Neuromedin U-23: rat gut-brain peptide for energy, stress & muscle research
A small signaling peptide from rats that helps control hunger, stress, and gut muscle squeezing; used only as a laboratory research tool, not a medicine.
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
Neuromedin U-23 (rat) is the rodent form of neuromedin U — a neuropeptide that regulates energy balance, smooth muscle contraction, the stress response, and pain signaling. The "U" in the name comes from its original defining property: potent stimulation of uterine smooth muscle contraction (uterotonic activity). Rat neuromedin U is 23 amino acids long, two residues shorter than the pig and human versions, and carries a C-terminal amide cap (–NH₂) not represented in the raw stored sequence; that amide-capped C-terminal heptapeptide is the structurally conserved pharmacophore responsible for receptor activation across species. In research settings, rat NMU-23 is used as a tool compound to probe the biology of neuromedin U receptors, particularly NMUR2, and to study how this neuropeptide intersects with dopamine signaling, energy homeostasis, and tumor microenvironments.
History
Neuromedin U was first isolated from porcine spinal cord by Minamino, Kangawa, and Matsuo in 1985, as part of a broader effort to characterize smooth-muscle-stimulating neuropeptides in neural tissue. The "U" designation reflected the peptide's potent uterotonic action in assays run at the time of discovery. The rat-specific 23-residue form was subsequently isolated and sequenced by the same group in 1988 (Minamino, Kangawa, Honzawa, and Matsuo; Biochemical and Biophysical Research Communications 156:355–360), which found nine amino acid replacements and two amino acid deletions relative to pig NMU-25, while the C-terminal heptapeptide remained fully conserved — and confirmed that rat NMU-23 was approximately twice as potent as pig NMU-25 in uterotonic assays. For over a decade after its discovery, the receptors for neuromedin U were unknown. In 2000, multiple independent groups — including Howard, Kojima, Fujii, and Hosoya and their respective colleagues — deorphanized two G protein-coupled receptors as the cognate neuromedin U receptors, now designated NMUR1 and NMUR2, catalyzing a rapid expansion of research into the peptide's roles in metabolism, stress, and cancer biology (Malendowicz and colleagues, Frontiers in Endocrinology, 2021).
What it does
Neuromedin U-23 activates two receptors, NMUR1 and NMUR2, which differ in where they are expressed and what happens when they are stimulated. NMUR1 is found primarily in peripheral tissues — the gut, lung, and other organs — while NMUR2 is expressed predominantly in the central nervous system, especially the hypothalamus and spinal cord. When neuromedin U reaches NMUR2 in the brain, it suppresses food intake and elevates energy expenditure, producing anti-obesity effects in rodents. Centrally administered NMU also activates the hypothalamic-pituitary-adrenal stress axis by stimulating corticotropin-releasing hormone (CRH) neurons, leading to ACTH and cortisol release. In the spinal cord, NMU-23 binding sites concentrate in the superficial dorsal horn — a region involved in pain processing — and intracerebroventricular administration of NMU increases pain sensitivity in rats. In the cardiovascular system, NMU produces brief elevations in blood pressure and causes endothelium-independent vasoconstriction in human arterial preparations. In the nucleus accumbens, central NMU signaling attenuates amphetamine-induced dopamine release and locomotor stimulation, implicating the peptide in reward circuit modulation (Vallöf and colleagues, PLOS ONE, 2016). Outside the nervous system, NMUR1 signaling in the tumor microenvironment of pancreatic ductal adenocarcinoma (PDAC) suppresses the anti-tumor activity of CD8+ T cells while promoting glycolysis in tumor cells (Zheng and colleagues, Cancer Science, 2024).
Evidence
- Human: No interventional clinical trials have been published for neuromedin U-23. In human pancreatic cancer tissue, NMU and its receptors are significantly overexpressed compared to healthy pancreatic tissue — NMUR2 mRNA was found approximately 149-fold higher in tumor relative to normal tissue — and elevated NMU serum levels correlate with poor PDAC prognosis (Ketterer and colleagues, Cancer Letters, 2009). Genetic variants in the human NMU gene (NMUAla19Glu and NMUArg165Trp) have been associated with altered metabolic phenotypes, including obesity onset (Malendowicz and colleagues, Frontiers in Endocrinology, 2021).
- Animal: Central administration of NMU reduces food intake and body weight in rats and mice, with effects mediated primarily through hypothalamic NMUR2. NMU knockout mice develop increased food intake and obesity, while NMU overexpression produces leanness. Rat NMU-23 shows approximately two-fold greater uterotonic potency than pig NMU-25 in smooth muscle preparations. In NMUR2-deficient mice, nociceptive responses are impaired. Central NMU administration significantly attenuated amphetamine-induced accumbal dopamine release and locomotor stimulation in rodents, with peak attenuation at 60 minutes post-administration (Vallöf and colleagues, PLOS ONE, 2016). NMU-knockout mice showed prolonged survival and reduced tumor burden in pancreatic cancer models (Zheng and colleagues, Cancer Science, 2024).
- In vitro: NMU overexpression in pancreatic cancer cell lines induces c-Met expression and increases HGF-mediated cell scattering and invasiveness; silencing NMU reverses these effects. NMUR1 activation in PDAC cells elevates glycolytic enzyme activity (pyruvate kinase, lactate dehydrogenase) and lactate production, which suppresses CD8+ T cell function. Structural studies of the cryo-EM complexes of human NMUR1 and NMUR2 confirmed that the conserved C-terminal heptapeptide (FLFRPRN-NH₂) establishes the core receptor-binding contacts at both subtypes, with sub-nanomolar affinity (You and colleagues, Nature Communications, 2022).
Known effects
- Uterotonic smooth muscle contraction — In vitro, original bioassay (rat and pig preparations)
- Food intake suppression and energy expenditure increase — Preclinical (rodent central administration, knockout models)
- HPA axis activation / stress response — Preclinical (rodent; CRH-dependent)
- Blood pressure elevation / vasoconstriction — Preclinical and ex vivo human vascular tissue
- Pro-nociception (increased pain sensitivity) — Preclinical (rat intracerebroventricular administration)
- Dopamine modulation in nucleus accumbens — Preclinical (attenuation of amphetamine-induced reward)
- Tumor microenvironment immunosuppression (PDAC) — Preclinical and human tissue expression (NMUR1-dependent CD8+ T cell suppression)
- Pancreatic cancer invasiveness — In vitro and human tissue (c-Met/HGF pathway)
Safety signals
No clinical safety data exist for exogenously administered neuromedin U-23 in humans, as the peptide has not entered clinical trials. Rodent studies using central NMU administration report activation of the stress axis (corticosterone elevation, anxiety-like behaviors) and increased pain sensitivity as pharmacodynamic effects rather than adverse events. NMU signaling in tumor biology is associated with immunosuppression and disease progression in pancreatic cancer, suggesting that in the context of PDAC, endogenous NMU may be detrimental by damping anti-tumor immunity (Zheng and colleagues, Cancer Science, 2024).
Regulatory status
- US: Not approved. No IND or clinical trial registration identified for rat NMU-23 or human NMU formulations.
- Research use: Available as a synthetic peptide reagent for laboratory research into NMUR1/NMUR2 pharmacology, energy homeostasis, and cancer biology.
- WADA: Not listed on the WADA Prohibited List.
Mechanism
Rat neuromedin U-23 is a 23-residue neuropeptide with the sequence YKVNEYQGPVAPSGGFFLFRPRN; the active drug carries a C-terminal amide (–NH₂) on the asparagine at position 23 that is essential for receptor binding and is absent from the raw stored sequence. The C-terminal heptapeptide FLFRPRN-NH₂ is fully conserved across mammalian species and constitutes the receptor-binding pharmacophore; the N-terminal extension (positions 1–16) shows species-specific variation and is less critical for receptor activation. Both NMUR1 and NMUR2 are class A GPCRs that couple predominantly to Gq/11 (mobilizing intracellular calcium and activating PI signaling) and also to Gi/o (inhibiting cAMP). Cryo-EM structural studies of human NMUR1 and NMUR2 show that the amidated asparagine at the C-terminus and the arginine at position 6 of the heptapeptide form an extensive polar interaction network with both receptor subtypes at sub-nanomolar affinity, explaining the conserved pan-receptor binding of endogenous NMU forms across subtypes (You and colleagues, Nature Communications, 2022). NMUR1 is expressed mainly in the gastrointestinal tract, lung, and peripheral tissues, and signals primarily via Gαq; NMUR2 is expressed predominantly in hypothalamic nuclei and the spinal dorsal horn, and shows stronger coupling to Gαi. Rat NMU-23's approximately two-fold greater uterotonic potency relative to the pig 25-residue form is attributable to N-terminal sequence differences that modulate receptor engagement kinetics without altering the core binding pharmacophore.
In the hypothalamus, NMUR2 activation by NMU suppresses orexigenic signaling and stimulates CRH neurons, linking the peptide to both energy balance and the HPA stress axis. In the nucleus accumbens, central NMU signaling dampens dopaminergic transmission, reducing amphetamine-induced dopamine overflow and reward-associated locomotion. In the tumor microenvironment of PDAC, NMU signaling through NMUR1 on tumor-infiltrating immune cells suppresses IFN-γ, perforin, and granzyme B production by CD8+ T cells, while simultaneously promoting aerobic glycolysis in tumor cells via pyruvate kinase and lactate dehydrogenase activation — a dual mechanism that both disarms immune surveillance and fuels tumor metabolism (Zheng and colleagues, Cancer Science, 2024).
Related peptides
- Neuromedin S peptide — a 33-residue paralog sharing the conserved C-terminal heptapeptide; co-activates NMUR1 and NMUR2 with comparable potency and has partially overlapping roles in energy homeostasis and circadian rhythm regulation
- Neurotensin — a structurally unrelated 13-residue neuropeptide that acts at the neurotensin receptor NTSR1; expressed in many of the same hypothalamic and brainstem circuits as neuromedin U but pharmacologically distinct — NMU effects on food intake and body weight persist in NTSR1-knockout mice (Rümenapf and colleagues, American Journal of Physiology, 2009)
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.
In neuromedin U-23, does the species-variable front end of the peptide determine whether it targets gut receptors or brain receptors, while the identical back end is responsible for activating either?
If true, drug designers could engineer modified NMU fragments that selectively target either the brain circuits controlling appetite and stress or the gut circuits controlling digestion, enabling more precise treatments for obesity, irritable bowel syndrome, or stress disorders.
Is rat neuromedin U-23 incorrectly linked to the neurotensin receptor in this record, and would correcting this to its actual receptor reveal different biology?
If true, fixing this mislabeling would prevent researchers from designing experiments or drugs based on a false premise, and would ensure the peptide's genuine roles in energy balance and stress responses are properly studied and developed.
Does neuromedin U act in the brain to turn up the body's stress-hormone response, and could blocking its receptor help people with anxiety disorders or PTSD regain control over their stress system?
If true, drugs blocking the neuromedin U brain receptor could provide a completely new type of anti-anxiety or anti-stress treatment that works differently from existing medications, potentially helping people who do not respond to current therapies.
Does neuromedin U, a gut-brain peptide, signal within tumors in a way that keeps immune cells from attacking the cancer, and could blocking this signal make immunotherapy drugs work better?
If true, combining a neuromedin U blocker with existing cancer immunotherapy drugs could improve how many patients respond to treatment, potentially benefiting the large fraction of cancer patients for whom checkpoint inhibitors currently fail.
▸full evidence table2 metrics
| metric | value | tool |
|---|---|---|
| ipTM | 0.7518717646598816 | boltz-2 |
| ranking score | 0.7170262932777405 | boltz-2 |
▸structural qualityopenfold3
| metric | value | note |
|---|---|---|
| gpde | 1.308 | 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{pep10707,
sequence = {YKVNEYQGPVAPSGGFFLFRPRN},
target = {ntsr1},
author = {peptidemodel},
year = {2026},
status = {computed}
}