Investigational peptidomimetic tripeptide (Cognitive-Nootropic research — angiotensin-IV analogue, HGF/c-Met positive modulator) Limited Human Data

Dihexa

Also Known As: PNB-0408, N-hexanoyl-Tyr-Ile-(6) aminohexanoic amide, N-hexanoyl-L-tyrosyl-L-isoleucyl-6-aminohexanoic acid amide

Dihexa (development code PNB-0408) is a peptidomimetic tripeptide chemically described as N-hexanoyl-L-tyrosyl-L-isoleucyl-6-aminohexanoic acid amide. It was synthesized in the laboratories of Joseph W. Harding and John W. Wright at Washington State University (WSU) from angiotensin IV (Val-Tyr-Ile-His-Pro-Phe) and licensed to M3 Biotechnology (later renamed Athira Pharma). The N-terminal hexanoyl cap confers lipophilicity, oral bioavailability and blood-brain-barrier permeability; the C-terminal 6-aminohexanoic acid amide replaces the proteolytically labile His-Pro-Phe segment. Only the central Tyr-Ile dipeptide of angiotensin IV is preserved — Dihexa is therefore a peptidomimetic, not a true peptide. Studies from the Harding group report Dihexa acting as a positive modulator of the hepatocyte growth factor (HGF) / c-Met system, augmenting MAPK / PI3K-AKT signalling, dendritic spinogenesis and hippocampal LTP. IMPORTANT EDITORIAL SCOPING — INTEGRITY OVERHANG: the foundational Benoist 2014 paper (J Pharmacol Exp Ther; PMID 25187433), which established the HGF/c-Met dependence and was the source of the widely-quoted claim that "Dihexa is seven orders of magnitude / approximately 10 million-fold more potent than BDNF", was formally retracted by the journal on 29 April 2025 (J Pharmacol Exp Ther 2025;392(4):103567); the McCoy 2013 paper (PMID 23055539) and the Kawas 2011 HGF-dimerization-mimic paper carry expressions of concern issued in 2021 in connection with the Athira / Leen Kawas image-integrity inquiry. The Sun 2021 paper (China Pharmaceutical University) is the most prominent independent-lineage replication and partially mitigates but does not erase the WSU lineage-dominance caveat. ClinicalTrials.gov v2 API audit on 2 May 2026: zero hits for "Dihexa" and zero hits for "PNB-0408". Dihexa MUST NOT be conflated with the separate Athira molecule fosgonimeton (ATH-1017 / NDX-1017) — fosgonimeton is a different compound; its trials (LIFT-AD NCT04488419, SHAPE / SHINE NCT04886063, ATH-1017 Phase 1 NCT03298672) are NOT Dihexa trials and are explicitly excluded here. Fosgonimeton failed its Phase 2/3 LIFT-AD Alzheimer's trial in 2023. WADA Class S0 (catch-all for non-approved substances). Limited human data — preclinical reports only. Research use only.

Identity & Chemistry

Chemical structure of Dihexa (PNB-0408), a tripeptide-like angiotensin IV analogue with an N-terminal hexanoyl cap, central L-tyrosyl–L-isoleucyl core, and C-terminal 6-aminohexanoic acid amide. Rendered from PubChem CID 125355097.
Image credit: Structure data from PubChem CID 125355097, U.S. National Library of Medicine (no canonical Wikimedia file as of 2026-05-02; PubChem 2D fallback used) · Public Domain (U.S. Government work — National Library of Medicine)
Amino Acid Sequence
N-hexanoyl–L-Tyr–L-Ile–(6)-aminohexanoic acid amide. Engineered from angiotensin IV (Val-Tyr-Ile-His-Pro-Phe) by capping the N-terminus with a hexanoyl (C6) acyl chain for blood-brain-barrier permeability and replacing the His-Pro-Phe segment with 6-aminohexanoic acid amide for proteolytic stability. Only the central Tyr-Ile dipeptide of angiotensin IV is preserved — Dihexa is therefore a peptidomimetic, not a true peptide.
Molecular Formula
C₂₇H₄₄N₄O₅
Molecular Weight
504.66 g·mol⁻¹ (504.66–504.67 Da across PubChem / MedChemExpress / EvitaChem; rounding variance only)
CAS Number
1401708-83-5
PubChem CID
125355097
IUPAC Name
N-[(2S,3S)-1-[(6-amino-6-oxohexyl)amino]-3-methyl-1-oxopentan-2-yl]-N²-hexanoyl-L-tyrosinamide. ChemSpider 57582587. No DrugBank entry exists for Dihexa as of audit date 2026-05-02 (the structurally distinct Athira clinical-stage compound fosgonimeton is a separate molecule).
Solubility
Soluble in DMSO; limited aqueous solubility (a known drug-like-property weakness that contributed to Athira's pivot to fosgonimeton). Quantitative aqueous solubility data are not publicly disclosed at PubChem CID 125355097. Vendor data sheets (e.g. MedChemExpress HY-16969) are the usual reference; for research use only.
Storage
Lyophilised powder: store at −20 °C protected from light (vendor guidance). In-solvent aliquots: store at −80 °C, single freeze-thaw recommended. Vendor / supplier certificate of analysis governs; for research use only.

Mechanism of Action

Studies from the Harding group at Washington State University report that Dihexa functions as a positive modulator of the hepatocyte growth factor (HGF) / c-Met receptor system, augmenting HGF-driven MAPK and PI3K-AKT signalling and downstream dendritic spinogenesis, hippocampal LTP and synaptogenesis. Dihexa is NOT an angiotensin II receptor (AT1 / AT2) agonist despite its angiotensin-IV lineage. Observed in research settings.

The mechanistic narrative built by the WSU group is that angiotensin IV–derived peptides act not via classical angiotensin receptors but via the brain HGF/c-Met neurotrophic system. Dihexa, the metabolically stabilised and brain-penetrant analogue of angiotensin IV, is reported in McCoy 2013 and Benoist 2014 to potentiate HGF binding to c-Met, drive dimerization disruption that paradoxically AUGMENTS HGF activity at low concentrations, and increase dendritic spine density in hippocampal cultures. In behavioural assays, Dihexa is reported to reverse scopolamine-induced Morris water maze deficits in rats, improve performance in aged rats with mixed cognitive baselines, and (Sun 2021) rescue cognitive performance and reduce neuroinflammation in APP/PS1 transgenic Alzheimer's-model mice. The widely repeated claim that "Dihexa is seven orders of magnitude (≈10 million-fold) more potent than BDNF" originates SPECIFICALLY in Benoist et al. 2014 — a paper formally RETRACTED by the Journal of Pharmacology and Experimental Therapeutics on 29 April 2025. Triscience treats this potency claim as unverified as of audit date 2026-05-02 and recommends omission from marketing-style copy. The broader HGF/c-Met-as-cognitive-target hypothesis remains an active area of research and was independently advanced into clinical trials by Athira Pharma using the separate molecule fosgonimeton (ATH-1017 / NDX-1017) — fosgonimeton, however, failed its Phase 2/3 LIFT-AD Alzheimer's trial in 2023, further weakening pathway-validation evidence. Mechanism statements here are intentionally hedged — studies report, observed in research settings — and never framed as established human pharmacology. Research use only.

Molecular Targets

  • HGF (hepatocyte growth factor) — Dihexa is reported to bind HGF with high affinity (Kd ≈ 65 pM, Benoist 2014; that paper was RETRACTED on 2025-04-29 — treat the quantitative affinity figure as unverified)
  • c-Met / HGFR (MET receptor tyrosine kinase) — downstream activation, with potentiation of MAPK/ERK and PI3K-AKT cascades reported in hippocampal neurons (Sun 2021)
  • PI3K / AKT axis — Sun 2021 (APP/PS1 mice): PI3K/AKT activation; the PI3K inhibitor wortmannin abolished the anti-inflammatory and anti-apoptotic effects
  • Synaptic plasticity readouts — dendritic spinogenesis in hippocampal neurons, hippocampal LTP enhancement, synaptophysin (SYP) upregulation

Signaling Pathways

  • HGF binding → disruption of HGF-HGF dimerization → paradoxical augmentation of c-Met activity at sub-threshold HGF concentrations → MAPK/ERK + PI3K-AKT (Harding-group model; quantitative affinity figures from a now-retracted paper)
  • PI3K/AKT pathway → reduced apoptosis / neuroinflammation in APP/PS1 mice (Sun 2021, independent lineage)
  • NOT AT1/AT2 — Dihexa bypasses classical angiotensin II receptor signalling (important disambiguation given its angiotensin-IV lineage)
  • AT4 / IRAP (insulin-regulated aminopeptidase) dependence of the procognitive effect is disputed in newer literature

Research Applications

The published evidence base is exclusively preclinical (rodent in vivo + hippocampal-culture / slice electrophysiology in vitro). The WSU Harding/Wright lineage (Kawas, Benoist, McCoy, Yamamoto) dominates the peer-reviewed Dihexa literature — analogous to Khavinson dominance for Epitalon and Goldspink dominance for PEG-MGF. The Sun 2021 paper from China Pharmaceutical University is the most prominent independent-lineage replication and partially mitigates (but does not erase) the single-lineage caveat. INTEGRITY OVERHANG: McCoy 2013 carries an expression of concern issued in 2021, Kawas 2011 likewise, and Benoist 2014 was formally retracted on 29 April 2025. Observed in research settings.

Scopolamine-induced amnesia (rat) — in vivo, Morris water maze

in vivo

Studies report that oral Dihexa (high-dose group, 2 mg/kg/day) was indistinguishable from scopolamine-untreated controls on all testing days; latency-to-platform improved relative to the scopolamine-only group. Editorial scoping: this paper has carried an expression of concern since 2021 (J Pharmacol Exp Ther 2021;378(3):311) as part of the Athira / Leen Kawas image-integrity inquiry.

— McCoy et al. 2013, J Pharmacol Exp Ther 344(1):141-154 (PMID 23055539; Expression of Concern 2021)

Aged-rat cognitive decline — in vivo, Morris water maze

in vivo

Studies report that mixed-age (22–26 months) aged rats receiving 2 mg/kg/day Dihexa performed significantly better than untreated aged controls; high inter-animal variability noted because not all aged rats are cognitively impaired. Editorial scoping: same expression-of-concern source as above.

— McCoy et al. 2013, J Pharmacol Exp Ther 344(1):141-154 (PMID 23055539; Expression of Concern 2021)

Hippocampal dendritic spinogenesis — in vitro, hippocampal cultures

in vitro

Studies report that subthreshold Dihexa (10⁻¹³ M) plus subthreshold HGF (2.5 ng/mL) produces spinogenesis equivalent to suprathreshold HGF (10 ng/mL) alone. IMPORTANT: this paper (Benoist 2014, J Pharmacol Exp Ther 351(2):390-402, PMID 25187433) was formally RETRACTED by the journal on 29 April 2025 (Retraction Notice: J Pharmacol Exp Ther 2025;392(4):103567); the widely-quoted "Dihexa is ~7 orders of magnitude more potent than BDNF" claim originates in this retracted paper and should be treated as unverified.

— Benoist et al. 2014, J Pharmacol Exp Ther 351(2):390-402 (PMID 25187433; RETRACTED 2025-04-29)

Alzheimer's-model cognitive rescue — APP/PS1 transgenic mice, in vivo

in vivo

Studies report that Dihexa restored Morris water maze performance, increased neuronal density and synaptophysin expression, reduced IL-1β / TNF-α and increased IL-10, and activated PI3K/AKT (wortmannin-reversible). This is the most prominent independent-lineage replication and partially mitigates the WSU lineage-dominance caveat.

— Sun et al. 2021, Brain Sciences 11(11):1487 (PMID 34827486; independent lineage, China Pharmaceutical University)

Hippocampal LTP enhancement — in vitro, hippocampal slice electrophysiology

in vitro

Studies report that Dihexa facilitates LTP induction in hippocampal slices; mechanistically consistent with the reported HGF/c-Met synaptogenesis model.

— Wright & Harding 2015, J Alzheimers Dis 45(4):985-1000 (PMID 25649658, review)

Clinical Status

Regulatory Status
Dihexa is NOT approved — by the FDA, EMA, MHRA, PMDA, Health Canada, TGA, NMPA or ANVISA — and does not appear in any Western or international pharmacopoeia as an active substance. A systematic ClinicalTrials.gov v2 API query on 2 May 2026 for "Dihexa" and "PNB-0408" returned zero registered human trials. Highest published phase: preclinical (rodent in vivo + in vitro hippocampal). CRITICAL DISAMBIGUATION: the molecule advanced into clinical trials by Athira Pharma is fosgonimeton (ATH-1017 / NDX-1017) — NOT Dihexa. Fosgonimeton is a separate compound described as a Dihexa-pathway prodrug. The Athira trials NCT04488419 (LIFT-AD), NCT04886063 (SHAPE / SHINE) and NCT03298672 (ATH-1017 Phase 1) are ALL fosgonimeton trials and are explicitly excluded from this Dihexa page; any source citing those NCTs as Dihexa trials is factually incorrect. Fosgonimeton failed its Phase 2/3 LIFT-AD Alzheimer's trial in 2023, further weakening the HGF/c-Met pathway-validation narrative. Anti-doping: Dihexa is not explicitly named on the WADA Prohibited List 2026, but falls under WADA Class S0 (Non-Approved Substances) as an investigational substance lacking approval from any regulator anywhere.
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Highest Trial Phase
Highest published phase: preclinical only (rodent in vivo + in vitro). NO registered human Phase 1/2/3 trial as of audit date 2026-05-02.
Sponsor
Discovery: Joseph W. Harding and John W. Wright, Washington State University. Commercial licensee chain: M3 Biotechnology → Athira Pharma (development code PNB-0408 for Alzheimer's disease). Athira concluded Dihexa lacked sufficient drug-like properties and pivoted to a separate molecule, fosgonimeton (ATH-1017 / NDX-1017), described as a Dihexa-pathway prodrug; fosgonimeton failed its Phase 2/3 LIFT-AD Alzheimer's trial in 2023. Dihexa itself was never advanced into a registered human trial.
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Safety Profile

Observed in research settings

Limited human data — preclinical reports only. In published rodent studies (McCoy 2013, with expression of concern; Sun 2021, independent lineage), Dihexa at procognitive doses (e.g. 2 mg/kg/day p.o. in rats) was reported without overt acute toxicity. No human safety dataset exists; vendor-driven self-administration anecdotes and forum reports do NOT constitute peer-reviewed safety evidence. Observed in research settings; for research use only.

Adverse Events Reported in Studies

  • Rodent studies: no overt acute toxicity at procognitive doses reported (McCoy 2013, with expression of concern)
  • Rodent studies: oral bioavailability and blood-brain-barrier penetration reported as the engineering rationale of the hexanoyl cap (McCoy 2013)
  • Human studies: ZERO — no systematically captured adverse events from human studies exist because zero registered human Dihexa or PNB-0408 trials exist worldwide (ClinicalTrials.gov v2 API audit 2026-05-02)

Serious Adverse Events

  • Human data gap: ZERO independent long-term pharmacovigilance dataset for Dihexa exists — multi-month or multi-year human safety data have not been published. Safety statements should be tagged exclusively as "limited human data — preclinical reports only"
  • Theoretical oncogenic concern (mechanism-derived, not observed): c-Met is a well-validated oncogene (MET amplification / activation drives multiple cancers); chronic systemic HGF/c-Met potentiation raises a theoretical proliferation risk that is not addressed in the public Dihexa literature
  • Chronic toxicity, cardiovascular effects, reproductive / developmental effects and drug-drug interactions: not characterised in published literature
  • Vendor-market caveat: Dihexa is widely sold by research-peptide vendors (MedChemExpress HY-16969, MedKoo, Xcess Biosciences, GlpBio, InvivoChem, ProbeChem) and prominent on nootropic forums under the headline "10 million-fold more potent than BDNF" — a claim that originates SPECIFICALLY in the retracted Benoist 2014 paper and must be treated as unverified. Triscience keeps Dihexa copy strictly research-only, not for human consumption; "smart-drug" or "limitless"-style marketing language is NOT validated by Triscience editorial. Anti-doping: Class S0 (Non-Approved Substances)

References

  1. McCoy AT, Benoist CC, Wright JW, Kawas LH, Bule-Ghogare JM, Zhu M, Appleyard SM, Wayman GA, Harding JW Evaluation of metabolically stabilized angiotensin IV analogs as procognitive/antidementia agents [Expression of Concern, 2021] Journal of Pharmacology and Experimental Therapeutics 2013;344(1):141-154. 2013 .

    DOI: 10.1124/jpet.112.199497 PMID: 23055539 View Source

  2. Benoist CC, Kawas LH, Zhu M, Tyson KA, Stillmaker L, Appleyard SM, Wright JW, Wayman GA, Harding JW The procognitive and synaptogenic effects of angiotensin IV–derived peptides are dependent on activation of the hepatocyte growth factor/c-Met system [RETRACTED 2025-04-29] Journal of Pharmacology and Experimental Therapeutics 2014;351(2):390-402. 2014 .

    DOI: 10.1124/jpet.114.218735 PMID: 25187433 View Source

  3. Kawas LH, McCoy AT, Yamamoto BJ, Wright JW, Harding JW Mimics of the dimerization domain of hepatocyte growth factor exhibit anti-Met and anticancer activity [Expression of Concern, 2021] Journal of Pharmacology and Experimental Therapeutics 2011;339(2):509-518. 2011 .

    DOI: 10.1124/jpet.111.185694 PMID: 21859929 View Source

  4. Sun X, Deng Y, Fu X, Wang S, Duan R, Zhang Y AngIV-Analog Dihexa Rescues Cognitive Impairment and Recovers Memory in the APP/PS1 Mouse via the PI3K/AKT Signaling Pathway Brain Sciences 2021;11(11):1487. 2021 .

    DOI: 10.3390/brainsci11111487 PMID: 34827486 View Source

  5. Wright JW, Harding JW The brain hepatocyte growth factor/c-Met receptor system: a new target for the treatment of Alzheimer's disease Journal of Alzheimer's Disease 2015;45(4):985-1000. 2015 .

    DOI: 10.3233/JAD-142814 PMID: 25649658 View Source

  6. Wright JW, Yamamoto BJ, Harding JW Angiotensin receptor subtype mediated physiologies and behaviors: new discoveries and clinical targets Progress in Neurobiology 2008;84(2):157-181. 2008 .

    DOI: 10.1016/j.pneurobio.2007.10.009 PMID: 18160199 View Source

  7. Benoist CC, Wright JW, Zhu M, Appleyard SM, Wayman GA, Harding JW Facilitation of hippocampal synaptogenesis and spatial memory by C-terminal truncated Nle1-angiotensin IV analogs Journal of Pharmacology and Experimental Therapeutics 2011;339(1):35-44. 2011 .

    DOI: 10.1124/jpet.111.182220 PMID: 21719467 View Source

  8. Hayes K, Bridges T, Sapir T, Hess H, Whittington D, Galasso J, Cain C, Lawrence J, Schaffer M, Hada B, Pollack S, Burstein A, Moebius H Fosgonimeton, a Novel Positive Modulator of the HGF/MET System, Promotes Neurotrophic and Procognitive Effects in Models of Dementia (cited for fosgonimeton context only — fosgonimeton is a SEPARATE molecule from Dihexa; LIFT-AD Phase 2/3 failed in 2023) Journal of Pharmacology and Experimental Therapeutics 2023. 2023 .

    PMID: 36538176 View Source

Frequently Asked Questions

Is Dihexa FDA-approved?
No. Dihexa (PNB-0408) is NOT approved by the FDA, EMA or any other regulatory agency. It is an investigational research compound with zero registered human clinical trials. It must not be used as a medicine.
Has Dihexa been tested in humans?
No. As of 2 May 2026, ClinicalTrials.gov searches for both "Dihexa" and "PNB-0408" return zero studies. All published efficacy data come from rodent and in-vitro experiments. Sources claiming Dihexa is in human trials are typically conflating it with the separate molecule fosgonimeton (ATH-1017), an Athira Pharma compound that failed its Phase 2/3 LIFT-AD Alzheimer's trial in 2023.
How does Dihexa differ from angiotensin IV?
Angiotensin IV is the natural hexapeptide Val-Tyr-Ile-His-Pro-Phe (a fragment of angiotensin II metabolism). Dihexa is engineered from it by (a) capping the N-terminus with a hexanoyl (C6) acyl chain for blood-brain-barrier penetration and oral bioavailability and (b) replacing the C-terminal His-Pro-Phe with 6-aminohexanoic acid amide for proteolytic stability. Only the central Tyr-Ile dipeptide is retained — Dihexa is therefore technically a peptidomimetic, not a true peptide.
What does "HGF/c-Met modulation" mean?
HGF (hepatocyte growth factor) is a neurotrophic protein; c-Met (also called MET or HGFR) is its receptor tyrosine kinase. The Harding-laboratory model proposes that Dihexa binds HGF, disrupts HGF-HGF dimerization, and paradoxically AUGMENTS HGF activity at the c-Met receptor at sub-threshold HGF concentrations, which drives MAPK and PI3K-AKT signalling and dendritic spinogenesis. The quantitative Kd ≈ 65 pM HGF-binding figure, however, originates in a paper formally retracted in April 2025, so the quantitative aspects of this model should be treated as unverified.
What is the difference between Dihexa and Semax?
They are entirely different molecules with different mechanisms and lineages. Semax is the Russian heptapeptide Met-Glu-His-Phe-Pro-Gly-Pro, an ACTH(4-7)-Pro-Gly-Pro analogue developed at the Russian Academy of Medical Sciences, reported to act via BDNF/NGF upregulation. Dihexa is the WSU angiotensin IV–derived tripeptidomimetic, reported to act via HGF/c-Met positive modulation. They are sometimes conflated on nootropic forums, but they share neither structure, target, nor research lineage.
Why are some Dihexa scientific papers marked with retractions or expressions of concern?
The two earliest peer-reviewed Dihexa papers (McCoy 2013, Benoist 2014) and two related Harding-lab papers (Kawas 2011, 2012) involve co-author Leen Kawas, who later became CEO of Athira Pharma. A research-integrity inquiry concluded that images in her dissertation and in several papers had been altered. As a result, in September 2021 the Journal of Pharmacology and Experimental Therapeutics issued expressions of concern on four papers including McCoy 2013, and on 29 April 2025 the same journal formally retracted Benoist et al. 2014 — the paper that established the HGF/c-Met dependence of Dihexa and the "more potent than BDNF" framing. Subsequent independent-lineage work (e.g. Sun et al. 2021) is unencumbered, but the foundational dataset is compromised, which is the principal reason Triscience classifies Dihexa as "Reduced".

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