# Dihexa

> Dihexa is a small, metabolically stabilized analog of angiotensin IV built from a hexanoyl-capped Tyr-Ile core linked to 6-aminohexanoic amide. Also coded PNB-0408, it was designed to be orally active and blood-brain barrier permeable, and it has been studied mainly in rodent and zebrafish models of memory, neurodegeneration and nerve injury. No human trial data appear in the indexed literature.

Canonical: https://peptideproperties.com/compounds/dihexa/

## Identity

- **Class:** Neuropeptides & Nootropic Research Compounds
- **Also known as:** PNB-0408, N-hexanoic-Tyr-Ile-(6) aminohexanoic amide
- **Molecular formula:** C27H44N4O5
- **Molecular weight:** 504.7 g/mol
- **Monoisotopic mass:** 504.3312 Da
- **CAS number:** 1401708-83-5
- **PubChem CID:** 129010512
- **InChIKey:** XEUVNVNAVKZSPT-JTJYXVOQSA-N
- **Sequence notes:** Dipeptide core Tyr-Ile with an N-terminal hexanoyl (hexanoic acid) cap and a C-terminal 6-aminohexanoic acid (Ahx) amide; not a standard-residue peptide

## Key facts

- Class: angiotensin IV-derived small-molecule peptidomimetic
- Structure: hexanoyl-Tyr-Ile linked to 6-aminohexanoic amide (Hexanoyl-Tyr-Ile-Ahx-NH2)
- Formula C27H44N4O5; molecular weight 504.7; CAS 1401708-83-5
- Codes and synonyms: PNB-0408, ATH-1001
- Derived from the angiotensin IV analog Nle1-angiotensin IV
- Proposed target: hepatocyte growth factor (HGF)/c-Met system
- Not FDA approved; evidence is preclinical (cell, zebrafish, rodent)

## What Is Dihexa?

Dihexa is a synthetic, angiotensin IV-based compound developed as a metabolically stable, orally active and blood-brain barrier permeable research molecule. Its chemical name, N-hexanoic-Tyr-Ile-(6) aminohexanoic amide, describes a short Tyr-Ile core capped at both ends to resist breakdown.[1]Researchers developed it to overcome the main limitation of earlier angiotensin IV peptides, which were degraded quickly and could not cross gut or blood-brain barriers.[1] Its developers described it as a first-in-class compound that facilitates memory consolidation in animal models of Alzheimer's disease.[2]Dihexa belongs to research on the brain renin-angiotensin system, a local network of angiotensin peptides in the central nervous system that has been linked to learning, memory and motor function.[3] Dihexa was created within that research program as a practical tool for testing angiotensin IV-related signaling in living animals.[1]All published evidence on dihexa is preclinical. A 2026 review of therapeutic peptides grouped it with other neuroactive peptides acting on HGF/c-Met pathways and noted a current lack of clinical trials across that group.[4]

## Chemical Structure and Molecular Identity

Dihexa has the molecular formula C27H44N4O5 and a molecular weight of 504.7. It is a modified dipeptide: L-tyrosine and L-isoleucine, an N-terminal hexanoyl group, and a C-terminal 6-aminohexanoic acid amide, often written Hexanoyl-Tyr-Ile-Ahx-NH2.The design traces to a structure-activity finding that the procognitive activity of norleucine1-angiotensin IV resides in its three N-terminal amino acids, Nle-Tyr-Ile. Investigators then modified the N- and C-termini to improve stability, and later increased hydrophobicity and reduced hydrogen bonding to reach an orally active analog.[1]
### Identifiers

- CAS: 1401708-83-5
- InChIKey: XEUVNVNAVKZSPT-JTJYXVOQSA-N
- Synonyms: PNB-0408, ATH-1001, N-hexanoic-Tyr-Ile-(6) aminohexanoic amideDespite its peptide origin, dihexa is usually classed as a small molecule. Its terminal caps are not standard amino acids, so it has no conventional one-letter sequence.

## Research History and Development

Dihexa emerged from a decades-long research program on angiotensin IV (AngIV) and its effects on learning and memory. AngIV-related peptides had long been recognized as procognitive, but metabolic instability and poor barrier penetration limited their use.[1]A 2013 study reported the stepwise modification of the Nle-Tyr-Ile tripeptide. Early analogs kept the ability to reverse scopolamine-induced deficits in the Morris water maze and to augment hippocampal synaptogenesis, and the final analog, dihexa, showed antidementia activity in scopolamine and aged rat models.[1]The question of which receptor these compounds act on remained contested. A 2015 review described controversy over the identity of the AT4 receptor: one group proposed insulin-regulated aminopeptidase (IRAP), while the dihexa developers presented evidence linking the AngIV/AT4 system to the HGF/c-Met receptor system.[3] The same review summarized the group's synthesis of several small AngIV-based molecules that are metabolically stable, penetrate the blood-brain barrier, and improved compromised memory and motor function in animal models of Alzheimer's and Parkinson's diseases.[3]A 2014 paper that proposed the HGF/c-Met mechanism is now indexed in PubMed as a retracted publication, so its findings should be read with that status in mind.[5]

## Mechanisms Studied in Research

The main mechanism proposed for dihexa is potentiation of hepatocyte growth factor (HGF) signaling through its receptor, c-Met. Later work also examined the PI3K/AKT pathway downstream of that receptor.[2][6]
### HGF/c-Met hypothesis
The retracted 2014 study reported that dihexa bound HGF with high affinity, induced c-Met phosphorylation in the presence of subthreshold HGF, and induced hippocampal spinogenesis and synaptogenesis, effects inhibited by an HGF antagonist and by c-Met knockdown.[5] Review articles by the same research group describe c-Met activation as promoting dendritic arborization, synaptogenesis and neuroprotection.[2]Independent support came from a zebrafish study that described dihexa as an HGF mimetic. The authors proposed that it forms a functional ligand by dimerizing with endogenous HGF to activate the HGF receptor. Its protective effect on hair cells was attenuated by the HGF antagonist 6-AH and partly by inhibitors of Akt, TOR and MEK, all downstream HGF targets.[7]
### PI3K/AKT and inflammation
In APP/PS1 transgenic mice, angiotensin IV levels in tissue rose after dihexa treatment compared with wild-type controls. Dihexa also activated PI3K/AKT signaling, and the PI3K inhibitor wortmannin significantly reversed its anti-inflammatory and anti-apoptotic effects.[6]

## Key Findings From Published Studies

Dihexa has produced positive results in several rodent and zebrafish models, along with at least one clearly negative study. No controlled human data appear in the literature reviewed for this page.
### Cognition and Alzheimer's disease models

- In scopolamine-treated and aged rats, dihexa showed antidementia activity in the Morris water maze and marked synaptogenic activity.[1]
- In APP/PS1 mice, dihexa restored spatial learning, increased neuronal counts and synaptophysin (SYP) expression, reduced astrocyte and microglia activation, lowered IL-1β and TNF-α, and raised IL-10.[6]
- A systematic review of non-human studies found that eight of nine studies in cognitive-deficit models reported improved performance with AngIV or its analogs, including dihexa. Of 450 articles screened, 32 met the review's inclusion criteria.[8]
### Hair cells and peripheral nerve
In the larval zebrafish lateral line, dihexa protected hair cells from the aminoglycosides neomycin and gentamicin without reducing gentamicin entry into the cells. Adding an amino group to its N-terminus weakened protection.[7] In a rat sciatic nerve transection-repair model, mesenchymal stem cells combined with dihexa in the gastrocnemius muscle significantly improved walking footprint grades at 8 to 16 weeks and mitigated foot flexion contractures.[9]
### Negative and in-vitro results
In 40 male Wistar rats exposed to 3-nitropropionic acid, a Huntington's disease-like model, dihexa did not protect against weight, motor or cognitive deficits.[10] In cell culture, a combination of vitamin C, dihexa and forskolin replaced growth factors to induce hepatic specification from human pluripotent stem cells.[11]
### Summary of study models
ModelEvidence typeReported outcomeScopolamine-treated and aged ratsAnimalImproved water maze performance; synaptogenesisAPP/PS1 miceAnimalRestored spatial learning; lower inflammatory markersLarval zebrafish lateral lineAnimalHair-cell protection from aminoglycosidesRat sciatic nerve repairAnimalBetter motor recovery when combined with stem cellsRat 3-NP Huntington's-like modelAnimalNo protectionHuman pluripotent stem cellsIn vitroPart of a growth-factor-free hepatic differentiation cocktailBecause dihexa findings depend on exact compound identity, researchers typically verify each lot with HPLC and mass spectrometry certificates of analysis.

## Regulatory and Research Status

Dihexa is not approved by the FDA or any major regulator for any human use. It remains an investigational research compound.Its evidence base consists of cell-culture, zebrafish and rodent studies. A 2026 review emphasized that, while preclinical findings for neuroactive peptides including dihexa are promising, clinical trials are lacking.[4] Much of the published work involves the compound's original developers and their collaborators, and independent replication remains limited. The mixed animal record, including the negative Huntington's model study and the retraction of a key mechanistic paper, means its pharmacology is not settled.[10][5]Open research questions include the identity of its primary receptor and whether results in rodent and zebrafish models translate to other species.[3] Dihexa is supplied for laboratory research only. PubChem lists the development codes PNB-0408 and ATH-1001 among its synonyms.

## FAQ

**What is the molecular weight of Dihexa?**
Dihexa has a molecular weight of 504.7 and the molecular formula C27H44N4O5, according to PubChem (CID 129010512), with an exact mass of 504.33. Its CAS number is 1401708-83-5. Chemically, it is a hexanoyl-capped Tyr-Ile dipeptide linked to a 6-aminohexanoic acid amide, often written Hexanoyl-Tyr-Ile-Ahx-NH2.

**Is Dihexa a peptide or a small molecule?**
Dihexa sits between the two. It was derived from the peptide angiotensin IV and contains tyrosine and isoleucine, but its developers modified both ends to make it metabolically stable and able to cross the blood-brain barrier. Because of its small size and non-standard terminal groups, it is usually described as a small-molecule peptidomimetic rather than a conventional peptide.

**Is Dihexa the same as PNB-0408?**
Yes. PNB-0408 is a code name for dihexa, and published studies use the two names interchangeably. PubChem also lists ATH-1001 as a synonym. All of these refer to N-hexanoic-Tyr-Ile-(6) aminohexanoic amide, the same compound with formula C27H44N4O5, so studies indexed under any of these names describe one molecule.

**How does Dihexa work?**
Dihexa is proposed to enhance hepatocyte growth factor (HGF) signaling through the c-Met receptor. A zebrafish study found its protective effects were blocked by an HGF antagonist and partly by Akt, TOR and MEK inhibitors, and a mouse study linked it to PI3K/AKT activation. A key 2014 mechanistic paper has since been retracted, so the mechanism is not fully settled.

**What does the research on Dihexa show?**
Published research is preclinical. Studies in scopolamine-treated rats, aged rats and APP/PS1 mice reported improved spatial learning and increased synaptic markers, and a zebrafish study found hair-cell protection from aminoglycosides. A rat Huntington's disease-like model, however, showed no protective effect. No human clinical trial results appear in the indexed literature.

**Is Dihexa FDA approved?**
No. Dihexa is not approved by the FDA for any human use. It is an investigational research compound whose evidence comes from cell-culture, zebrafish and rodent studies, and a 2026 review noted that clinical trials for this group of neuroactive peptides are lacking.

**How is Dihexa different from angiotensin IV?**
Angiotensin IV is a natural six-residue peptide (VYIHPF) that is rapidly degraded and does not cross biological barriers well. Dihexa keeps only a Tyr-Ile core from the angiotensin IV analog Nle1-angiotensin IV and adds terminal caps that improve stability and allow oral activity and blood-brain barrier penetration in animal studies.

## References

1. McCoy AT, Benoist CC, Wright JW, et al. Evaluation of metabolically stabilized angiotensin IV analogs as procognitive/antidementia agents. The Journal of pharmacology and experimental therapeutics 2013. PMID: 23055539
2. Wright JW, Harding JW. The Brain Hepatocyte Growth Factor/c-Met Receptor System: A New Target for the Treatment of Alzheimer's Disease. Journal of Alzheimer's disease : JAD 2015. PMID: 25649658
3. Wright JW, Kawas LH, Harding JW. The development of small molecule angiotensin IV analogs to treat Alzheimer's and Parkinson's diseases. Progress in neurobiology 2015. PMID: 25455861
4. Rahman OF, Lee SJ, Seeds WA. Therapeutic Peptides in Orthopaedics: Applications, Challenges, and Future Directions. Journal of the American Academy of Orthopaedic Surgeons. Global research & reviews 2026. PMID: 41490200
5. Benoist CC, Kawas LH, Zhu M, et al. The procognitive and synaptogenic effects of angiotensin IV-derived peptides are dependent on activation of the hepatocyte growth factor/c-met system. The Journal of pharmacology and experimental therapeutics 2014. PMID: 25187433
6. Sun X, Deng Y, Fu X, et al. AngIV-Analog Dihexa Rescues Cognitive Impairment and Recovers Memory in the APP/PS1 Mouse via the PI3K/AKT Signaling Pathway. Brain sciences 2021. PMID: 34827486
7. Uribe PM, Kawas LH, Harding JW, et al. Hepatocyte growth factor mimetic protects lateral line hair cells from aminoglycoside exposure. Frontiers in cellular neuroscience 2015. PMID: 25674052
8. Ho JK, Nation DA. Cognitive benefits of angiotensin IV and angiotensin-(1-7): A systematic review of experimental studies. Neuroscience and biobehavioral reviews 2018. PMID: 29733881
9. Weiss JB, Phillips CJ, Malin EW, et al. 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. Annals of medicine and surgery (2012) 2021. PMID: 34703584
10. Wells RG, Azzam AF, Hiller AL, et al. Effects of an Angiotensin IV Analog on 3-Nitropropionic Acid-Induced Huntington's Disease-Like Symptoms in Rats. Journal of Huntington's disease 2024. PMID: 38489193
11. Pan T, Wang N, Zhang J, et al. Efficiently generate functional hepatic cells from human pluripotent stem cells by complete small-molecule strategy. Stem cell research & therapy 2022. PMID: 35410439