Skip to main content
Order by 2 pm ET on a business day, ships that dayFree FedEx 2-Day over $250.00
Bag 0 items
Research library
PeptidomimeticSource retracted

Dihexa

A metabolically stabilized three-residue analogue derived from angiotensin IV, studied in rodent and zebrafish models of the hepatocyte growth factor pathway, and carrying a retracted mechanism paper that the field still cites.

For in-vitro research only.Reviewed 2026-09-20

Key findings

  • The compound was produced by modifying the Nle-Tyr-Ile core of an angiotensin IV analogue to raise hydrophobicity and lower hydrogen bonding, which the authors report as giving metabolic stability and barrier permeability. [1]
  • In larval zebrafish lateral line hair cells the compound reduced loss after aminoglycoside exposure, and that reduction was attenuated by a hepatocyte growth factor antagonist and by Akt, TOR and MEK inhibitors, which the authors read as pathway dependence. [2]
  • Adding an amino group to the N terminus of the molecule weakened the measured protection in the same zebrafish assay, indicating that small substitutions change target specificity. [2]
  • The compound did not attenuate the deficits produced by the mitochondrial toxin 3-nitropropionic acid in rats, a reported negative result in a model where the authors had expected activity. [3]

Identity and structure

Chemical name
N-hexanoic-Tyr-Ile-(6) aminohexanoic amide, also reported under the laboratory code PNB-0408 [1][3]
Origin
Built from the three N-terminal residues Nle-Tyr-Ile of the angiotensin IV analogue norleucine(1)-angiotensin IV, which the earlier work identified as the core structural information of that peptide [1]
Publication status of the cited mechanism paper
The 2014 paper linking the molecule to hepatocyte growth factor and c-Met was retracted by the journal in 2025, and the retraction notice is cited alongside it here [4][5]
Receptor assignment in the cited literature
The angiotensin IV binding site is reported as insulin-regulated aminopeptidase by one group and as the hepatocyte growth factor c-Met system by another, and the review states the identity is unresolved [6]
Form as supplied
Sterile lyophilized powder

Mechanism as studied

The pathway account in the cited literature runs through hepatocyte growth factor rather than through a receptor for the molecule itself. The zebrafish work describes the compound as a synthetic mimetic that dimerizes with endogenous hepatocyte growth factor to form a functional ligand, and reports that a hepatocyte growth factor antagonist attenuates the measured effect. [2]

Downstream signalling was probed pharmacologically rather than structurally. Inhibitors of Akt, TOR and MEK each partly attenuated the zebrafish result, and in an APP/PS1 mouse study the PI3K inhibitor wortmannin reversed the reported changes in inflammatory and apoptotic markers. [2][7]

The central mechanism paper for this molecule is retracted, so the claim that its activity depends on activation of the hepatocyte growth factor and c-Met system rests on the remaining reports rather than on that publication. A review from the originating laboratory records that the identity of the angiotensin IV binding site was itself contested. [4][5][6]

Research findings

Preclinical in vivo
System
Rodent models of scopolamine induced deficit and of ageing, with a series of N-terminal and C-terminal modified angiotensin IV analogues screened alongside the final compound rather than the compound alone
Measured
Metabolic stability of each analogue, permeability across biological barriers, Morris water maze performance and hippocampal synaptogenesis
Reported
Several terminal modifications raised stability while retaining the water maze and synaptogenesis readouts. Further modification for higher hydrophobicity and lower hydrogen bonding produced the barrier permeant compound, which the authors report as active in both rodent models and as markedly synaptogenic. [1]
Preclinical in vivo
System
Larval zebrafish lateral line, whose hair cells the authors describe as homologous to mammalian inner ear hair cells
Measured
Hair cell loss after neomycin or gentamicin exposure across a concentration range, uptake of fluorescently tagged gentamicin, and the effect of the hepatocyte growth factor antagonist 6-AH, of Akt, TOR and MEK inhibitors, and of an N-terminal amino substitution
Reported
A concentration of 1 µM gave the largest reduction in hair cell loss for either aminoglycoside. Pre-exposure did not change the amount of labelled gentamicin entering hair cells, so the authors attribute the effect to intracellular events rather than to blocked entry. The hepatocyte growth factor antagonist attenuated the effect, the three downstream inhibitors partly attenuated it, and the N-terminal amino substitution weakened it. [2]
Preclinical in vivo
System
Forty male Wistar rats randomized to vehicle, to chronic 3-nitropropionic acid exposure, and to 3-nitropropionic acid with the compound
Measured
Body weight gain, motor function and spatial learning over five weeks, then histopathology
Reported
The toxin reduced weight gain, impaired spatial learning and memory consolidation and produced marked motor dysfunction. The compound did not protect the rats from those deficits, and the authors conclude it was not efficacious in this model. [3]
Preclinical in vivo
System
APP/PS1 mice compared with wild type, with the PI3K inhibitor wortmannin used as a pathway control
Measured
Tissue angiotensin IV content, Morris water maze performance, neuronal cell counts and SYP protein by Nissl staining, astrocyte and microglia activation, IL-1 beta, TNF alpha and IL-10 levels, and PI3K and AKT activation
Reported
Tissue angiotensin IV rose relative to the wild type group. Water maze performance, neuronal cell counts and SYP expression increased, astrocyte and microglia activation and the two pro-inflammatory cytokines fell while IL-10 rose, and wortmannin significantly reversed the reported anti-inflammatory and anti-apoptotic changes. [7]
Preclinical in vivo
System
Male Lewis rats in a sciatic nerve transection and repair model, across ten groups in which the compound was given alone or combined with mesenchymal stem cells or granulocyte colony stimulating factor rather than alone only
Measured
Sensory function in the peroneal, tibial and sural distributions on a four point grade and motor function by walking footprint grade, at one to two week intervals to sixteen weeks
Reported
Sensory function returned to near normal grades by eight weeks across all groups combined, with peroneal recovery by one week and sural recovery by four weeks. Motor footprint grades at eight to sixteen weeks improved significantly with stem cells combined with the compound and with stem cells combined with the colony stimulating factor. [8]
Review
System
Review from the originating laboratory covering the brain renin angiotensin system and the angiotensin IV analogue series that produced this molecule
Measured
Narrative assembly of the analogue development work and of the competing assignments for the angiotensin IV binding site
Reported
The review records that one group identifies the site as insulin-regulated aminopeptidase and that the authors' own group places it with the hepatocyte growth factor and c-Met system, and states that the identity of the receptor protein is contested. [6]

Handling for in-vitro work

Solvent in cited work
Applied in the bathing medium of larval zebrafish at micromolar concentration in the hair cell assay [2]
Stability reported
The terminal modifications were introduced specifically to resist metabolic degradation, and the molecule is reported as chemically stable relative to native hepatocyte growth factor [1][2]
Storage
Lyophilized at -20 °C, dark and dry; reconstituted aliquots kept cold and used promptly

Open questions

  • The 2025 retraction withdraws the 2014 paper that reported high affinity binding of this molecule to hepatocyte growth factor, c-Met phosphorylation at subthreshold hepatocyte growth factor concentrations, augmented hepatocyte growth factor dependent cell scattering, hippocampal spinogenesis and synaptogenesis, and the blockade of the water maze result by a hepatocyte growth factor antagonist. None of those findings should be treated as established.
  • The binding affinity for hepatocyte growth factor is not supported by a standing publication in the cited set, so the affinity figure often quoted for this molecule has no unretracted source here.
  • The identity of the angiotensin IV binding site is contested in the cited review, between insulin-regulated aminopeptidase and the hepatocyte growth factor c-Met system.
  • The rat 3-nitropropionic acid result is negative while the mouse and zebrafish results are positive, and the cited work does not reconcile the difference between the models.

A clinical literature on angiotensin IV analogues exists and concerns finished formulations; it is out of scope for a research material profile.

Lot records

Check the record for the exact material you order. A published paper and a batch certificate answer different questions.

No published lot is available for this exact compound name.

Read a certificate of analysis ↗

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.

    PubMed 23055539 · doi:10.1124/jpet.112.199497

  2. 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.

    PubMed 25674052 · doi:10.3389/fncel.2015.00003

  3. 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.

    PubMed 38489193 · doi:10.3233/JHD-231507

  4. Retracted. Read the notice before citing.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.

    PubMed 25187433 · doi:10.1124/jpet.114.218735

  5. Benoist CC, Kawas LH, Zhu M, et al. 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]. The Journal of pharmacology and experimental therapeutics. 2025.

    PubMed 40312093 · doi:10.1016/j.jpet.2025.103567

  6. 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.

    PubMed 25455861 · doi:10.1016/j.pneurobio.2014.11.004

  7. 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.

    PubMed 34827486 · doi:10.3390/brainsci11111487

  8. 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.

    PubMed 34703584 · doi:10.1016/j.amsu.2021.102917

Publication records fetched from PubMed on 2026-09-20. Profile text reviewed 2026-09-20.