[Dihexa](/products/dihexa) (N-hexanoic-Tyr-Ile-(6) aminohexanoic amide) is a synthetic peptide analogue developed at Washington State University. It was designed as a potent, orally bioavailable agonist of the HGF/c-Met signaling system, a pathway that plays a critical role in synaptic formation and cognitive function.
Key Findings
- Dihexa is a synthetic hexapeptide derived from angiotensin IV, targeting the HGF/c-Met receptor system.
- Research has shown it is approximately 10 million times more potent than BDNF at inducing synaptogenesis in hippocampal cultures.
- It promotes dendritic spine formation and long-term potentiation, suggesting relevance to memory and learning research.
- Animal studies have demonstrated cognitive enhancement in models of Alzheimer disease and cognitive decline.
- The potency and mechanism make it a compound of significant interest for neurodegeneration research protocols.
Origins and Design
Dihexa was derived from angiotensin IV (Ang IV) and its parent compound Norleucine-1-Ang IV, through a series of structure-activity relationship studies aimed at identifying the minimum active sequence with maximum CNS penetration and oral bioavailability.
The hexanoic acid modification dramatically improves lipophilicity, enabling oral administration - a critical advantage over most peptides that require parenteral routes. This was intentional: the goal was a CNS-active peptide that could be studied orally in aging and neurodegeneration models.
Mechanism: HGF/c-Met Axis
Dihexa's primary target is the hepatocyte growth factor (HGF) / c-Met receptor system. While named for its liver biology, HGF/c-Met signaling is highly active in the brain, particularly in the hippocampus.
HGF/c-Met and synaptic plasticity:
- c-Met activation drives dendritic spine formation and stabilization
- It promotes synaptogenesis - the formation of new synaptic connections
- It upregulates NMDA receptor trafficking to the synapse
- It enhances LTP (long-term potentiation) - the cellular correlate of memory formation
Dihexa has been described as a "super potent" HGF/c-Met agonist with affinity reportedly ~1 million times greater than HGF itself for promoting synaptogenesis in hippocampal cultures.
Cognitive Research Findings
The original Dihexa publications (Wright et al.) used the Morris Water Maze and passive avoidance paradigms in aged rat models:
- Aged rats treated with Dihexa performed comparably to young rats in spatial memory tasks
- Improvements were observed in both acquisition (learning) and retention (recall)
- Hippocampal synaptophysin levels (a marker of synaptic density) were significantly elevated in treated animals
- Effects persisted beyond the treatment period in some protocols, suggesting structural rather than purely functional changes
These findings positioned Dihexa as a candidate for Alzheimer's disease and age-related cognitive decline research.
Oral Bioavailability: A Key Advantage
Dihexa's oral bioavailability is a major research advantage. Most peptides are degraded in the GI tract and require injection. Dihexa's modified structure allows it to survive digestion and cross the blood-brain barrier.
This makes it uniquely accessible for chronic dosing protocols and for research contexts where injection is not feasible. Studies have administered it via drinking water, gavage, and subcutaneous injection - all with demonstrable CNS effects.
Current Research Landscape
Dihexa remains a primarily preclinical compound. No human clinical trials have been completed. Its extraordinary potency in animal models has generated significant interest, but also appropriate caution - the consequences of potent synaptogenesis at non-optimal brain regions or developmental stages are not fully characterized.
Current research directions include: Alzheimer's disease models, traumatic brain injury, post-stroke cognitive recovery, and the basic biology of HGF/c-Met in adult neuroplasticity.
Where to Buy Dihexa for Research
Where to buy Dihexa online for research: Blackwell BioLabs offers Dihexa at ≥99% HPLC-verified purity with batch-specific Certificate of Analysis (COA). Same-day US shipping via USPS Priority Mail. Accepts Bitcoin (BTC), Litecoin (LTC), Monero (XMR), Cash App, and Venmo. Sold for research purposes only — no prescription required.
Dihexa specifications at Blackwell BioLabs:
- Purity: ≥99% by HPLC
- Format: Lyophilized powder
- COA: Batch-specific, third-party tested — available at blackwellbiolabs.com/coa
- Shipping: Same-day from US (orders before 2PM HST), USPS Priority Mail
- Price: $299.99
Dihexa is orally bioavailable, making it suitable for both oral and parenteral research protocols. Verify HPLC purity and mass spectrometry confirmation. COA available at /coa.
Order at: blackwellbiolabs.com/products/dihexa
Published References
PMC3563294
Dihexa: orally active synaptogenic HGF/c-Met agonist
25674052
Hallberg M, Nyberg F. Dihexa (N-hexanoic-Tyr-Ile-(6) aminohexanoic amide). HGF/c-Met agonism. Eur J Pharmacol. 2015.
25187433
McCoy AT, et al. Evaluation of dihexa, an angiotensin IV agonist, for cognitive improvement in aged rats. J Pharmacol Exp Ther. 2013.
27532814
Mathapati S, et al. Small-molecule-directed hepatocyte-like cell differentiation of human pluripotent stem cells via HGF agonist Dihexa. Curr Protoc Stem Cell Biol. 2016.
Research Use Only. All content is for informational and educational purposes regarding preclinical research. None of the compounds discussed have been approved by the FDA for human therapeutic use. This information does not constitute medical advice.