Dihexa
Synthetic angiotensin IV-derived oligopeptide
A synthetic peptide studied in synaptogenesis and cognitive research.
Overview
Dihexa (N-hexanoic-Tyr-Ile-(6) aminohexanoic amide) is a synthetic derivative of angiotensin IV developed by researchers at Washington State University as a candidate for cognitive and neurotrophic research.
At a glance
What Dihexa does
Dihexa is a small orally-active peptide derived from angiotensin IV, designed specifically to be a potent inducer of synapse formation. What it does in research is promote synaptogenesis and dendritic spine growth, meaning it acts at the structural level of neural connectivity rather than producing a transient neurochemical shift. In laboratory studies it has restored or enhanced measures of synaptic density and, in some models, procognitive performance.
Its defining mechanism is potentiation of the hepatocyte growth factor (HGF) / c-Met system. Dihexa binds HGF with high affinity and, in the presence of subthreshold HGF, induces phosphorylation (activation) of the c-Met receptor on neurons. Activated c-Met drives the PI3K/Akt and MAPK/ERK signaling cascades, which upregulate pre- and post-synaptic scaffolding proteins such as PSD-95 and synaptophysin and increase dendritic spine density. The synaptogenic and procognitive effects are abolished when the HGF/c-Met axis is blocked by an HGF antagonist or by shRNA knockdown of c-Met, which is the key evidence that this pathway is the operative mechanism.
Crucially, the entire evidence base is preclinical: rodent hippocampal preparations, cultured neurons, and animal cognition models (including scopolamine-impaired rats). A widely-cited University of Arizona study reported large increases in synaptogenesis markers. There are no controlled human clinical trials, and because a growth-factor pathway is being potentiated, its long-term safety profile in humans is unknown.
Effects reported in research
- Induced hippocampal synaptogenesis and dendritic spinogenesis in rodent tissue, reported at multiples of baseline in cell studies (animal/in-vitro).
- Bound HGF with high affinity and triggered c-Met receptor phosphorylation at subthreshold HGF levels (in-vitro).
- Upregulated post-synaptic scaffolding protein PSD-95 and pre-synaptic synaptophysin (preclinical).
- Activated PI3K/Akt and MAPK/ERK signaling downstream of c-Met (in-vitro).
- Reversed cognitive deficits in scopolamine-impaired rodent memory models (animal).
- Effects on synaptogenesis abolished by HGF antagonist or c-Met shRNA knockdown, confirming pathway dependence (in-vitro).
- Orally bioavailable and CNS-penetrant in rodents, distinguishing it from most angiotensin-IV analogs (animal).
- No human clinical trials; all cognitive and synaptic effects remain preclinical only.
Effects listed reflect findings reported in the research literature — many in animal or in-vitro models. Listing an effect is not a claim of efficacy or a therapeutic indication in humans.
Mechanism of action
Dihexa was designed as an orally active, blood-brain-barrier-penetrant small molecule derived from angiotensin IV. Research reports that it acts as a hepatocyte growth factor (HGF)/c-Met system modulator, potentiating HGF signaling to promote synaptogenesis and dendritic spine formation. These effects are the basis for its study as a pro-cognitive agent in preclinical models.
Mechanistic description reflects published research-literature understanding. Much peptide research is preclinical (in-vitro or animal-model); mechanism in humans may differ and is not established for many compounds.
What it's studied for
Research contexts in which Dihexa appears in the literature. Listing a research area is not a claim of efficacy or a therapeutic indication.
Key characteristics
- Derived from angiotensin IV and designed for metabolic stability and CNS penetration
- Proposed to work by potentiating the HGF/c-Met signaling system
- Studied preclinically for promotion of synapse formation and cognitive effects
- Reported to be far more potent than its parent peptide in preclinical assays
- Research-only; no approved human clinical use
Reported research dosing reference only
Educational reference, not dosing guidance. The figures below summarize amounts reported in published research and research-community protocols, provided for educational and research context only. They are not medical advice, not a recommendation, and not instructions for human use. Dihexa is a research compound.
Reported dosing is preclinical only, drawn from rodent studies, and no validated human dose exists. These are reference figures for research context only, not human dosing guidance.
- Preclinical reference figures commonly cited around 10-20 mg (rodent/oral context)
No human PK/half-life established; a key 2014 paper was retracted, so preclinical claims should be treated cautiously
How it compares
Dihexa is distinguished by its proposed HGF/c-Met-mediated pro-synaptogenic mechanism, unlike the melanocortin (Semax) or tuftsin (Selank) peptides.
Handling & Stability
Lyophilized peptides are stored cold, protected from light, and reconstituted only at the time of intended in-vitro work.
- Avoid repeated freeze-thaw cycles
- Verify supplier lot and Certificate of Analysis
- Follow institutional lab-safety protocols
Analytical & COA Concepts
Reputable research suppliers publish a third-party Certificate of Analysis per batch. Key analytical concepts referenced in COAs include:
Category Context
Dihexa sits in the Cognitive & Nootropic area of the PeptiDex library.
- Entry type: Research compound reference
- Browse the full library →
- Glossary of terms →
Where researchers source Dihexa
For researchers studying Dihexa, third-party suppliers such as Practically Natty Peptides offer research-grade material with third-party Certificates of Analysis and US-based shipping.
PeptiDex does not maintain a direct supplier listing for this compound. The link above goes to a third-party research-supplier directory.
Frequently asked questions
What is Dihexa and what is its proposed mechanism?
Dihexa (PNB-0408) is an orally active angiotensin-IV-derived peptidomimetic engineered as a potent hepatocyte growth factor (HGF) / c-Met modulator. In preclinical work it is reported to bind HGF with high affinity and potentiate c-Met signaling, with the proposed downstream effect of promoting synaptogenesis.
How is Dihexa different from typical research peptides?
Dihexa is a small peptidomimetic, not a natural peptide sequence, chemically described as Hexanoyl-Tyr-Ile-Ahx-NH2 with N-hexanoic-acid modifications. These modifications were engineered to confer oral bioavailability and blood-brain-barrier penetration, which most native peptides lack.
What is the state of evidence for Dihexa?
Evidence for Dihexa is entirely preclinical, drawn from rodent cognition models such as scopolamine-treated and aged rats. There are no human clinical trials, and researchers should note that a prominent 2014 publication associated with the compound was retracted over data-integrity concerns.
Is Dihexa orally bioavailable?
In preclinical reports Dihexa shows meaningful oral bioavailability, on the order of roughly a third of an oral dose reaching circulation, along with blood-brain-barrier penetration. This is unusual for a peptide-based molecule and is a direct result of its engineered lipophilic modifications.
Is Dihexa approved for human use?
No. Dihexa is a preclinical research compound with no regulatory approval in any jurisdiction. It is handled strictly as a laboratory research material.
Answers are educational summaries of research-literature context and do not constitute medical advice. See the Research Library, COA guide, and Storage & Handling guide for more.