Dihexa

Dihexa (also known as N-hexanoic-Tyr-Ile-(6)-aminohexanoic amide, PNB-0408, Dihexa) is a nootropic research peptide. An angiotensin IV derivative reported to be orders of magnitude more potent than BDNF at driving synaptogenesis. Its mechanism runs through c-Met — the same receptor that drives many cancers.

Dihexa (N-hexanoic-Tyr-Ile-(6)-aminohexanoic amide) is a small, highly lipophilic angiotensin IV analogue developed at Washington State University as an orally active, blood-brain-barrier-penetrant neurotrophic compound. It does not act as a growth factor itself: it potentiates hepatocyte growth factor (HGF) signalling at its receptor c-Met, stabilising the HGF/c-Met interaction and amplifying downstream PI3K/AKT and MAPK signalling that drives dendritic spine formation and synaptogenesis. The frequently repeated claim that it is "seven orders of magnitude more potent than BDNF" comes from a specific in vitro spinogenesis assay and should not be read as a general potency statement. In animal models it reversed cognitive deficits in scopolamine-treated rats and in the APP/PS1 Alzheimer's mouse model, with effects attributed to PI3K/AKT signalling. It reached preclinical development for Alzheimer's disease but no human clinical trial has been completed. The core safety concern is structural: c-Met is a proto-oncogene, dysregulated in a wide range of carcinomas, and a compound whose entire mechanism is amplification of HGF/c-Met signalling amplifies a growth pathway indiscriminately — there is no data establishing whether that risk is theoretical or real in humans.

1 Mechanism of action

Binds and stabilises the hepatocyte growth factor (HGF) dimer, potentiating its activation of the c-Met receptor tyrosine kinase. Downstream PI3K/AKT and MAPK activation drives dendritic spine formation, synaptogenesis and neuronal survival. Its lipophilic design (hexanoic acid and aminohexanoic amide caps) enables oral bioavailability and CNS penetration that native angiotensin IV lacks.

Primary targets: HGF/c-Met axis (allosteric potentiation) · AT4 receptor (IRAP) — parent pharmacology

2 Reported effects

Effects below are those reported in the published literature cited on this page. They are not claims of clinical benefit and not medical advice.

2.1 Reported benefits

• Reversed cognitive deficits in scopolamine and APP/PS1 Alzheimer's rodent models
• Potent synaptogenic activity in vitro at picomolar concentrations
• Orally bioavailable and blood-brain-barrier penetrant by design
• Acts by amplifying an endogenous neurotrophic system rather than substituting for it
• Neuroprotective effects reported in hair cell and neuronal injury models

2.2 Side effects

• No human safety data whatsoever
• Theoretical oncogenic risk from systemic c-Met pathway amplification
• Headache and irritability reported anecdotally
• Unknown effects on non-neural tissues expressing c-Met (liver, kidney, epithelium)
• Potential for aberrant synaptic remodelling with chronic use

3 Chemical and physical properties

3.1 Amino acid sequence

4 Research dosages

Rodent studies used sub-milligram-per-kilogram oral and intraperitoneal doses. No human protocol exists; circulating figures of 8–45 mg/day are extrapolation without support.

5 Research studies (8)

1. AngIV-Analog Dihexa Rescues Cognitive Impairment and Recovers Memory in the APP/PS1 Mouse via the PI3K/AKT Signaling Pathway
   Brain Sciences (2021) · Preclinical · N/A (murine)
   Dihexa administration in the APP/PS1 transgenic Alzheimer's mouse model with behavioural and molecular endpoints.
   Key finding: Rescued cognitive impairment and restored memory performance, with effects mediated through PI3K/AKT signalling.
2. The procognitive and synaptogenic effects of angiotensin IV-derived peptides are dependent on activation of the hepatocyte growth factor/c-Met system
   Journal of Pharmacology and Experimental Therapeutics (2013) · Preclinical · N/A (in vitro and rodent)
   Mechanistic study establishing HGF/c-Met dependence of dihexa's synaptogenic and procognitive effects.
   Key finding: Blocking c-Met abolished the procognitive and spinogenic effects, confirming HGF/c-Met as the required mechanism.
3. AngIV-Analog Dihexa Rescues Cognitive Impairment and Recovers Memory in the APP/PS1 Mouse via the PI3K/AKT Signaling Pathway.
   Brain sciences (2021) · Preclinical
   The renin-angiotensin system (RAS) is a paracrine RAS within the central nervous system (CNS) and is closely related to Alzheimer's disease (AD).
4. Cognitive benefits of angiotensin IV and angiotensin-(1-7): A systematic review of experimental studies.
   Neuroscience and biobehavioral reviews (2018) · Systematic Review
   Studies of cognitive impairment show salutary effects of acute administration of Ang IV and its analogs, as well as AT4R activation.
5. Hepatocyte growth factor mimetic protects lateral line hair cells from aminoglycoside exposure.
   Frontiers in cellular neuroscience (2015) · Preclinical
   Loss of sensory hair cells from exposure to certain licit drugs (e.g., aminoglycoside antibiotics, platinum-based chemotherapy agents) can result in permanent hearing loss.
6. 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) · Preclinical
   A subset of angiotensin IV (AngIV)-related molecules are known to possess procognitive/antidementia properties and have been considered as templates for potential therapeutics.
7. Evaluation of metabolically stabilized angiotensin IV analogs as procognitive/antidementia agents.
   The Journal of pharmacology and experimental therapeutics (2013) · Preclinical
   Angiotensin IV (AngIV: VYIHPF)-related peptides have long been recognized as procognitive agents with potential as antidementia therapeutics.
8. Dimeric DOTA-alpha-melanocyte-stimulating hormone analogs: synthesis and in vivo characteristics of radiopeptides with high in vitro activity.
   Journal of receptor and signal transduction research (2007) · Preclinical
   Dimeric analogs of alpha-melanocyte-stimulating hormone (alpha-MSH) labeled with radiometals are potential candidates for diagnosis and therapy of melanoma by receptor-mediated tumor targeting.

6 Safety and risk profile

6.1 Regulatory status

Dihexa is currently classified as Not approved. It has no approved human indication in the United States; availability elsewhere does not imply demonstrated safety or efficacy.

Safety score: 32/100 — high concern. Derived from clinical data volume, known risks and regulatory status.

6.2 Contraindications

Conditions and populations in which use is contraindicated:

• Known or suspected malignancy, or history of cancer
• Family history of c-Met-driven cancers (gastric, renal, hepatocellular)
• Pregnancy or lactation
• Proliferative disorders of any kind

6.3 Drug interactions

6.4 Long-term risks

• Theoretical but mechanistically grounded oncogenic risk from chronic c-Met stimulation
• Unknown consequences of sustained synaptic remodelling
• No chronic toxicology data in any species at human-relevant exposures

6.5 Research best practices

• Store lyophilised at −20 °C, desiccated and protected from light
• Highly lipophilic — dissolves poorly in water; DMSO or lipid vehicles are used in research
• Verify identity by mass spec: the molecule is small and easily substituted
• Treat all human dosing figures as unvalidated extrapolation

7 Frequently asked questions

Is dihexa really millions of times stronger than BDNF?

That figure comes from a specific in vitro dendritic spine formation assay, where dihexa was active at picomolar concentrations against BDNF's nanomolar activity. It is a valid assay result and an invalid general claim — potency in one spinogenesis assay does not translate to overall neurotrophic superiority in a living brain.

What is the cancer concern?

c-Met is a proto-oncogene; aberrant HGF/c-Met signalling drives proliferation, invasion and metastasis in many carcinomas, and multiple approved cancer drugs are c-Met inhibitors. Dihexa amplifies that exact pathway systemically and non-selectively. No study has established whether this translates into human risk, which is itself the problem.

Has dihexa been tested in humans?

No completed human clinical trial exists. All efficacy data is from cell culture and rodent models. It is sold as a research chemical, occasionally in oral form, without human pharmacokinetic or safety data.

8 References

1. AngIV-Analog Dihexa Rescues Cognitive Impairment and Recovers Memory in the APP/PS1 Mouse via the PI3K/AKT Signaling Pathway. PubMed (2021). Sun X, et al.. View source
2. Cognitive benefits of angiotensin IV and angiotensin-(1-7): A systematic review of experimental studies. PubMed (2018). Ho JK, et al.. View source
3. Hepatocyte growth factor mimetic protects lateral line hair cells from aminoglycoside exposure. PubMed (2015). Uribe PM, et al.. View source
4. The procognitive and synaptogenic effects of angiotensin IV-derived peptides are dependent on activation of the hepatocyte growth factor/c-met system. PubMed (2014). Benoist CC, et al.. View source

9 See also

• Peptide encyclopedia index
• Peptide reconstitution calculator
• Glossary of peptide research terms