Dihexa

Dihexa (also known as PNB-0408, N-hexanoic-Tyr-Ile-(6) aminohexanoic amide) is a small-molecule oligopeptide analog derived from angiotensin IV (Ang IV). It has a molecular formula of C25H33N3O4, a molecular weight of 439.55 g/mol, and CAS number 1401708-83-5. Dihexa was developed at Washington State University by the laboratory of Dr. Joseph Harding and colleagues as part of a program to identify orally bioavailable, blood-brain barrier (BBB)-penetrant analogs of angiotensin IV capable of restoring cognitive function in preclinical models of neurodegeneration.

Dihexa is classified as a hepatocyte growth factor (HGF) mimetic and positive modulator of the HGF/c-Met signaling axis. Preclinical research has associated Dihexa with the facilitation of synaptogenesis, dendritic spine formation, and long-term potentiation (LTP) in hippocampal circuits, effects that have been reported at femtomolar to picomolar concentrations in cultured neurons. Published reports describe Dihexa as approximately seven orders of magnitude more potent than brain-derived neurotrophic factor (BDNF) in inducing spinogenesis in dissociated hippocampal cultures, positioning it among the most potent pro-cognitive small molecules characterized to date in the preclinical literature.

What differentiates Dihexa from other Ang IV analogs and from parent neurotrophins such as HGF and BDNF is its combination of low molecular weight, resistance to peptidases, oral bioavailability, and BBB permeability. These pharmacokinetic properties allow the compound to be administered systemically in animal studies and still reach central nervous system targets—an obstacle that has historically limited the therapeutic development of large neurotrophic proteins. In rodent models of scopolamine-induced amnesia and aged-rat cognitive decline, Dihexa has been reported to restore performance in Morris water maze tasks even after cholinergic disruption, suggesting a mechanism independent of classical acetylcholinergic signaling. It is important to note that Dihexa remains an investigational research compound; it has not been approved by any regulatory agency, and all references herein describe in vitro and in vivo preclinical findings intended solely for laboratory research use.

Dihexa's biological activity in preclinical models has been attributed primarily to positive modulation of the hepatocyte growth factor (HGF) / c-Met receptor tyrosine kinase signaling system, with additional interactions relevant to the angiotensin IV / AT4 (IRAP) axis. Its mechanism is best understood as a combination of allosteric HGF facilitation and downstream neurotrophic signaling.

HGF / c-Met Facilitation. Wright, Harding, and colleagues reported that Dihexa binds HGF and enhances its dimerization, thereby potentiating activation of the c-Met receptor tyrosine kinase on neuronal membranes. c-Met activation triggers autophosphorylation of intracellular tyrosine residues and recruits adaptor proteins such as Gab1 and Grb2, which in turn drive downstream PI3K/Akt and MAPK/ERK cascades. These pathways are strongly implicated in dendritic spine formation, actin cytoskeletal remodeling, and activity-dependent synaptic plasticity. Blocking c-Met with selective inhibitors (e.g., SU11274) or with anti-HGF antibodies abolishes Dihexa's spinogenic and pro-cognitive effects in vitro, providing pharmacological validation of the HGF/c-Met pathway as its principal target.

Synaptogenesis and Dendritic Spine Formation. In dissociated hippocampal cultures, Dihexa has been reported to induce a robust increase in the number of mushroom-shaped dendritic spines and PSD-95-positive synaptic puncta at concentrations in the 10⁻¹² to 10⁻¹⁰ M range. The compound also potentiates long-term potentiation (LTP) at Schaffer collateral–CA1 synapses in hippocampal slices, an electrophysiological correlate of learning and memory encoding.

Angiotensin IV / AT4 (IRAP) Context. Dihexa was developed from the parent hexapeptide Nle¹-angiotensin IV (Nle-AngIV), which binds the AT4 receptor, now identified as insulin-regulated aminopeptidase (IRAP). Although the AT4/IRAP site contributed to the medicinal chemistry rationale, current data indicate that the pro-cognitive effects of Dihexa are mediated predominantly through HGF/c-Met rather than through direct IRAP inhibition. This distinguishes it mechanistically from earlier Ang IV analogs whose activity was ascribed solely to aminopeptidase modulation.

Comparison to Neurotrophins. Unlike BDNF, which signals through TrkB, or NGF, which acts on TrkA, Dihexa acts upstream of a distinct receptor tyrosine kinase. The reported ~10⁷-fold higher spinogenic potency compared to BDNF in cultured neurons—if replicated in additional models—would represent a substantial mechanistic advance, though independent laboratory confirmation of these potency values remains an active area of investigation.

The following table summarises the verified chemical and physical properties of Dihexa (PNB-0408) for research reference. Values are cross-referenced against PubChem and primary literature reporting the compound's synthesis and characterisation.

Researchers should note that Dihexa is not a conventional peptide in the sense of possessing only amide-linked amino acid residues — the terminal caps (hexanoyl and 6-aminohexanoic acid amide) are aliphatic modifications introduced specifically to overcome the pharmacokinetic limitations of native angiotensin IV. As a result, Dihexa is best classified as a peptidomimetic small molecule rather than a peptide proper, which explains its markedly different solubility profile compared with conventional research peptides.

Dihexa is supplied here as a finished oral capsule (5 mg per capsule, 60 capsules per bottle), not as a lyophilised powder for reconstitution. The handling notes below reflect that presentation.

• Storage. Keep the bottle sealed at room temperature, away from direct light and humidity. No cold chain is required and no refrigeration step is involved in shipping.
• Desiccant. Leave the supplied desiccant in the bottle. Dihexa’s lipophilic hexanoyl cap makes the compound itself stable, but capsule shells are hygroscopic and soften with repeated humidity exposure.
• Lot traceability. Each bottle carries a lot number that maps to its Certificate of Analysis. Record the lot alongside experimental data so results remain traceable to a specific batch analysis.
• Solubility, for reference. As a free compound Dihexa shows limited aqueous solubility owing to the hexanoyl group, and DMSO is the solvent generally reported for stock preparation in the published in vitro work. That applies to the raw compound in a laboratory setting; it is not a preparation step for this capsule product.

This product is supplied for laboratory research use only. It is not a dietary supplement, not a drug, and not intended for human or veterinary consumption.