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A hexanoyl-capped dipeptide mimetic of angiotensin IV with rodent memory data, zero human trials, and a retracted mechanism paper.
Also known as: PNB-0408 · ATH-1001 · N-hexanoyl-Tyr-Ile-(6)-aminohexanamide
Part of the Neuropeptides & signaling cluster
Overview
Dihexa (PNB-0408; C27H44N4O5, ≈505 Da) is a small, orally available, blood-brain-barrier-permeable peptidomimetic derived from angiotensin IV: N-hexanoyl-tyrosyl-isoleucyl-6-aminohexanamide. It was designed as a metabolically stabilised procognitive agent and is proposed to act by potentiating hepatocyte growth factor signalling at the c-Met receptor. Its evidence is entirely preclinical — rodent memory models and cell work — with no registered human trial and no approval; a central 2014 mechanism paper has been retracted.
Source & context
Biological / chemical source: Synthetic modified peptide derived from angiotensin IV
Primary research or clinical context: Research compound — no approval, no registered clinical trial. Rodent and cell data only; one key mechanism paper has been retracted.
What Dihexa is
Dihexa is a small synthetic molecule derived from angiotensin IV, the hexapeptide fragment of angiotensin that has procognitive effects in animals. Chemically it is N-hexanoyl-L-tyrosyl-L-isoleucyl-6-aminohexanamide — a tyrosine-isoleucine dipeptide capped at one end with a six-carbon fatty acid and at the other with an aminohexanamide — with formula C27H44N4O5 and mass about 505 Da. It was produced by a Washington State University programme that set out to chemically modify a procognitive angiotensin IV-derived tripeptide to improve metabolic stability and barrier permeability (McCoy et al., Journal of Pharmacology and Experimental Therapeutics 2013). It is orally active and crosses the blood–brain barrier in mice (Sun et al., Brain Sciences 2021).
Structure: a peptidomimetic, not a peptide chain
Dihexa contains only two amino acids, so it is better called a peptidomimetic than a peptide, and it has no one-letter sequence to display. The hexanoyl cap and the aminohexanamide tail are the stabilising modifications the 2013 programme found: several N- and C-terminal changes dramatically improved stability while retaining the ability to reverse scopolamine-induced deficits in the Morris water maze (McCoy et al., 2013). Those caps also make the molecule lipophilic enough for oral absorption and brain entry, which is unusual for anything angiotensin-derived.
The proposed mechanism — and the retraction
The mechanism advanced by the developers is that angiotensin IV analogues act through the brain hepatocyte growth factor / c-Met receptor system, whose activation stimulates neurogenesis, synaptogenesis and protection against tissue insults (Wright & Harding, Journal of Alzheimer's Disease 2015). The paper that most directly tested this — reporting that the procognitive and synaptogenic effects of angiotensin IV-derived peptides depend on activation of HGF/c-Met (Benoist et al., JPET 2014) — carries a retraction notice in PubMed. The retraction does not by itself disprove the hypothesis, but it removes the main experimental support cited for it, and readers should weigh the remaining evidence accordingly.
What the animal studies show
Independent of the retracted paper, a systematic review of angiotensin IV and its analogues found that in models of cognitive deficit, eight of nine studies reported that angiotensin IV and analogues including Dihexa improved spatial working memory and passive-avoidance performance, with effects most reliable when given close to learning (Ho et al., Neuroscience & Biobehavioral Reviews 2018). A 2021 study reported that orally administered Dihexa rescued cognitive impairment and memory in APP/PS1 Alzheimer's-model mice via the PI3K/AKT pathway (Sun et al., 2021). Outside the brain, Dihexa protected zebrafish lateral-line hair cells from aminoglycoside toxicity as an HGF mimetic (Uribe et al., Frontiers in Cellular Neuroscience 2015) and is used in small-molecule cocktails to drive hepatic differentiation of human stem cells (Pan et al., Stem Cell Research & Therapy 2022).
| Study | Model | Finding |
|---|---|---|
| McCoy 2013 | Rat, scopolamine deficit | Stabilised analogues reversed water-maze deficits |
| Benoist 2014 — RETRACTED | Rodent / cell | HGF/c-Met dependence (no longer citable as support) |
| Ho 2018 (systematic review) | 32 animal studies | Ang IV analogues improved memory in 8/9 deficit models |
| Sun 2021 | APP/PS1 mouse | Oral Dihexa rescued memory via PI3K/AKT |
| Any human trial | — | None registered |
Human evidence
There is none. ClinicalTrials.gov lists no study of Dihexa, and the 17 PubMed records in the pack contain no human pharmacokinetics, safety or efficacy data. The c-Met receptor that Dihexa is proposed to potentiate is a growth-factor receptor tyrosine kinase involved in cell proliferation and migration, which is why the developers themselves framed it as a target that needs careful evaluation; the absence of any toxicology in the public record is the central fact about this compound.
Regulatory status and the nootropic market
Dihexa is not approved anywhere and has no IUPHAR ligand record. It is sold online as a research chemical and marketed as a nootropic, frequently with potency claims drawn from cell-culture comparisons that have no clinical meaning. A 2026 orthopaedics review lists it among emerging peptides without human data (Rahman et al., 2026). Nothing sold under the name has been characterised in humans. This profile is educational; it is not guidance on obtaining or using any product and it is not medical advice.
Structure & chemistry
Molecular identity & reference confidence
Source-supported reference
Reference values are taken from the cited molecular record or curated profile. A database match is not independent laboratory verification; modifications, counter-ions, and formulations can change the measured mass.
- Molecular form
- Not a linear peptide: a Tyr-Ile dipeptide capped N-terminally with hexanoic acid and C-terminally with 6-aminohexanamide, derived from the angiotensin IV core
- Species
- Not established by this molecular identity audit
- Termini (N / C)
- Not specified / Not specified
Average reference mass
Reference policy updated: 2026-10-05
- PubChem molecular record · 2026-10-01
- Molecular formula
- C27H44N4O5
- Average reference mass
- ≈ 504.7
- Receptors
- Proposed: potentiation of hepatocyte growth factor (HGF) signalling at the c-Met receptor tyrosine kinase; AT4 receptor activation is the angiotensin IV framing (Wright & Harding, 2015; Ho et al., 2018)
- Backbone
- Not a linear peptide: a Tyr-Ile dipeptide capped N-terminally with hexanoic acid and C-terminally with 6-aminohexanamide, derived from the angiotensin IV core
- Status
- Research compound; no approval; no ClinicalTrials.gov entry. Benoist et al. 2014 (JPET), a key mechanism paper, is retracted.
- PubChem CID: 129010512
- CAS RN: 1401708-83-5
- UNII: 9WYX65A5C2
Chemistry values: curated profile, PubChem · fetched 2026-10-01.
Dihexa — reconstitution calculator
Enter how much peptide is in the vial and how much diluent (e.g. bacteriostatic water) is added. The tool returns the resulting solution concentration — and, for any amount you type, the volume it corresponds to. This is educational arithmetic, not a dosing recommendation.
Reference form: Not a linear peptide: a Tyr-Ile dipeptide capped N-terminally with hexanoic acid and C-terminally with 6-aminohexanamide, derived from the angiotensin IV coreAverage reference mass: 504.7 Da
Enter an amount to see the volume it corresponds to.
Educational concentration mathematics only. This tool does not recommend a dose, amount, or protocol, and nothing here is medical advice. Many peptides are not authorized by Health Canada for human use — see our reconstitution and bacteriostatic-water guides for context.
Change log
Dated observations from the data pipeline (registry flags, trial footprints, identifiers) and editorial reviews of this profile.
- EditorialProfile content reviewed and updated by the editorial team.
FAQ about Dihexa
What is Dihexa?+
Dihexa (PNB-0408; C27H44N4O5, ≈505 Da) is a small, orally available, blood-brain-barrier-permeable peptidomimetic derived from angiotensin IV: N-hexanoyl-tyrosyl-isoleucyl-6-aminohexanamide. It was designed as a metabolically stabilised procognitive agent and is proposed to act by potentiating hepatocyte growth factor signalling at the c-Met receptor. Its evidence is entirely preclinical — rodent memory models and cell work — with no registered human trial and no approval; a central 2014 mechanism paper has been retracted.
What Canadian product status is recorded for Dihexa?+
Canadian product status for Dihexa has not been verified in this profile. No verified record here does not mean no authorization exists. Status depends on the product, formulation and use; consult Health Canada's product records.
What is the typical length of Dihexa?+
Dihexa is not a classic amino-acid chain peptide in the same sense; see the profile for classification details.
What is Dihexa?+
A small angiotensin IV-derived peptidomimetic (N-hexanoyl-Tyr-Ile-6-aminohexanamide, about 505 Da) designed for metabolic stability and brain entry, studied for memory effects in rodents.
How does Dihexa work?+
The proposed mechanism is potentiation of hepatocyte growth factor signalling at the c-Met receptor. The key paper supporting that mechanism has been retracted; a 2021 mouse study points to the PI3K/AKT pathway.
Has Dihexa been tested in humans?+
No. There is no registered clinical trial and no human pharmacokinetic, safety or efficacy data.
Is Dihexa a peptide?+
Barely — it contains a two-residue Tyr-Ile core with fatty-acid and aminohexanamide caps, so it is usually described as a peptidomimetic.
Is Dihexa approved?+
No, nowhere.
What are Dihexa's side effects?+
Unknown. No human safety data exist, and its proposed target, c-Met, is a growth-factor receptor, which is why the lack of toxicology matters.
Further reading
- Not a peptideIs 5-Amino-1MQ a Peptide? No — It Is a Small-Molecule NNMT Inhibitor With Only Animal Data5-Amino-1MQ is marketed next to peptides but is a small quinolinium molecule that inhibits the enzyme NNMT. This guide explains what it is, what the mouse studies showed, why there are no human data, and its regulatory status.
- Not a peptideIs NAD+ a Peptide? No — It Is a Coenzyme. What NAD+, NMN and NR Actually Are and What the Evidence Shows“NAD+ peptide” is a search term with no molecule behind it: NAD+ is a nucleotide coenzyme, not a peptide. This guide explains what NAD+ is, why it appears in peptide catalogues, what the precursors NMN and NR do, what human trials have and have not shown, and the regulatory status of each.
- SafetyPeptide Safety and Risks: A Balanced Educational OverviewAn objective, balanced overview of what research does and does not establish about peptide risks—unknowns, purity and contamination concerns, and why unapproved compounds carry uncertainty. Not reassurance and not medical advice.
- FoundationsWhat Are Research Peptides? A Clear Educational GuideLearn what “research peptides” means, how they differ from approved peptide drugs, quality markers (COA, purity), and how to study them responsibly.
Related peptides
References & further reading
- 1.Weiss et al. (2021). Stem cell, Granulocyte-Colony Stimulating Factor and/or Dihexa to promote limb function recovery in a rat sciatic nerve damage-repair model: Experimental animal studies. Ann Med Surg (Lond)
- 2.Sun et al. (2021). AngIV-Analog Dihexa Rescues Cognitive Impairment and Recovers Memory in the APP/PS1 Mouse via the PI3K/AKT Signaling Pathway. Brain Sci
- 3.McCoy AT et al. (2013). Evaluation of metabolically stabilized angiotensin IV analogs as procognitive/antidementia agents. Journal of Pharmacology and Experimental Therapeutics
- 4.Benoist CC et al. (2014). The procognitive and synaptogenic effects of angiotensin IV-derived peptides are dependent on activation of the HGF/c-Met system. JPET — RETRACTED
- 5.Wright JW, Harding JW (2015). The brain hepatocyte growth factor/c-Met receptor system: a new target for the treatment of Alzheimer's disease. Journal of Alzheimer's Disease
- 6.Uribe PM et al. (2015). Hepatocyte growth factor mimetic protects lateral line hair cells from aminoglycoside exposure. Frontiers in Cellular Neuroscience
- 7.Ho JK, Nation DA (2018). Cognitive benefits of angiotensin IV and angiotensin-(1-7): a systematic review of experimental studies. Neuroscience & Biobehavioral Reviews
- 8.Pan T et al. (2022). Efficiently generate functional hepatic cells from human pluripotent stem cells by complete small-molecule strategy. Stem Cell Research & Therapy
- 9.PubChem — Dihexa