Neurotensin: brain-and-gut signaling hormone
A natural peptide made in the brain and gut that influences pain, appetite, digestion, and dopamine activity; used mainly as a lab 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.
Endogenous peptide — produced naturally and routinely synthesized for research
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Endogenous peptide — receptor binding and activity established in published literature
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What this is
Neurotensin is a 13-amino-acid peptide produced naturally in the brain and gut. First isolated from bovine hypothalamus, it acts as both a neuropeptide in the central nervous system and a hormone in the gastrointestinal tract, influencing pain perception, dopamine signaling, appetite, and digestion. It has drawn sustained research interest for its potential connections to psychiatric conditions, metabolic regulation, and cancer biology (Clynen and colleagues 2014; Petruzziello and colleagues 2012).
The stored sequence QLYENKPRRPYIL is the unmodified 13-residue human tridecapeptide. In biological systems, neurotensin is rapidly degraded by peptidases in the blood and at cell membranes — a short half-life that has driven the development of metabolically stabilized analogs for research and therapeutic purposes (Dobner 2006, cited in the pain modulation literature; 10.7150/thno.4024).
History
Neurotensin was isolated from bovine hypothalamus and later shown to be widely distributed across the nervous system and gastrointestinal tract. Research over the following decades established its presence as a co-transmitter alongside dopamine in midbrain neurons, its release from intestinal N-cells in response to fat ingestion, and its involvement in a range of physiological processes from pain modulation to glucose homeostasis. Early neurochemical work characterized two distinct membrane-associated degrading activities that rapidly cleave the peptide, with the endopeptidase inhibitor thiorphan shown to block the membrane-bound activity (10.1111/j.1471-4159.1983.tb04753.x). The cloning of the rat neurotensin receptor (later classified as NTS1/NTSR1) in 1990 opened the door to receptor-level pharmacology (referenced in 10.1016/j.ejphar.2015.05.025).
What it does
Neurotensin acts primarily at two G protein-coupled receptors, NTS1 (NTSR1) and NTS2, which are expressed in the brain, spinal cord, and peripheral organs. In the central nervous system, it modulates pain — intracisternal administration inhibits responsiveness to noxious stimuli in animal models, an effect that can be separated from opioid pathways (10.1113/jphysiol.2008.167429). It also influences dopamine neurotransmission in regions relevant to psychosis and reward, and neurotensin concentrations in cerebrospinal fluid have been correlated with symptoms and drug response in psychotic patients (10.1038/sj.mp.4000761).
In the periphery, neurotensin is released from gut endocrine cells and stimulates the exocrine pancreas, with fat-induced neurotensin release affecting pancreatic secretion (10.1159/000055831). It has also been found to support beta-cell survival in pancreatic islets and to participate in glucose homeostasis through neurotensin receptors on metabolic tissues (10.3389/fendo.2012.00184; 10.1111/bph.12953). Beyond these physiological roles, sustained or dysregulated neurotensin signaling has been linked to the proliferation of several tumor types, including gliomas and pancreatic carcinomas, acting through NTSR1 and downstream MAPK, PI3-kinase, and EGF-receptor pathways (10.1002/1878-0261.12815; 10.1016/j.ejphar.2017.03.046).
Evidence
- Human: CSF neurotensin levels correlate with symptom severity and antipsychotic drug response in psychotic patients (Nemeroff and colleagues, cited in 10.1038/sj.mp.4000761). No clinical trials with exogenous neurotensin in humans have been reported in the dossier sources.
- Animal: Intracisternal neurotensin inhibits nociceptive responses in mice; neurotensin (300 nM) reduces evoked inhibitory postsynaptic current amplitude in spinal cord preparations via a TRPV1-dependent mechanism (10.1113/jphysiol.2008.167429). Anticonvulsant effects observed in the 6 Hz corneal stimulation model; neurotensin levels reduced in cortex and hippocampus in the kainic acid epilepsy model (Clynen and colleagues 2014). Neurotensin-loaded PLGA/cellulose nanocrystal nanofibers accelerated wound healing in diabetic mice with sustained release over approximately two weeks (10.1208/s12249-025-03172-x).
- In vitro: Neurotensin stimulates DNA synthesis in PC3 prostate cancer cells through MAP-kinase, PI3-kinase, and EGF-receptor pathways (Hassan and colleagues 2004, cited in 10.1016/j.ejphar.2017.03.046). Neurotensin promotes glioma cell progression through NTSR1 (Ouyang and colleagues 2015, cited in 10.1002/1878-0261.12815). Neurotensin receptor expression documented in pancreatic ductal carcinomas (Korner and colleagues 2015, cited in 10.1002/1878-0261.12815).
Known effects
- Pain modulation — Preclinical (rodent intracisternal models); partially opioid-independent
- Antipsychotic-related signaling — Correlational human CSF data; mechanistic preclinical work
- Anticonvulsant activity — Preclinical (6 Hz corneal model)
- Glucose homeostasis and beta-cell survival — Preclinical and mechanistic
- Gut hormone / pancreatic stimulation — Preclinical and ex vivo
- Tumor-proliferative signaling (NTSR1-mediated) — In vitro; glioma, pancreatic, prostate cancer models
- Wound healing (nanofiber delivery) — Preclinical (diabetic mouse model)
Safety signals
No human clinical trial safety data for exogenous neurotensin administration appear in the dossier. The peptide is an endogenous signaling molecule. Its oncological role — promoting glioma and pancreatic cancer cell growth through NTSR1 — is noted across multiple in vitro studies (10.1002/1878-0261.12815; 10.1016/j.ejphar.2017.03.046) and has been flagged as a consideration for any therapeutic application targeting NTSR1 agonism.
Mechanism
Neurotensin binds to NTS1 (NTSR1) and NTS2, both G protein-coupled receptors. NTS1 is the higher-affinity receptor and is widely expressed in the CNS; NTS2 is implicated in antinociception and interacts functionally with opioid receptor pathways (10.1016/j.neuroscience.2010.08.016). In neurons, NTSR1 activation mobilizes intracellular calcium and can modulate inhibitory synaptic transmission — in spinal cord preparations, neurotensin reduces evoked IPSC amplitude through a mechanism requiring TRPV1 (10.1113/jphysiol.2008.167429). In peripheral tumor cells, NT signaling through NTSR1 activates MAPK, PI3-kinase, and EGF-receptor cascades to drive DNA synthesis and proliferation (10.1016/j.ejphar.2017.03.046).
The peptide is cleaved rapidly by both membrane-bound and soluble peptidases, with the endopeptidase inhibitor thiorphan blocking the membrane-bound activity — a degradation profile that limits the half-life of native neurotensin in vivo and has motivated the design of protease-resistant analogs (10.1111/j.1471-4159.1983.tb04753.x; 10.7150/thno.4024).
Related peptides
- β-Lactotensin — A tetrapeptide fragment (HIRL) derived from bovine β-lactoglobulin that acts as a neurotensin receptor agonist, characterized as an endogenous food-derived NTS1 ligand (10.1271/bbb.67.940).
- Cyclopsychotride A, a cyclic plant peptide from Psychotria longipes, has been characterized as a neurotensin antagonist in vitro (10.1105/tpc.104.021790), illustrating the receptor's tractability for small-molecule and peptide-based modulation.
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 a stable neurotensin reduce both the drive to overeat and physical hunger by acting on the brain and gut at once?
If it works on both reward-driven cravings and hunger, it could help patients who do not respond fully to current weight-loss drugs.
Does the branched shape of the final leucine fit the receptor specifically, or would any greasy amino acid do?
Knowing which features are required at the tail would tell drug designers how much they can change when building stable analogs.
Could shielding the bond around neurotensin's arginine pair help it survive longer in the body while still hitting its receptor?
A longer-lasting neurotensin could become a non-addictive painkiller or psychiatric drug candidate, an alternative to opioids worth testing.
▸full evidence table2 metrics
| metric | value | tool |
|---|---|---|
| ipTM | 0.8160384893417358 | boltz-2 |
| ranking score | 0.7710570693016052 | boltz-2 |
▸structural qualityopenfold3
| metric | value | note |
|---|---|---|
| gpde | 0.906 | 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{pep04480,
sequence = {QLYENKPRRPYIL},
target = {ntsr1},
author = {peptidemodel},
year = {2026},
status = {bioassayed}
}