Signaling
A metabolically stabilized angiotensin IV–derived peptidomimetic studied as an HGF/c-Met system probe in neuronal-culture, synaptogenesis, and rodent cognitive-model research.
Dihexa is a small synthetic peptidomimetic derived from the brain peptide angiotensin IV. Developed as a metabolically stabilized, blood-brain-barrier–permeant analog, it has been studied as a probe of the hepatocyte growth factor (HGF)/c-Met receptor tyrosine kinase system. The published literature examines it in receptor-binding and cell-signaling assays, hippocampal neuron-culture synaptogenesis assays, and rodent learning and memory models. Several foundational mechanistic papers from the originating laboratory were subsequently retracted, which is essential context for interpreting the body of work.
Type
Synthetic peptidomimetic (modified tripeptide-like angiotensin IV analog)
Molecular formula
C27H44N4O5
Molecular weight
~504.66 g/mol
CAS number
1401708-83-5
Fatty acid chain
N-terminal hexanoyl cap (hexanoic acid)
Sequence
N-hexanoic-Tyr-Ile-(6)aminohexanoic amide
Modification
N-terminal hexanoyl cap replacing the N-terminal residue of norleucine1-AngIV; C-terminal 6-aminohexanoic amide moiety replacing the His-Pro-Phe segment; designed to eliminate peptidase-sensitive bonds and increase metabolic stability and blood-brain-barrier permeance.
Dihexa is a peptidomimetic in the angiotensin IV (AngIV) analog class, engineered from norleucine1-angiotensin IV by retaining the Tyr-Ile pharmacophore identified as the procognitive core and replacing peptidase-labile termini with an N-terminal hexanoyl cap and a C-terminal 6-aminohexanoic amide. These modifications confer increased hydrophobicity, metabolic stability, and blood-brain-barrier permeability. Mechanistic studies proposed that Dihexa acts at the level of the hepatocyte growth factor (HGF)/c-Met receptor tyrosine kinase system — specifically at HGF dimerization and availability — with downstream readouts examined in PI3K/Akt and MAPK/ERK signaling. Historically, the parent AngIV system was associated with the AT4 binding site, later identified as insulin-regulated aminopeptidase (IRAP); the shift toward an HGF/c-Met framing is a contested element of the literature, and the key papers asserting direct HGF binding were subsequently retracted.
Research Focus
Studied in receptor pharmacology, cell-signaling, neuronal-culture synaptogenesis, and rodent cognitive and neuroprotection model systems.
Dihexa emerged from a research program on the brain renin-angiotensin system. Angiotensin IV (AngIV; Val-Tyr-Ile-His-Pro-Phe), once considered an inactive metabolite, was reported to influence long-term potentiation and memory consolidation in rodent paradigms. Albiston and colleagues (2001, Journal of Biological Chemistry) identified the AngIV 'AT4' binding site as insulin-regulated aminopeptidase (IRAP) via protein-purification approaches. Lew and colleagues (2003, Journal of Neurochemistry) characterized AT4 ligands including AngIV as competitive IRAP inhibitors using recombinant human IRAP cleavage assays. Albiston, Fernando, and colleagues subsequently used IRAP-knockout mice to probe the binding site and examined spatial-memory phenotypes, motivating alternative mechanistic framings for AngIV-derived analogs. A 2020 Frontiers in Pharmacology review (Hallberg and colleagues) situates Dihexa within the stepwise medicinal-chemistry conversion of the AngIV hexapeptide into drug-like, orally administrable peptidomimetics.
Benoist and colleagues (2011, Journal of Pharmacology and Experimental Therapeutics) used C-terminal–truncated norleucine1-AngIV analogs in scopolamine-deficit Morris water maze testing and in mRFP-β-actin–transfected rat hippocampal neuron cultures to localize the procognitive pharmacophore to the N-terminal tripeptide and to correlate it with dendritic spine formation. This structure-activity finding directly motivated the design of Dihexa: retaining the Tyr-Ile pharmacophore while adding an N-terminal hexanoyl cap and C-terminal 6-aminohexanoic amide to eliminate peptidase-sensitive bonds. McCoy and colleagues (2013, Journal of Pharmacology and Experimental Therapeutics) described Dihexa as a metabolically stabilized, blood-brain-barrier–permeant analog, characterizing a notably prolonged circulating half-life in adult male Sprague-Dawley rats following intravenous and intraperitoneal administration, and examining spinogenesis in hippocampal cultures together with scopolamine-deficit and aged-rat water-maze paradigms. That paper carries a 2021 Notice of Concern from the journal regarding figure integrity. The widely cited comparison to BDNF in an in-vitro synaptogenesis assay should be read as a cross-assay statement — BDNF and Dihexa were not directly compared within the same publication, as noted in the Alzheimer's Drug Discovery Foundation Cognitive Vitality profile of the compound.
A series of papers proposed that AngIV analogs act on the HGF/c-Met system. Yamamoto and colleagues (2010, Journal of Pharmacology and Experimental Therapeutics) characterized the antagonist norleual as an HGF/c-Met inhibitor with properties of a hinge-region mimic that blocks HGF dimerization. Kawas and colleagues (2011, Journal of Pharmacology and Experimental Therapeutics) extended this to a family of dimerization-domain mimics (Notice of Concern, 2021). Kawas and colleagues (2012, Journal of Pharmacology and Experimental Therapeutics) developed AngIV analogs as HGF/Met modifiers — this paper was formally retracted in April 2025 following an institutional investigation. Benoist and colleagues (2014, Journal of Pharmacology and Experimental Therapeutics) reported that Dihexa binds HGF and potentiates c-Met phosphorylation at subthreshold HGF concentrations, and that it induces hippocampal spinogenesis blocked by HGF/c-Met antagonists. This paper was also formally retracted in April 2025; the retraction notice documents that certain figures were found to contain falsified and/or fabricated data following an institutional investigation. The specific HGF-binding affinity and dimerization claims from these papers should be treated with corresponding caution.
Some Dihexa work originates outside the retracted core. Uribe and colleagues (2015, Frontiers in Cellular Neuroscience) examined Dihexa in the larval zebrafish lateral-line model of aminoglycoside ototoxicity, using the HGF antagonist 6-AH together with Akt/TOR and MAPK inhibitors to examine the hair-cell phenotype and implicate HGF/c-Met–linked pathways. Sun and colleagues (2021, Brain Sciences), an independent group at China Pharmaceutical University, studied Dihexa administered orally in the APP/PS1 transgenic mouse model, examining Morris water maze performance, Nissl staining, synaptophysin expression, glial activation, cytokine ELISA readouts, and PI3K/AKT pathway proteins using wortmannin as a PI3K inhibitor probe. Weiss and colleagues (2021, Annals of Medicine and Surgery) evaluated Dihexa alongside mesenchymal stem cells and G-CSF in a rat sciatic nerve transection-repair model with motor and sensory endpoints. A 2025 Neurotrauma Reports study (Martino and colleagues) examined an HGF/MET activator in a rat repeated mild traumatic brain injury working-memory model.
A clinical-stage candidate in the dihexa chemical class has been characterized as a positive modulator of HGF/MET. Hua and colleagues (2022, Journal of Alzheimer's Disease; NCT03298672) reported a randomized, placebo-controlled, double-blind Phase 1 trial in healthy volunteers and Alzheimer's subjects, examining safety, tolerability, pharmacokinetics, and electrophysiological pharmacodynamic markers. Dihexa itself has no published human trials and no published human safety profile. Review articles by Wright, Kawas, and Harding (2015, Progress in Neurobiology) and by Wright and Harding (2015, Journal of Alzheimer's Disease) frame the HGF/c-Met system as a research target in Alzheimer's and Parkinson's disease contexts. Given that HGF/c-Met is an oncogenic signaling axis, the literature also notes a theoretical tumorigenesis consideration that has not been experimentally addressed for Dihexa.
Lyophilized
Store dry and sealed
short term at 0–4 °C, long term at −20 °C.
Reconstituted
Poorly water-soluble
laboratory stock solutions are typically prepared in DMSO. Aliquot to avoid freeze-thaw; store at −80 °C long term or −20 °C short term.
Dry compound reported stable at ambient shipping temperatures for short periods. Batch molecular weight may vary with degree of hydration. For research use only.
Reviews
Hallberg M, et al. (2020). Frontiers in Pharmacology — Review of the medicinal-chemistry conversion of AngIV into IRAP-inhibiting peptidomimetics, situating Dihexa
Wright JW, Kawas LH, Harding JW. (2015). Progress in Neurobiology — Review of AngIV analogs including Dihexa framed as HGF/c-Met–targeting candidates in Alzheimer's and Parkinson's disease research
Wright JW, Harding JW. (2015). Journal of Alzheimer's Disease — Review proposing the HGF/c-Met receptor system as an Alzheimer's disease research target, contextualizing Dihexa
Clinical
Hua X, Church K, Walker W, et al. (2022). Journal of Alzheimer's Disease — Randomized, placebo-controlled, double-blind Phase 1 trial of a clinical-stage HGF/MET modulator in the dihexa chemical class in healthy volunteers and Alzheimer's subjects
Primary research
Martino KA, Nakhre A, Demarest RM, Devilbiss DM. (2025). Neurotrauma Reports — Rat repeated mild traumatic brain injury working-memory study of an HGF/MET activator
Kawas LH, McCoy AT, Yamamoto BJ, Wright JW, Harding JW. (2025). Journal of Pharmacology and Experimental Therapeutics — Formal journal retraction notice for the Kawas et al. 2012 AngIV analogs/HGF–Met modifiers paper
Benoist CC, Kawas LH, Zhu M, et al. (2025). Journal of Pharmacology and Experimental Therapeutics — Formal journal retraction notice for the Benoist et al. 2014 HGF/c-Met cell-signaling and synaptogenesis paper
Sun X, Deng Y, Fu X, Wang S, Duan R, Zhang Y. (2021). Brain Sciences — APP/PS1 transgenic mouse model study of orally administered Dihexa with Morris water maze and PI3K/AKT pathway readouts
Weiss JB, Phillips CJ, Malin EW, Gorantla VS, Harding JW, Salgar SK. (2021). Annals of Medicine and Surgery — Rat sciatic nerve transection-repair model study of Dihexa, mesenchymal stem cells, and G-CSF with motor and sensory endpoints
Uribe PM, Kawas LH, Harding JW, Coffin AB. (2015). Frontiers in Cellular Neuroscience — Zebrafish lateral-line aminoglycoside ototoxicity model study examining Dihexa and HGF/c-Met pathway probes
Benoist CC, Kawas LH, Zhu M, et al. (2014). Journal of Pharmacology and Experimental Therapeutics — Cell-signaling and hippocampal-culture study proposing AngIV-derived peptides act via HGF/c-Met — retracted 2025
McCoy AT, Benoist CC, Wright JW, Kawas LH, et al. (2013). Journal of Pharmacology and Experimental Therapeutics — SAR, pharmacokinetic, and rodent cognition study introducing Dihexa as a metabolically stabilized BBB-permeant AngIV analog — Notice of Concern (2021)
Kawas LH, McCoy AT, Yamamoto BJ, Wright JW, Harding JW. (2012). Journal of Pharmacology and Experimental Therapeutics — Development of AngIV analogs as HGF/Met modifiers — retracted 2025
Kawas LH, Yamamoto BJ, Wright JW, Harding JW. (2011). Journal of Pharmacology and Experimental Therapeutics — HGF dimerization-domain mimics study — Notice of Concern (2021)
Benoist CC, Wright JW, Zhu M, Appleyard SM, Wayman GA, Harding JW. (2011). Journal of Pharmacology and Experimental Therapeutics — SAR study localizing Nle1-AngIV procognitive activity to the N-terminal tripeptide using hippocampal synaptogenesis and water-maze readouts
Yamamoto BJ, Elias PD, Masino JA, et al. (2010). Journal of Pharmacology and Experimental Therapeutics — Characterization of the AngIV analog norleual as an HGF/c-Met inhibitor and hinge-region mimic
Lew RA, Mustafa T, Ye S, McDowall SG, Chai SY, Albiston AL. (2003). Journal of Neurochemistry — Enzyme-kinetic study showing AT4 ligands including AngIV act as competitive IRAP inhibitors
Albiston AL, McDowall SG, Matsacos D, et al. (2001). Journal of Biological Chemistry — Protein-purification study identifying the AngIV AT4 receptor as insulin-regulated aminopeptidase (IRAP)
Research Use Only
These products are intended for research purposes only and are not for human consumption. Not FDA approved. Not intended to diagnose, treat, cure, or prevent any disease.
