Synaptogenesis & HGF/c-Met Cognitive Enhancement
Dihexa (PNB-0408) — HGF/c-Met Signaling Enhancer
Dihexa (PNB-0408) is a small molecule peptidomimetic derived from angiotensin IV, developed by researchers at Washington State University. It is one of the most potent pro-cognitive compounds identified in preclinical research, with reported activity approximately 7 orders of magnitude (10 million times) more potent than BDNF in promoting synaptogenesis in hippocampal cell culture models.
Dihexa's mechanism of action centers on the hepatocyte growth factor (HGF) / c-Met signaling pathway — a receptor tyrosine kinase system with well-established roles in neuronal survival, axonal guidance, and synaptogenesis. By potentiating HGF/c-Met signaling, dihexa promotes the formation of new synaptic connections, which is the cellular basis of learning, memory consolidation, and cognitive recovery.
Dihexa is a modified tripeptide with the structure N-hexanoyl-Tyr-Ile-Leu-OH, derived from the C-terminal tripeptide of angiotensin IV (Ang IV). The N-hexanoyl modification at the N-terminus dramatically enhances lipophilicity and blood-brain barrier penetration compared to the parent angiotensin IV peptide. The molecular weight is 397.55 Daltons.
The compound is classified as a peptidomimetic rather than a standard peptide, as the N-hexanoyl modification confers drug-like properties including oral bioavailability and CNS penetration.
Dihexa acts as a potentiator of hepatocyte growth factor (HGF) binding to its receptor c-Met (MET proto-oncogene), a receptor tyrosine kinase expressed on neurons, astrocytes, and oligodendrocytes throughout the brain. HGF/c-Met signaling activates multiple downstream pathways including PI3K/Akt (neuronal survival), MAPK/ERK (cell proliferation and differentiation), and Rac1/Cdc42 (actin cytoskeleton remodeling for synaptogenesis).
The net effect is a robust promotion of dendritic spine formation and synaptogenesis — the structural correlates of long-term memory. McCoy et al. (2013) at Washington State University demonstrated that dihexa reversed cognitive deficits in aged rats and in a scopolamine-induced amnesia model, with potency far exceeding that of BDNF.
Dihexa also promotes neurogenesis in the hippocampal dentate gyrus and has neuroprotective effects in models of Alzheimer's disease pathology.
Dihexa is a small peptide developed by researchers at Washington State University, derived from angiotensin IV (a fragment of the blood pressure hormone angiotensin). It was specifically designed to cross the blood-brain barrier — a major challenge for most peptides — and to potently stimulate synaptogenesis: the formation of new synaptic connections between neurons.
Dihexa works primarily through the HGF/c-Met signaling pathway. HGF (Hepatocyte Growth Factor) and its receptor c-Met are key regulators of synaptogenesis and neuronal survival. Dihexa binds to HGF and dramatically potentiates its activity at the c-Met receptor, leading to increased formation of new dendritic spines and synapses. In animal studies from WSU, Dihexa was reported to be approximately 10 million times more potent than BDNF at promoting synaptogenesis — a remarkable claim that has attracted significant research interest.
Synapse loss is the primary correlate of cognitive decline in Alzheimer's disease and other neurodegenerative conditions. A compound that potently stimulates synaptogenesis — the rebuilding of those connections — is of enormous potential interest for neurodegenerative disease research. The WSU research team's data is compelling, though independent replication has been limited and the compound is still in early-stage research.
Dihexa is one of the most potent synaptogenesis-promoting compounds identified to date, based on WSU preclinical data. Its ability to cross the blood-brain barrier and its HGF/c-Met mechanism make it a unique tool for cognitive neuroscience research. Independent replication of the most dramatic potency claims is still needed. Research-only compound with no clinical approval.
Potentiates HGF binding to c-Met receptor tyrosine kinase, activating downstream signaling cascades that drive synaptogenesis.
c-Met-mediated PI3K/Akt activation promotes neuronal survival and inhibits apoptosis in hippocampal and cortical neurons.
Activates Rho GTPases Rac1 and Cdc42, driving actin cytoskeleton remodeling for dendritic spine formation and synaptogenesis.
Promotes neurogenesis in the hippocampal dentate gyrus, contributing to the cellular substrate of learning and memory.
Cognitive Research
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| Compound Class | Peptidomimetic (N-hexanoyl modified tripeptide) |
| Molecular Weight | 397.55 Da |
| Target Pathway | HGF / c-Met receptor tyrosine kinase |
| Potency vs. BDNF | ~10⁷ fold more potent in synaptogenesis assays |
| BBB Penetration | Yes — N-hexanoyl modification enhances lipophilicity |
| Available Sizes | 100mg vials |
| Form | Lyophilized powder |
| Purity | ≥99% (third-party tested) |
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Purchase Dihexa at Purgo LabsMedical Disclaimer: All content on this site is for educational and research purposes only. Research peptides are not FDA-approved for human use. Always consult a qualified healthcare professional before considering any peptide or supplement protocol. Nothing on this site constitutes medical advice, diagnosis, or treatment.
