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Nle1-Angiotensin IV is a six-amino-acid peptide, angiotensin IV with its first residue swapped for norleucine. It is the research compound the whole dihexa and fosgonimeton family grew out of, and it improved memory in rats in several laboratories through the late 1990s and 2000s. ⚠️ It is almost always described as an AT4 receptor agonist, and both halves of that are wrong. The AT4 receptor turned out to be IRAP, an enzyme rather than a receptor, and this peptide blocks its active site. It is an enzyme inhibitor that has been called a receptor agonist for thirty years out of habit. Every rodent experiment injected it directly into the brain, because it does not survive the bloodstream or cross into the brain on its own.
- Its target is real and independently replicated, which the rest of this family cannot claim
- Improved learning and reversed scopolamine-induced deficits in several rodent studies
- Produces a form of synaptic potentiation that does not need NMDA receptors
- Weakened contraction and ejection in isolated heart, a finding no nootropic write-up carries
- Blocking IRAP would be expected to disturb oxytocin and vasopressin balance, which has never been characterised for it
- No human exposure and no toxicology of any kind
Mechanism
The established target is IRAP, -regulated aminopeptidase. The protein long called the AT4 receptor was purified and sequenced as IRAP in 2001, using a radiolabelled form of this very as the tracer [1]. Two years later the same group showed that angiotensin IV ligands inhibit IRAP's enzyme activity competitively, meaning they sit in its catalytic site rather than at a separate regulatory one [2].
That gives a coherent proposed mechanism. IRAP normally chews up oxytocin, vasopressin and Met-, so blocking it should let those memory-relevant peptides persist longer. It is a sensible story and it has never been shown to be the actual cause of the behavioural effects.
In brain slices the raised responses in a way that outlasted washout, was blocked by an , and produced potentiation that did not need receptors, with calcium coming from outside the cell [3].
⚠️ The picture is not uniformly positive, and the exceptions are rarely repeated. In living rats the was less effective than angiotensin IV itself at enhancing potentiation in the dentate gyrus, and both compounds suppressed normal potentiation by 90 minutes, which the authors described as unexplained [4]. In the amygdala it decreased field potential amplitude, the opposite of what angiotensin II does there [5]. Direction depends on the brain region and on how long you wait.
⚠️ The hepatocyte growth factor account does not apply here. The single paper reporting that this activates c-Met was retracted in 2025 after the originating university found falsified and fabricated data [11][12]. That mechanism should not be attributed to this compound.
receptor fingerprint
IRAP / -regulated aminopeptidase (the AT4 site)Competitive active-site inhibitor
dependent potentiationEnhances (indirect)
c-Met / HGF systemClaim retracted
Evidencehow good the literature is
A consistent body of rodent memory work from the late 1990s and 2000s, all delivered directly into the brain.
A single injection into the ventricles improved learning in a Barnes maze at both 100 picomoles and 1 nanomole, and the improvement was blunted by co-administering an antagonist of the same site [6]. In an earlier study the peptide restored water-maze performance in rats impaired by scopolamine back to control levels [7].
⚠️ The behavioural results are real but their cause is not established. IRAP binding is measured and replicated; the behavioural effects are measured; nobody has demonstrated that the first produces the second. The proposal that the peptide instead worked through hepatocyte growth factor came from one laboratory and its central paper for this compound has been retracted [11].
The lineage matters for anyone reading about the descendants: this peptide is the acknowledged starting point that led to dihexa and then to fosgonimeton [10], and the later molecules exist because this one could not be given by any practical route.
Dosingtypical ranges, not medical advice
interested in protocols and clinical dosages? make an account to see them! ^_^
Safetyrisks and cautions, not medical advice
No human has taken it in any published study, and no toxicology exists.
⚠️ There is one documented adverse pharmacology finding and it is never mentioned in nootropic discussions. In isolated rabbit heart the peptide reduced the left ventricle's pressure-generating and ejection capability and sped its relaxation [8]. That is a negative inotropic effect in a real preparation.
⚠️ A second concern follows from the mechanism rather than from an experiment. IRAP is the enzyme that degrades oxytocin and vasopressin, so inhibiting it throughout the body would be expected to disturb the balance of both hormones, with effects on water handling and blood pressure. IRAP also sits on the vesicles that traffic the GLUT4 glucose transporter. Neither consequence has been characterised for this peptide.
History
The peptide came out of work on angiotensin fragments in the 1990s, when a distinct binding site for angiotensin IV was labelled the AT4 receptor. In 2001 that site was purified and turned out to be an enzyme, IRAP, which changed what the whole field was studying without changing the vocabulary it used.
Research groups in Washington State, Melbourne and Brussels worked on it in parallel, and the Washington State line pursued chemical modification to solve the delivery problem, producing dihexa and eventually the injectable prodrug fosgonimeton that failed a large Alzheimer's trial in 2024. Three foundational papers from that line were retracted in 2025.
Resources
This entry is here for reference.
Research
- 1998first citedOpposite effects of angiotensin II and IV in the lateral nucleus of the amygdala
- 2025most recentRetraction notice to "The Procognitive and Synaptogenic Effects of Angiotensin IV-Derived Pepti…
- 1.Evidence that the angiotensin IV (AT(4)) receptor is the enzyme insulin-regulated aminopeptidase
- 2.Angiotensin AT4 ligands are potent, competitive inhibitors of insulin regulated aminopeptidase (IRAP)
- 3.AT4 receptor activation increases intracellular calcium influx and induces a non-N-methyl-D-aspartate dependent form of long-term potentiation
- 4.Angiotensin IV enhances LTP in rat dentate gyrus in vivo
- 5.Opposite effects of angiotensin II and IV in the lateral nucleus of the amygdala
- 6.Effect of I.C.V. injection of AT4 receptor ligands, NLE1-angiotensin IV and LVV-hemorphin 7, on spatial learning in rats
- 7.Attenuation of scopolamine-induced spatial learning impairments by an angiotensin IV analog
- 8.Angiotensin IV has mixed effects on left ventricle systolic function and speeds relaxation
- 9.Facilitation of hippocampal synaptogenesis and spatial memory by C-terminal truncated Nle1-angiotensin IV analogs
- 10.The Brain Hepatocyte Growth Factor/c-Met Receptor System: A New Target for the Treatment of Alzheimer's Disease
- 11.The procognitive and synaptogenic effects of angiotensin IV-derived peptides are dependent on activation of the hepatocyte growth factor/c-met system.
- 12.Retraction notice to "The Procognitive and Synaptogenic Effects of Angiotensin IV-Derived Peptides Are Dependent on Activation of the Hepatocyte Growth Factor/c-Met System" [J Pharmacol Exp Ther 351 (2014) 390-402].
12 listed here; entry last updated August 2026
Reviews
My notesprivate to this device
FAQ
Is this an AT4 receptor agonist?
No, on both counts, though nearly every source says so. What was called the AT4 receptor was purified in 2001 and turned out to be IRAP, an enzyme rather than a receptor, and this peptide is a competitive inhibitor of its active site. The old name stuck to the literature after the biology underneath it changed.
Can it be taken orally or injected under the skin?
Not usefully. It is six unmodified amino acids with nothing protecting it from digestion or blood enzymes and no feature that helps it cross into the brain. Every study showing an effect put it directly into brain tissue or the ventricles, and the field developed dihexa specifically because this molecule could not be delivered any other way.
How does it relate to dihexa?
It is the starting point. Dihexa was built from this peptide to solve its delivery problem, and fosgonimeton is dihexa with a phosphate group added. The mechanism story shifted across those generations from IRAP to hepatocyte growth factor, and the papers making that shift were retracted in 2025.
Limitations of the evidence
- A plain unmodified peptide with no protection from breakdown and no blood-brain-barrier design
- Every rodent study injected it directly into the brain, because no other route delivers it
- Called an AT4 receptor agonist almost everywhere; the site is an enzyme and it is an inhibitor
- Its effect on potentiation reverses depending on brain region and time, including outright suppression at 90 minutes
- The hepatocyte growth factor mechanism attributed to it comes from a paper retracted for fabricated data
- Nobody has shown that IRAP inhibition is what produces the behavioural effects
Adverse effects
- Weakened contraction and ejection in isolated heart, a finding no nootropic write-up carries
- Blocking IRAP would be expected to disturb oxytocin and vasopressin balance, which has never been characterised for it
- No human exposure and no toxicology of any kind