Substance P receptor activator (CHEMBL1651026)
A lab-made peptide that switches on the substance P receptor, a signal involved in pain and inflammation; 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
CHEMBL1651026 is a synthetic nine-residue research peptide derived from the C-terminal "message" region of substance P, designed as a highly potent, NK1-selective agonist of the tachykinin NK1 receptor (TACR1). The stored sequence RPKPQQFFL is a standard-letter approximation of an analog in the well-characterized [Sar9,Met(O2)11]-substance P family — research-grade reference ligands that swap Gly9 for sarcosine (N-methyl-glycine) and oxidize the C-terminal Met11 to a methionine sulfone, with the carboxyl group amidated. Neither the sarcosine substitution, the methionine oxidation, nor the C-terminal amide is captured by the 1-letter code; they are what make the molecule resistant to proteolysis and selective for NK1 over NK2/NK3. The compound is a chemical tool used in receptor pharmacology and ligand-discovery screens — not a clinical drug.
History
The parent peptide, substance P, was the first peptide ever described in the modern neuropeptide era: von Euler and Gaddum (1931) extracted a smooth-muscle-contracting "preparation" (the "P" of substance P) from horse brain and intestine at the National Institute for Medical Research in London. Forty years later, Chang, Leeman and Niall (Nature New Biology, 1971) purified the active material from bovine hypothalamus and sequenced it as the undecapeptide Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH₂. Replacing Gly9 with sarcosine and oxidizing Met11 to its sulfone yielded [Sar9,Met(O2)11]-substance P, which became a standard radioligand-grade NK1 agonist after autoradiographic mapping studies in the late 1980s and early 1990s (Dam et al., Brain Research, 1990). CHEMBL1651026 sits within this class as one of several truncated or sarcosine-substituted analogs catalogued by the ChEMBL bioactivity database.
What it does
The molecule binds with sub-nanomolar affinity to the human NK1 receptor and activates it as an agonist. ChEMBL records report IC50 values of 0.11 nM in displacement binding assays against human NK1 (with additional values from related assays ranging 0.14–2.1 nM depending on the format). NK1 is a Gαq- and Gαs-coupled G-protein-coupled receptor expressed in the central nervous system, dorsal-horn spinal neurons, and immune and gut tissue; its endogenous ligand, substance P, is the principal neurotransmitter mediating neurogenic inflammation, pain transmission, and nausea/emesis signaling (Steinhoff et al., Physiological Reviews, 2014; Mantyh, Journal of Clinical Psychiatry, 2002). As a selective agonist, CHEMBL1651026 mimics substance P at NK1 with minimal cross-activity at NK2 (tachykinin neurokinin A receptor) or NK3 (neurokinin B receptor) — the basis of its use as a pharmacological tool.
Mechanism
NK1 belongs to the Family A (rhodopsin-like) GPCR superfamily. Cryo-electron microscopy structures of human NK1 in complex with substance P and either Gq or Gs heterotrimers show the C-terminal "message" region of substance P (positions 6–11, FFGLM-NH₂) inserted deep into the orthosteric pocket between transmembrane helices 3, 5, 6 and 7, while the N-terminal "address" region (positions 1–4, RPKP) extends out toward the extracellular vestibule and helps define receptor subtype selectivity (Thom et al., Science Advances, 2021). Truncating substance P to its C-terminal 6–8 residues retains NK1 agonism but loses NK1 selectivity; the full N-terminal address sequence — Arg-Pro-Lys-Pro — that this analog retains is the structural feature that keeps it NK1-selective against NK2/NK3. The Sar9 substitution removes the only proteolytically labile peptide bond in the message region (Gly-Leu) and the Met(O2)11 modification blocks oxidative inactivation of the C-terminal methionine, together extending plasma stability without disrupting receptor engagement. Substance-P-class agonists at NK1 are biased toward distinct Gq-versus-β-arrestin signaling outputs depending on residue substitutions in the message region (Harris et al., Nature Chemical Biology, 2021).
Evidence
- In vitro: Radioligand-displacement and functional NK1 binding assays — IC50 0.11 nM, Ki 0.14 nM at human NK1 receptor across multiple published assay reports indexed in ChEMBL under CHEMBL1651026.
- Animal: The broader [Sar9,Met(O2)11]-substance P class has been used as a tool agonist in rodent models of neurogenic inflammation, nociception, and emesis; no animal pharmacology has been published for the specific CHEMBL1651026 analog itself.
- Human: No human trials. This is a research-grade chemical tool, not a clinical candidate.
Regulatory status
- US: Not an approved drug; not in clinical development. Available only as a research chemical.
- EU: Not an approved drug; not in clinical development.
- WADA: Not specifically listed. Substance-P agonists as a class have no anti-doping relevance.
For context, the NK1 receptor antagonist class — the opposite pharmacology — has produced several FDA-approved drugs for chemotherapy-induced nausea and vomiting, including aprepitant (Emend, approved 2003), fosaprepitant (Emend IV, approved 2008), and rolapitant (Varubi, approved 2015). CHEMBL1651026 is an agonist and is unrelated to these therapeutics.
Related peptides
The closest family member already on the platform is the endogenous parent peptide, substance P (Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH₂), and the other endogenous mammalian tachykinins (neurokinin A, neurokinin B) that share the C-terminal FXGLM-NH₂ message motif but engage NK2 and NK3 in preference to NK1 (Steinhoff et al., 2014). NK1-receptor-targeting research analogs in this series differ chiefly in N-terminal truncation, single-residue substitutions, and C-terminal amide chemistry.
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 this card store a stripped 9-residue version that is missing the chemical modifications and C-terminal amide of the actual ChEMBL ligand?
The 0.11 nM potency on this card belongs to the full modified analog (sarcosine, methionine-sulfone, amidated C-terminus), not to the bare RPKPQQFFL stored here. Anyone using the stored sequence as an NK1 reference could badly overestimate its activity. Flagging the mismatch protects NK1 screening data.
Does the Arg-Pro-Lys prefix act as a docking guide that speeds binding rather than tightening grip?
Substance P is known to have a two-part design: a positively charged N-terminal 'address' that steers it to the receptor and a C-terminal 'message' that activates it. If the address mainly speeds up binding, designers could tune it to control how fast NK1 drugs act, which matters for emergency pain or nausea care. (This rests on the established two-domain model, not on any structure prediction for this specific card.)
Could the stored sequence, lacking the modifications and C-terminal amide of the real ligand, show activity at NK2 and NK3 rather than being NK1-selective?
Tachykinin-receptor selectivity comes mostly from the peptide's makeup as a whole, so a degraded fragment may behave very differently from the intended NK1-selective compound. Confirming this would prevent misreading pain, nausea, or inflammation results obtained with the stored sequence. (Note: selectivity is driven more by the overall sequence than by the sarcosine and sulfone groups alone, so the premise is worth testing but not assured.)
▸full evidence table1 metrics
| metric | value | tool |
|---|---|---|
| IC50 | 0.11 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{pep10446,
sequence = {RPKPQQFFL},
target = {tacr1},
author = {peptidemodel},
year = {2026},
status = {bioassayed}
}