Substance P fragment: pain and inflammation research tool (RPKPQQFF)
A shortened piece of the natural pain-signaling molecule Substance P, used in labs to study how the brain and body process pain and inflammation; a research tool, not an approved drug.
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
Substance P [1–8] (RPKPQQFF) is the first eight residues of the naturally occurring neuropeptide Substance P, which was originally identified in mammalian nervous tissue and belongs to the tachykinin family of signaling peptides. The full-length Substance P is an eleven-residue peptide (RPKPQQFFGLM-NH₂) whose C-terminus carries an amide group; the [1–8] fragment lacks the C-terminal tripeptide GLM and its amide cap, making it a distinct truncated species used in research to dissect which parts of the parent molecule drive receptor binding and biological activity. It engages the neurokinin-1 receptor (NK1R, encoded by TACR1), the same receptor that full-length Substance P prefers.
History
Substance P itself was among the first neuropeptides described, and its sequence and precursor genetics have been studied since the 1980s. Kawaguchi and colleagues (1986) characterized cloned cDNA for the rat Substance P precursor and identified a third precursor form, establishing the gene-level basis for SP production. Steinhoff and colleagues (2014) provided a comprehensive account of how tachykinins — including Substance P — derive from alternate processing of three Tac genes and interact with neurokinin G protein-coupled receptors. The [1–8] truncation emerged from structure–activity studies aimed at understanding which residues are necessary and sufficient for receptor recognition at NK1R, and it became a reference tool in tachykinin pharmacology.
What it does
Substance P [1–8] interacts with the neurokinin-1 receptor (NK1R), the principal target of full-length Substance P. NK1R signalling participates in neurogenic inflammation, pain sensitization, and immune activation. Douglas and colleagues (2011) reviewed how the SP/NK1R pathway activates nuclear factor-κB (NF-κB) and drives proinflammatory cytokine release, situating it as a central node in both neural and immune communication. Steinhoff and colleagues (2014) documented tachykinin involvement across the nervous, immune, gastrointestinal, respiratory, and urogenital systems. By retaining the N-terminal basic residues (Arg-Pro-Lys) and the two C-terminal phenylalanines of the parent sequence while lacking the C-terminal GLM-NH₂ extension, [1–8] fragments have been used to probe which structural features determine agonist versus partial-agonist or competitive behavior at NK1R — information relevant to the development of NK1R-targeted therapeutics.
Evidence
- Human: No clinical trials with Substance P [1–8] as the study compound are registered on ClinicalTrials.gov. The fragment is used as a research tool, not as a clinical therapeutic.
- Animal: Substance P and its fragments have been studied extensively in rodent pain and neuroinflammation models. The broader tachykinin literature, reviewed by Steinhoff and colleagues (2014), documents preclinical evidence for NK1R contributions to pain, inflammation, and stress responses across species.
- In vitro: Structural and binding studies using the full SP sequence and truncated analogs including [1–8] have characterized the amphipathic architecture of SP — a positively charged N-terminal region paired with hydrophobic C-terminal residues — as relevant to receptor engagement and to antimicrobial-like membrane interactions (Miao and colleagues, 2020).
Known effects
- NK1R engagement — Research tool; in vitro and preclinical evidence
- Neurogenic inflammation modulation — Preclinical; mechanistic studies on NK1R/NF-κB pathway (Douglas and colleagues, 2011)
- Pain signaling reference — Used in structure–activity studies; preclinical only
- Anticonvulsant drug target context — Clynen and colleagues (2014) include the tachykinin/NK1R pathway among neuropeptide systems relevant to seizure pharmacology
Mechanism
Substance P [1–8] binds NK1R, a G protein-coupled receptor (GPCR) encoded by TACR1. NK1R exists in full-length and truncated receptor isoforms with differing functional properties (Douglas and colleagues, 2011). Receptor activation by SP and its fragments engages NF-κB signalling and promotes the release of proinflammatory cytokines. Schank and colleagues (2017) have characterized the SP/NK1R axis as a key stress-responsive system, comparing its role in the central stress response to that of corticotropin-releasing factor (CRF). The structural basis for SP's activity — N-terminal polycationic residues paired with C-terminal hydrophobic phenylalanines in an amphipathic arrangement — is preserved in the [1–8] fragment, though the loss of the GLM-NH₂ C-terminus alters the full binding profile compared with the parent peptide (Miao and colleagues, 2020; Steinhoff and colleagues, 2014).
Related peptides
- Substance P (full-length) — The parent eleven-residue tachykinin (RPKPQQFFGLM-NH₂); [1–8] is its truncated N-terminal fragment. See the full tachykinin family overview in Steinhoff and colleagues (2014).
- Neurokinin A — A related tachykinin (HKTDSFVGLM-NH₂) that shares the C-terminal GLM motif with Substance P and also acts at NK receptors (Steinhoff and colleagues, 2014).
▸full evidence table2 metrics
| metric | value | tool |
|---|---|---|
| ipTM | 0.9325780868530273 | boltz-2 |
| ranking score | 0.7734156250953674 | boltz-2 |
▸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{pep10634,
sequence = {RPKPQQFF},
target = {tacr1},
author = {peptidemodel},
year = {2026},
status = {synthesized}
}