Pain-research peptide that blocks the substance P receptor (CHEMBL389651)
A small lab-made peptide designed to block the body's pain-signal receptor, explored as a possible pain reliever, research tool only, never tested in people.
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
CHEMBL389651 is a six-residue peptide (Tyr-Gly-Phe-Leu-Pro-Leu) catalogued in ChEMBL that binds to the neurokinin 1 receptor (NK1R), also called the substance P receptor or TACR1. It represents the truncated core scaffold of a bifunctional research series designed to block NK1R signaling while simultaneously activating opioid receptors — a dual strategy explored as a potential approach to pain relief with reduced tolerance liability. This is a research tool compound with no clinical history; it has never been tested in humans.
The stored six-residue sequence is a simplified representation. The full bifunctional compound from which this binding affinity derives (compound 4 in Yamamoto and colleagues, 2007) carries a D-Ala at position 2 in place of Gly, a C-terminal Trp residue, and a 3,5-bis(trifluoromethyl)benzyl ester modification — none of which are present in the six-letter sequence shown here. The Ki = 0.8 nM reported for this ChEMBL entry reflects the full compound's affinity at the rat NK1 receptor, not the bare hexapeptide alone.
History
The NK1 receptor's story begins with Substance P, an 11-amino-acid neuropeptide first isolated from horse brain and intestine in 1931 by von Euler and Gaddum. The receptor itself was molecularly cloned in 1991, giving drug developers their first direct target for the substance P signaling pathway.
The bifunctional peptide series that includes CHEMBL389651 was developed at the University of Arizona by Yamamoto, Hruby, Yamamura and colleagues, building on the observation that NK1 receptor upregulation in the spinal cord is mechanistically linked to the development of opioid tolerance. If a single molecule could activate opioid receptors while simultaneously blocking NK1R, the reasoning went, it might deliver analgesia with a reduced tendency to produce tolerance. The 2007 paper in the Journal of Medicinal Chemistry (Yamamoto and colleagues) described the first systematic SAR exploration of this bifunctional scaffold, with compound 4 (the progenitor of this ChEMBL entry) achieving sub-nanomolar NK1 affinity alongside nanomolar delta-opioid potency.
What it does
CHEMBL389651's pharmacophore blocks TACR1 (NK1R), the primary receptor for Substance P. Under normal physiology, Substance P released from pain-sensing neurons binds NK1R in the spinal cord and brain, amplifying pain signals and driving neuroinflammatory cascades. The bifunctional compounds in this series also carry an enkephalin-derived opioid agonist head that activates delta and mu opioid receptors, producing analgesia through a complementary pathway. The dual mechanism was designed to interrupt the vicious cycle in which opioid-driven NK1 upregulation progressively erodes analgesic effect.
Evidence
- Human: No human studies. This is a research-stage compound with no reported clinical testing.
- Animal: The parent bifunctional series (TY005/TY027, closely related scaffolds) showed antinociceptive effects in rodent models of neuropathic pain with reduced tolerance compared to morphine, as reported by subsequent publications from the same research group.
- In vitro: Yamamoto and colleagues (2007) measured radioligand binding at rat NK1 (rNK1) and opioid receptors. Compound 4 (the progenitor mapped to this ChEMBL entry) showed rNK1 Ki = 0.80 nM, δ-opioid Ki = 5.0 nM, and μ-opioid Ki = 23 nM in membrane preparations.
Mechanism
TACR1 is a class A GPCR with seven transmembrane domains and 407 amino acids. Its primary coupling partner is Gq/11, activating phospholipase C, releasing intracellular calcium, and triggering protein kinase C and MAPK/ERK cascades. The receptor also links to NF-κB signaling, which underlies its proinflammatory role. Substance P binding leads to receptor internalization via a clathrin-dependent endosomal pathway.
The NK1 antagonist pharmacophore in the CHEMBL389651 series is anchored to a C-terminal Trp-O-3,5-Bzl(CF₃)₂ moiety: modeling studies indicated that two aromatic groups in this C-terminal region interact with His197 and His265 in the human NK1 binding pocket (Yamamoto and colleagues, 2007). The N-terminal Tyr-D-Ala-Gly-Phe tetrapeptide engages opioid receptors through a separate binding interface, enabling simultaneous NK1 block and opioid agonism from a single molecule.
Known effects
- NK1 receptor antagonism — sub-nanomolar affinity at rat NK1R in vitro (Yamamoto and colleagues, 2007); no functional data for the bare hexapeptide
- δ-opioid agonism (full bifunctional compound) — nanomolar potency in radioligand binding assays; δ-selectivity over μ (Yamamoto and colleagues, 2007)
- Reduced opioid tolerance (preclinical, related scaffold) — TY005 and related bifunctional derivatives attenuated tolerance development in rodent pain models relative to morphine
Regulatory status
- US: Not approved; not an IND candidate; research chemical only.
- EU: Not approved.
- WADA: No specific listing for this compound.
- ClinicalTrials.gov: No registered trials for CHEMBL389651 or the YGFLPL sequence.
Related peptides
The bifunctional opioid/NK1 field produced several closely related scaffolds. TY005 and TY027 (Tyr-D-Ala-Gly-Phe-Met-Pro-Leu-Trp with varied C-terminal modifications) are the most-studied analogues in the same series and were the subject of subsequent SAR, glycosylation, and in vivo studies. The clinically approved NK1 antagonists — aprepitant (Emend, FDA 2003) and fosaprepitant (FDA 2008) — are small molecules used for chemotherapy-induced nausea and vomiting; they share the TACR1 target but have no structural relation to peptide-based ligands.
▸full evidence table1 metrics
| metric | value | tool |
|---|---|---|
| Ki | 0.8 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{pep10456,
sequence = {YGFLPL},
target = {tacr1},
author = {peptidemodel},
year = {2026},
status = {bioassayed}
}