulate pain transmission, neurogenic inflammation, smooth muscle tone, and the emetic reflex (Garcia-Recio and Gascón 2015, BioMed Research International). Whether CHEMBL2370435 acts as an agonist, partial agonist, or antagonist at this site has not been established in publicly available literature; the ChEMBL entry documents binding affinity only.
Evidence
- Human: No human studies specifically on this compound are registered on ClinicalTrials.gov or in published literature. The broader TACR1 pharmacological axis is validated in humans through approved NK1R antagonist drugs (aprepitant, fosaprepitant, netupitant) used clinically for chemotherapy-induced nausea and vomiting.
- Animal: Not reported for this specific compound.
- In vitro: Ki = 0.41 nM at human TACR1 (ChEMBL, bioassay CHEMBL2370435).
Mechanism
TACR1 is a seven-transmembrane G protein-coupled receptor (GPCR) with 407 amino acids. On activation by Substance P or related tachykinins, it couples primarily through Gq/11 to activate phospholipase Cβ, producing IP3 and DAG; IP3 triggers endoplasmic reticulum calcium release while DAG activates protein kinase C. The NK1 receptor is also capable of signalling through β-arrestin following phosphorylation of its C-terminal intracellular domain, leading to receptor internalisation (StatPearls, Biochemistry: Substance P).
The tachykinin C-terminal consensus motif (-Phe-X-Gly-Leu-Met-NH₂) is the primary pharmacophore for NK1R activation: deamidation of the C-terminal Met-NH₂ suppresses biological activity, and all naturally occurring tachykinins retain this amidated tail (Garcia-Recio and Gascón 2015). CHEMBL2370435 lacks Met at position 11 and carries Ala rather than Gly at position 9; its sub-nanomolar binding affinity nonetheless indicates productive engagement with the orthosteric binding pocket. The N-terminal segment (Arg-Pro-Lys-Pro-Gln-Gln) contributes selectivity toward NK1R over the related NK2 and NK3 subtypes, as established in structure–activity studies of Substance P analogs (Cascieri and colleagues 1992, Molecular Pharmacology).
Related peptides
- CHEMBL1651026 (/card/pep-10446) — a nine-residue NK1R research agonist (RPKPQQFFL) from the [Sar⁹,Met(O₂)¹¹]-substance P family; shares the same RPKPQQFF N-terminal core.
- Ranatachykinin C (/card/pep-10453) — a frog-derived 10-residue tachykinin (HNPASFIGLM-NH₂) that activates TACR1 at EC50 = 13.5 nM and provides a non-mammalian comparator for the tachykinin binding mode.
- Neurokinin A (/card/pep-04472) — the co-produced tachykinin from the TAC1 gene that preferentially activates NK2R; shares biosynthetic origin with Substance P and illustrates how N-terminal sequence determines tachykinin receptor selectivity.
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 swapping one amino acid turn this peptide from a substance P mimic into a substance P blocker on the NK1 receptor?
If true, this peptide could be a useful starting template for designing drugs that block chronic pain and chemotherapy-induced nausea without switching the receptor on, an area with few good options.
Does removing the tail end of substance P accidentally create a peptide that targets only the NK1 receptor and not its close relatives?
A highly selective NK1 blocker would be safer than drugs that hit multiple receptor types, potentially reducing respiratory or central nervous system side effects in patients being treated for pain or nausea.
Do the two proline residues that create a sharp bend force the peptide into exactly the right shape to grip the NK1 receptor very tightly?
Understanding which structural feature drives the very tight binding could allow chemists to design small, stable drug molecules that mimic just that feature, making better pain or nausea medications that do not need to be injected.
Could this peptide, which binds tightly to a receptor overactive in some cancers, slow the growth or spread of those tumors?
If this peptide suppresses tumor growth through the NK1 receptor, it could be a starting point for new cancer treatments, especially for pancreatic or brain cancers where good therapies are scarce.
Could forming a ring out of this peptide stop it from being broken down in the bloodstream and let it enter the brain to treat pain or depression?
A stable, brain-penetrant version would open doors to new treatments for central pain conditions and possibly depression, for patients who do not respond to current therapies.
▸full evidence table1 metrics
| metric | value | tool |
|---|---|---|
| Ki | 0.41 nM | GPCRDB/ChEMBL |
▸structural qualityopenfold3
| metric | value | note |
|---|---|---|
| gpde | 1.431 | 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{pep10451,
sequence = {RPKPQQFFAL},
target = {tacr1},
author = {peptidemodel},
year = {2026},
status = {bioassayed}
}