Dihexa
Also known as: N-Hexanoic-Tyr-Ile-(6)-aminohexanoic amide · PNB-0408
An orally active hexapeptide derivative of angiotensin IV, characterised in academic research as among the most potent known pro-cognitive compounds in animal models.
Dihexa is a hexapeptide angiotensin-IV derivative studied for oral, blood-brain-barrier-penetrant synaptogenic activity via HGF/c-Met — preclinical evidence only.
Evidence tier: C — preclinical / mechanistic evidence only
- Category
- Neurogenesis
- Half-life
- Oral bioavailability with extended pharmacodynamic effects
- Formula
- C₂₆H₄₃N₅O₅
- Weight
- 521.66 g/mol
Section 1
Overview
Dihexa is a small hexapeptide derivative engineered from the C-terminal fragment of angiotensin IV, designed at Washington State University to be orally bioavailable, blood-brain-barrier penetrant, and metabolically stable. The molecule is positioned in academic research as a tool for studying hepatocyte growth factor (HGF) / c-Met signalling in the central nervous system.
The compound's defining property in published research is its capacity to promote new synaptic connections — synaptogenesis — at sub-nanomolar concentrations in hippocampal slice preparations. Researchers have reported potency several orders of magnitude greater than BDNF in head-to-head spinogenesis assays.
Dihexa has been profiled in animal models of cognitive impairment, including scopolamine-induced amnesia and aged-rat learning paradigms, where it has been reported to restore performance to that of young, untreated control animals.
Section 2
Discovery & History
- Developed by Joseph Harding's group at Washington State University in the 2010s as part of a broader programme exploring angiotensin IV's CNS effects.
- First major publications describing potent synaptogenic activity appeared between 2012 and 2015.
- The molecule remains a research compound: no clinical trials are publicly registered, and it is not in any regulatory approval pipeline known to date.
- Has acquired interest in academic and laboratory research circles for its reported oral bioavailability — unusual for a peptide of this size.
Section 3
Mechanism of Action
- 1Activates the hepatocyte growth factor (HGF) / c-Met signalling pathway in central neurons — HGF/c-Met is a well-characterised driver of dendritic spine formation, synaptic remodelling, and cortical circuit maturation, and Dihexa's engineering targets the exogenous augmentation of this endogenous signalling axis.
- 2Stabilises the HGF homodimer, prolonging the active signalling species and producing sustained rather than pulsatile pro-synaptogenic stimulus — the mechanistic difference from injectable HGF alone.
- 3Promotes dendritic spine density increases of 30–80% in hippocampal pyramidal neurons in published in-vitro slice preparations at picomolar-to-nanomolar concentrations, an efficacy ratio that has driven much of the academic interest.
- 4Downstream effects include activation of the PI3K-Akt and MAPK/ERK pathways, both implicated in long-term potentiation induction and memory consolidation, and both known BDNF signalling intersects — providing mechanistic convergence with the BDNF-inducing peptide family.
- 5Facilitates long-term potentiation (LTP) in hippocampal slice electrophysiology — the cellular correlate of learning — with augmentation at the same picomolar concentrations that drive the spinogenic effect.
- 6Modulates the AT4 receptor axis via its angiotensin-IV parentage, though the AT4-independent c-Met component is the dominant mechanism in the published cognitive literature.
- 7Preserves oral bioavailability and blood-brain-barrier penetration through the terminal N-hexanoyl and C-6-aminohexanoic acid amide modifications, which resist gastrointestinal proteolysis and enable CNS delivery from an oral dose — the mechanistically distinctive property versus most CNS-relevant peptides.
Section 4
Researched Benefits
Findings reported in the published preclinical and clinical literature. Effects in research contexts do not constitute claims of therapeutic benefit in humans.
- 1Restoration of cognitive performance in aged-rat learning paradigms — reported recovery to young-adult control performance in Morris water-maze and radial-arm maze tasks in the published work.
- 2Reversal of scopolamine-induced amnesia in rodent models, with the reversal effect emerging within hours of oral administration.
- 3Promotion of dendritic spine density in hippocampal pyramidal neurons — the flagship in-vitro finding with an unusually high efficacy-to-concentration ratio.
- 4Oral bioavailability — distinctive among small peptides and the property that has made Dihexa a research-tool candidate rather than a strict injectable.
- 5Facilitation of long-term potentiation in hippocampal preparations — a cellular-level cognitive correlate that ties the in-vitro spinogenic effect to a behaviourally-relevant mechanism.
- 6Potential research utility as a probe of the HGF/c-Met axis in the CNS, and as a candidate reference synaptogenic tool for comparative studies against BDNF-mimetic peptides.
- 7Reported effects on synaptic protein expression (PSD-95, synaptophysin) in the published work — supporting the interpretation of a genuine synaptogenic effect rather than an activity-dependent state.
Section 5
Theoretical Dosing & Protocols
| Route | Dosage | Frequency | Duration |
|---|---|---|---|
| Oral (research) | Animal study doses scale broadly across the literature; no validated human protocol exists | Once daily in most rodent protocols | Study durations vary; chronic dosing has been examined in animal work only |
Note: Human pharmacokinetic data is not available in published peer-reviewed sources.
Section 6
Administration Routes
- Oral — the molecule's defining feature is its capacity to survive enteric proteolysis and reach the CNS after oral administration in animal research; propylene-glycol vehicle is the reference solvent in the published protocols.
- Sublingual and transdermal routes have been explored in laboratory work — early anecdotal literature suggests both are viable but the peer-reviewed pharmacokinetic characterisation is limited.
- Parenteral (subcutaneous, intramuscular) routes are used in some animal-research contexts where dose-response control is prioritised over administration convenience.
- Intranasal delivery has been examined but has not been shown to offer meaningful advantage over the oral route for a molecule with genuine oral bioavailability.
Section 7
Safety Profile
Commonly reported
- · Limited safety data — human pharmacovigilance data is not available; the safety profile is described only in animal research contexts.
- · Reported animal-model tolerability at cognitive-relevant doses has been good, without observable weight, behaviour, or gross-pathology changes at course lengths of 4–8 weeks.
- · Theoretical considerations relate to systemic activation of c-Met signalling in tissues where c-Met is expressed at cognitively-irrelevant levels.
- · No dependence, tolerance, or withdrawal phenomena have been described in the published animal work, though the observation period is limited.
Rare / theoretical
- · c-Met activation is implicated in oncogenic signalling pathways — long-term mitogenic implications have not been characterised in published human research and constitute the single most significant theoretical concern about chronic Dihexa use.
- · No long-term toxicology data in any species is publicly available — the compound has not been through a GLP toxicology package.
- · Theoretical fibrogenic risk in tissues where c-Met activation drives fibroblast proliferation and myofibroblast transdifferentiation.
- · No reproductive or developmental toxicology data — the compound should be considered contraindicated in any reproductive-context research use.
Contraindications
- · Not authorised for human use in any jurisdiction — Dihexa remains a preclinical research chemical.
- · Theoretical contraindication in any subject with active or historic malignancy, given the c-Met pathway involvement in tumour progression across multiple cancer types.
- · No data in pregnancy, lactation, or developmental contexts — treat as absolutely contraindicated in reproductive-relevant research use.
- · Theoretical contraindication with active fibrotic conditions or a personal history of interstitial lung disease, given c-Met's fibrogenic role.
Section 8
UK & EU Regulatory Context
United Kingdom
Not a licensed medicine. Research chemical for laboratory and preclinical use only.
European Union
Not approved by the EMA. No clinical authorisation in any EU jurisdiction.
Section 9
Clinical Studies Summary
Dihexa as a synaptogenic agent — hippocampal slice study
Application of Dihexa at sub-nanomolar concentrations to hippocampal slice preparations produced robust increases in dendritic spine density in CA1 pyramidal neurons, with the effect co-localised to synaptic markers and blocked by c-Met receptor antagonism, establishing the receptor-level mechanism of action. The concentration-response profile was several orders of magnitude below the effective range for BDNF in matched assays.
Reversal of scopolamine amnesia in rats
Behavioural pharmacology study in which oral Dihexa restored Morris water-maze learning performance in a scopolamine-amnesia rat model to the level of scopolamine-free control animals, at doses that produced no observable behavioural side-effects. The scopolamine-amnesia paradigm is the standard research-model probe for cholinergic-cognitive interventions.
HGF/c-Met activation as the molecular basis of Dihexa's effects
Mechanistic dissection demonstrating that Dihexa's pro-cognitive and pro-synaptogenic effects are abolished by pharmacological antagonism of the c-Met receptor and by c-Met knockdown, providing a genetic-pharmacological demonstration that the c-Met axis is the necessary and sufficient effector of the cognitive phenotype.
Dihexa in aged-rat learning paradigms
Behavioural study in aged Sprague-Dawley rats reporting recovery of Morris water-maze performance to young-adult control levels following a 14-day oral Dihexa course, alongside preserved dendritic spine density in post-mortem hippocampal analysis.
Angiotensin IV derivative design — the Dihexa origin study
The foundational medicinal-chemistry study describing the design and characterisation of Dihexa as an angiotensin-IV-derived hexapeptide engineered for oral bioavailability, blood-brain-barrier penetration, and metabolic stability — the paper that positioned the molecule as a research candidate.
Section 10
Frequently Asked Questions
Section 10a
Practical Research Guidance
Cycle guidance
Reconstitution & storage
UK sourcing notes
Section 11
Sourcing for Laboratory Research
Sourcing Dihexa for laboratory research
Researchers in the United Kingdom and elsewhere typically obtain Dihexa from specialist research-chemical suppliers. Purity, third-party testing, and supplier transparency are the principal differentiators worth evaluating before placing an order. The two suppliers below are commonly referenced in UK research contexts.
Reminder: research peptides are sold strictly for in vitro and preclinical laboratory purposes. Importation or supply for human consumption is not permitted under UK medicines legislation.