Pain & nausea receptor blocker (CHEMBL2112246)
A lab-made peptide that blocks the substance P receptor, which carries pain, nausea, and stress signals in the brain, experimental, not yet 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
CHEMBL2112246 is a synthetic cyclic peptide designed to block the substance P receptor — a signalling protein in the brain and nervous system that plays a role in pain, nausea, and stress responses. Researchers at the University of Pennsylvania built it by grafting key recognition elements of substance P, the receptor's natural activating hormone, onto the structural backbone of somatostatin — a different but structurally related peptide scaffold. The goal was to convert an activating signal (agonist) into a blocking one (antagonist) by exploiting a striking geometric similarity between the two peptide families (Liu and colleagues, Journal of Medicinal Chemistry, 2000). The stored sequence GACKNFFTFTS is an 11-residue linear approximation; the actual compound is a 14-residue cyclic peptide that includes a disulfide bridge between Cys3 and Cys14, a D-tryptophan residue, and a non-standard amino acid — none of which are visible in the stored sequence.
History
The compound emerged from a structural biology programme led by Amos B. Smith III and Ralph Hirschmann at the University of Pennsylvania, in collaboration with pharmacologists at Merck Research Laboratories. The 2000 paper by Liu, Underwood, Cascieri, Rohrer, Cantin, Chicchi, Smith, and Hirschmann examined how placing substance P pharmacophore elements onto a somatostatin-like cyclic scaffold shifts a peptide from receptor activation toward receptor blockade — a conceptually important question in GPCR drug design. The study also interrogated the role of pseudosymmetry (the near-mirror-image structural relationship between substance P and somatostatin active-site elements) in determining whether a peptide acts as an agonist or antagonist at tachykinin receptors.
What it does
CHEMBL2112246 competes with the body's own substance P for binding to two closely related receptors: TACR1 (the neurokinin-1 receptor, or NK1R) and TACR2 (the neurokinin-2 receptor, or NK2R). By occupying the receptor without triggering the downstream signal, it blocks the effects that substance P and neurokinin A would otherwise produce — including pain transmission, pro-inflammatory signalling, and smooth muscle contraction. In cell-based binding assays using radiolabelled substance P as the competing tracer, the compound displaced the natural ligand from both receptors, with somewhat higher potency at NK2R than at NK1R (Liu and colleagues, 2000).
Evidence
- Human: No human studies. This is a research-stage compound characterised in cell-based receptor binding assays only.
- Animal: None reported for this compound.
- In vitro: Radioligand displacement assays in CHO cells expressing human NK1R or NK2R confirmed competitive binding. IC50 = 220 nM at TACR1/NK1R (with [¹²⁵I]substance P as radioligand); IC50 = 27 nM at TACR2/NK2R; IC50 = 240 nM at wild-type human NK1R. Histidine-to-alanine mutagenesis at NK1R identified two residues critical for binding: H197A reduced affinity approximately 4-fold (IC50 950 nM) and H265A reduced it approximately 28-fold (IC50 6100 nM), implicating both positions in the ligand–receptor contact interface (Liu and colleagues, Journal of Medicinal Chemistry, 2000).
Mechanism
TACR1 and TACR2 are class A G protein-coupled receptors. Both are expressed in the central and peripheral nervous systems; TACR1 predominates in brain regions governing emesis, pain, and mood, while TACR2 is more prominent in peripheral smooth muscle of the airways, gut, and genitourinary tract (Bhatt and colleagues, BioMed Research International, 2015). The endogenous ligands are the tachykinin neuropeptides: substance P (11 amino acids, encoded by TAC1) preferentially activates TACR1, and neurokinin A (also TAC1-encoded) preferentially activates TACR2, though with some cross-reactivity. Somatostatin-family cyclic peptides can block NK1R because somatostatin and substance P share a pseudo-symmetric pharmacophore arrangement — the key side chains that contact the receptor can be displayed in the same spatial orientation from either scaffold. CHEMBL2112246 exploits this geometry to fit the tachykinin receptor binding pocket without triggering receptor activation. The mutagenesis data from Liu and colleagues (2000) indicate that histidine residues H197 and H265 on NK1R contribute meaningfully to this interaction, with H265 playing the larger role.
Known effects
- TACR1 (NK1R) binding — In vitro, IC50 220–240 nM (CHO cell radioligand displacement)
- TACR2 (NK2R) binding — In vitro, IC50 27 nM (CHO cell radioligand displacement)
- Receptor blockade (antagonism) — Characterised as a substance P antagonist; no agonist activity described in the source publication
- Mutagenesis sensitivity — Binding at NK1R substantially dependent on H197 and H265; loss of either histidine impairs affinity
Regulatory status
- US: Not approved. Research compound only; no IND or clinical development record identified.
- EU: Not approved.
- WADA: No specific listing. Research compound with no established use in sport.
Related peptides
The substance P / somatostatin scaffold crossover approach sits at the intersection of two well-studied receptor families. Substance P itself is the reference endogenous ligand for TACR1. The somatostatin family includes vapreotide — a cyclic somatostatin analog that independently exhibits NK1R antagonist activity (IC50 ~330 nM in guinea-pig bronchial tissue; Bétoin and colleagues, European Journal of Pharmacology, 1995), demonstrating that this pharmacological crossover is not unique to designed chimeras. Among approved drugs targeting the same receptor pathway, aprepitant (a non-peptide NK1R antagonist, FDA-approved 2003) established proof-of-concept that NK1R blockade is clinically useful for chemotherapy-induced nausea and vomiting.
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 the borrowed somatostatin backbone make this compound bind somatostatin receptors alongside its intended substance P targets?
If it does, doctors would need to watch for possible hormone-related side effects, but it could also open a path to treating pain together with certain gut or hormone conditions using one drug.
Might this peptide control the full wave of chemotherapy nausea, including the later phase that current single-receptor drugs can miss?
If it works against both nausea receptors, some cancer patients might manage severe chemo nausea with fewer drugs, improving their quality of life during treatment.
Could blocking the receptors that carry pain signals also reduce the nerve-triggered inflammation seen in conditions like asthma or inflammatory bowel disease?
If it pans out, some patients with hard-to-control asthma or IBD driven by nerve signalling might benefit from a compound first explored for pain and nausea.
▸full evidence table1 metrics
| metric | value | tool |
|---|---|---|
| IC50 | 220 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{pep10448,
sequence = {GACKNFFTFTS},
target = {tacr1},
author = {peptidemodel},
year = {2026},
status = {bioassayed}
}