Compound reference
Dihexa
Also known as PNB-0408
Dihexa is an orally active, brain-penetrant angiotensin IV-derived compound that potentiates HGF/c-Met signaling and, by one spinogenesis measure, is vastly more potent than BDNF. Its cognitive data are striking but entirely preclinical — no human trials, and an unknown safety profile.
- CAS
- 1401708-83-5
- Formula
- C₂₇H₄₄N₄O₅
- Molar mass
- ≈504.7 g/mol
- Sequence
- N-hexanoyl-Tyr-Ile-(6)-aminohexanoic amide — an angiotensin IV-derived oligopeptide
Research compound; not FDA-approved as a drug.
Mode of action
Dihexa (developmental code PNB-0408) is a small oligopeptide derived from angiotensin IV — chemically N-hexanoyl-Tyr-Ile-(6)-aminohexanoic amide — engineered to be metabolically stable, orally active, and able to cross the blood-brain barrier. Its mechanism is not classical receptor agonism: dihexa binds hepatocyte growth factor (HGF) with very high affinity (reported Kd ≈ 65 pM) and potentiates HGF's activity at its receptor, c-Met. Because HGF/c-Met signaling drives dendritic spine formation and synaptogenesis, dihexa acts as a powerful pro-synaptogenic agent. In a neurotrophic spinogenesis assay it was reported to be on the order of seven orders of magnitude more potent than BDNF — a striking, frequently-quoted figure that should be read as assay-specific rather than a general statement of potency.
Main intended effect
To enhance synapse formation and cognition by amplifying HGF/c-Met signaling — pursued primarily as an Alzheimer's and cognitive-impairment strategy.
Areas of interest
The lead interest is cognitive impairment and Alzheimer's disease; related preclinical work spans peripheral nerve repair and protection of sensory (hair) cells, reflecting HGF/c-Met's broad regenerative role. In the consumer market dihexa is marketed — on the back of the "more potent than BDNF" claim — as an exceptionally strong nootropic.
Evidence for intended effects
The animal evidence is real and, in places, dramatic. In APP/PS1 Alzheimer's-model mice, oral dihexa rescued cognitive impairment and restored memory, with signaling traced through the PI3K/AKT pathway; a systematic review of brain renin-angiotensin-system peptides catalogues consistent procognitive effects of angiotensin-IV-type compounds across experimental studies; and dihexa shows HGF-mimetic protection in nerve-injury and hair-cell models.
But it is entirely preclinical. There are no human trials of dihexa, so none of the cognitive claims — least of all the headline potency figure — have been tested in people. The mechanism also carries an inherent caution: potentiating a growth-factor receptor (c-Met) that is implicated in tumor growth raises a theoretical proliferative/oncogenic risk that has not been characterized for chronic human use. So dihexa is a remarkably potent preclinical compound with a real mechanistic basis and an unproven, unmonitored safety profile.
| Strand | What exists | Tier |
|---|---|---|
| Alzheimer's models | Oral dihexa rescues cognition (PI3K/AKT) | Strong preclinical |
| Mechanism | HGF binding / c-Met potentiation; synaptogenesis | Well characterized |
| Regeneration | Nerve-repair and hair-cell protection models | Preclinical |
| Human | None | No trials |
Studied amounts (literature dosing context)
Animal studies used dihexa in the low mg/kg range — for example intragastric dosing around 1.4–2.9 mg/kg in the APP/PS1 cognition study, and 2–4 mg/kg delivered locally in the nerve-repair model. There is no established human dose. These are animal-study figures, and this page does not provide dosing guidance.
Safety and regulatory status
There is no human safety data for dihexa, because there have been no human studies. It is not an approved drug in any jurisdiction; it is sold as a research compound and "nootropic," with the usual unverified identity and purity of gray-market peptides. The growth-factor-potentiating mechanism makes long-term safety a genuine open question rather than a formality. Mechanistically it sits alongside P21 as a small procognitive/neurotrophic compound advanced only to the preclinical stage.
Sources
AngIV-Analog Dihexa Rescues Cognitive Impairment and Recovers Memory in the APP/PS1 Mouse via the PI3K/AKT Signaling Pathway
Sun and colleagues treated six-month-old APP/PS1 transgenic Alzheimer's-model mice and wild-type controls with intragastric dihexa at 1.44 or 2.88 mg/kg for three months, using the PI3K inhibitor wortmannin (0.5 mg/kg) as a mechanistic probe. Morris water maze testing showed improved spatial learning and memory, and dihexa increased brain AngIV levels, raised neuronal counts and synaptophysin expression, lowered pro-inflammatory IL-1beta and TNF-alpha while raising anti-inflammatory IL-10, and reduced GFAP and Iba-1 glial activation markers. Activation of the PI3K/AKT pathway was demonstrated, and wortmannin reversed the protective effects, implicating that pathway in dihexa's action. This is a rodent study from a group independent of the original developers; dihexa is research-stage and human efficacy and safety are not established.
Cognitive benefits of angiotensin IV and angiotensin-(1-7): A systematic review of experimental studies
Ho and Nation conducted a systematic review of 32 experimental animal studies (screened from 450 records) examining brain renin-angiotensin system peptides and their cognitive effects, including angiotensin IV, angiotensin-(1-7), and Ang IV analogs such as dihexa and Nle1-Ang IV. Across normal animals, seven of 11 studies found Ang IV improved passive/conditioned avoidance and object recognition; in cognitive-impairment models, eight of nine studies found Ang IV and its analogs improved spatial working memory and passive avoidance. The authors reported the strongest effects from intracerebroventricular administration timed near learning events and concluded the cognitive effects of these peptides rest entirely on experimental (non-human) data. Dihexa remains research-stage; the review describes no human efficacy or safety data, which are not established.
Hepatocyte growth factor mimetic protects lateral line hair cells from aminoglycoside exposure
Uribe and colleagues tested dihexa as a hepatocyte growth factor (HGF) mimetic in the larval zebrafish lateral line, whose hair cells are homologous to mammalian inner-ear cells, with dose-response curves and a 1 µM optimal concentration. Dihexa produced dose-dependent protection against the aminoglycosides neomycin and gentamicin during acute exposure, acting through intracellular mechanisms rather than blocking drug entry. Co-treatment with the HGF antagonist 6-AH eliminated protection, and inhibitors of downstream Akt, TOR, and MEK partially attenuated it, supporting an HGF/c-Met-pathway mechanism; dihexa did not protect against cisplatin toxicity. This in vitro/in vivo zebrafish study supports dihexa's proposed HGF-mimetic mechanism in a non-mammalian model; dihexa is research-stage and human efficacy and safety are not established.
Stem cell, Granulocyte-Colony Stimulating Factor and/or Dihexa to promote limb function recovery in a rat sciatic nerve damage-repair model: Experimental animal studies
Weiss and colleagues used a rat sciatic nerve transection-repair model with 10 experimental groups (n=6-8 per group) to test dihexa (2-4 mg/kg) delivered locally via hydrogel at the repair site, intraperitoneally, and/or by direct gastrocnemius muscle injection, alone or combined with stem cells and G-CSF. Over a 16-week follow-up, sensory function was measured by cutaneous pinch reaction and motor function by walking footprint analysis. Groups receiving dihexa into the gastrocnemius muscle showed significant improvement in motor function (P<0.05) and significant reduction in flexion contractures (P<0.01) versus vehicle controls. This is an exploratory rodent peripheral-nerve study; dihexa is research-stage and human efficacy and safety are not established.