Dihexa is a small molecule derived from angiotensin IV research, chemically named N-hexanoic-Tyr-Ile-(6)-aminohexanoic amide. It was developed at Washington State University by researchers John W. Wright and Joseph W. Harding as part of a long-running academic program on the brain angiotensin system, and it is studied in the literature in connection with the hepatocyte growth factor (HGF) and c-Met receptor signaling pathway. Dihexa exists only as a research compound: there is no FDA-approved drug product containing it, and the material sold here is supplied strictly for laboratory research, not for human or animal use.
Dihexa at a glance
| Attribute | Detail |
|---|---|
| Chemical name | N-hexanoic-Tyr-Ile-(6)-aminohexanoic amide |
| Molecular formula | C27H44N4O5 |
| Class | Angiotensin IV-derived small molecule (peptidomimetic) |
| Origin | Washington State University angiotensin IV / AT4 receptor research program |
| Related endogenous peptide | Angiotensin IV (and the stabilized analog Nle1-angiotensin IV used in early studies) |
| Proposed pathway studied | Hepatocyte growth factor (HGF) / c-Met receptor signaling |
| Models examined in cited literature | Rodent behavioral models (scopolamine-induced amnesia, aged rats); cell-based signaling assays |
| Regulatory status | No FDA-approved drug product; not listed among substances evaluated for the Section 503A bulk drug substances list |
| Form supplied | Lyophilized powder for laboratory reconstitution |
How was dihexa developed at Washington State University?
Dihexa traces back to a decades-long research program at Washington State University on the brain renin-angiotensin system, led by John W. Wright and Joseph W. Harding. That program examined angiotensin IV (AngIV) and a metabolically stabilized analog, Nle1-AngIV, in rodent behavioral testing linked to the AT4 receptor binding site (Wright et al., 1999). The same laboratory later reported a series of truncated and chemically modified AngIV-derived analogs designed to improve oral availability and metabolic stability, with dihexa described as one of these analogs (McCoy et al., 2013). The compound is also referenced in the literature under the code PNB-0408.
What is dihexa's chemical structure?
Dihexa is built from a short Tyr-Ile dipeptide core. A hexanoyl (six-carbon fatty acid) group is attached to the amino terminus of the tyrosine residue, and the isoleucine carboxyl terminus is extended through an amide linkage to 6-aminohexanoic acid, which ends in a primary amide. This gives the full chemical name N-hexanoic-Tyr-Ile-(6)-aminohexanoic amide and a molecular formula of C27H44N4O5, as listed in PubChem. The hexanoyl cap and the extended, non-standard C-terminal residue were reported as modifications intended to resist the peptidase degradation that limits the stability of unmodified angiotensin peptides (McCoy et al., 2013).
How does dihexa relate to angiotensin IV?
Angiotensin IV is a naturally occurring fragment of the renin-angiotensin system, generated from angiotensin II through sequential enzymatic cleavage. The Washington State University group's earlier work established that AngIV and stabilized analogs such as Nle1-AngIV bind an AT4 receptor site and were examined in rodent spatial learning paradigms (Wright et al., 1999). Dihexa is not angiotensin IV itself. It is a smaller, chemically distinct molecule designed within that same research lineage, built to retain activity associated with the AT4 binding site while improving oral and metabolic stability compared with the parent peptide fragments (McCoy et al., 2013).
What is the HGF/c-Met hypothesis in the dihexa literature?
A hypothesis advanced by the Washington State University group proposed that the AT4 receptor system corresponds, at least in part, to the hepatocyte growth factor (HGF) and c-Met receptor tyrosine kinase system, and that AngIV-derived analogs including dihexa act by promoting HGF dimerization and HGF-dependent c-Met activity. This mechanistic framework was described across several papers from the same laboratory, including a 2015 review of small-molecule angiotensin IV analogs (Wright, Kawas and Harding, 2015). In the literature, c-Met activation is discussed in connection with dendritic and synaptic changes examined in cell and rodent models, not as an established clinical mechanism. Readers evaluating this hypothesis should be aware of the research-integrity findings described below, which affect specific primary papers that reported the HGF-dimerization data underlying this proposal.
What did rodent studies examine?
The primary development paper for dihexa reported behavioral testing in two rodent paradigms: a scopolamine-induced amnesia model and a study in aged rats, alongside assessment of oral bioavailability and blood-brain barrier penetration using pharmacokinetic methods in rodents (McCoy et al., 2013). The same paper reported markers of synaptogenic activity in these models. These are described in the source as findings from specific rodent experiments, not as demonstrated outcomes in humans, and the paper does not describe dihexa as a treatment. No clinical trial of dihexa in humans is indexed in the sources cited for this article.
Is dihexa an approved drug or regulated substance?
Dihexa is not an FDA-approved drug. No prescription or over-the-counter drug product containing dihexa exists. It also does not appear among the bulk drug substances the FDA has evaluated or placed on the Section 503A bulk drug substances list for human drug compounding, based on the agency's published bulk drug substances resources (FDA, Bulk Drug Substances Used in Compounding Under Section 503A). Research-grade dihexa sold by Homegrown Peptides is intended solely for laboratory research applications such as in vitro assays and other non-clinical study uses, and is not labeled, marketed, or supplied for human or animal administration.
What should researchers know about the retracted papers?
In April 2025, the Journal of Pharmacology and Experimental Therapeutics published a retraction notice for "Development of Angiotensin IV Analogs as Hepatocyte Growth Factor/Met Modifiers" (Kawas et al., 2012), one of the papers that first proposed the HGF-dimerization mechanism for this analog series. The retraction followed an investigation into image handling in figures from the Harding and Wright laboratory. A separate 2013 paper describing dihexa's development, its oral and blood-brain-barrier data, and the rodent behavioral findings summarized above (McCoy et al., 2013) has not itself been retracted, but a formal notice of concern was published for it in 2021 pending the same institutional review. Researchers citing dihexa's proposed mechanism of action should check the current status of each specific paper rather than relying on secondary summaries, since the mechanistic claims and the behavioral/pharmacokinetic data were reported in different papers with different editorial outcomes.
How is dihexa supplied and handled in the lab?
Dihexa is supplied as a lyophilized powder, the standard form for small peptide-like research compounds, and it should be reconstituted according to standard bench technique before use in an assay. For the general math and technique involved in bringing a lyophilized research compound into solution, see Reconstituting Lyophilized Peptides: The Math, Step by Step. As with other research materials, the vial and any reconstituted solution should be labeled, tracked, and used only within a laboratory research setting; see What 'Research Use Only' Means, and Why It Is on Every Vial for what that labeling requires of a research buyer. Homegrown Peptides' current dihexa lot page and certificate of analysis are available at our dihexa research listing. Background on the broader monograph for this compound, including its listed identifiers, is maintained at the Dihexa research library entry.
Frequently asked questions
Is dihexa the same thing as angiotensin IV?
No. Angiotensin IV is a naturally occurring peptide fragment of the renin-angiotensin system. Dihexa is a separate, smaller molecule designed by the Washington State University group within the same research lineage, built with a hexanoyl-modified tyrosine-isoleucine core rather than the angiotensin IV sequence itself (McCoy et al., 2013).
What pathway does the dihexa literature focus on?
The literature from its developing laboratory focuses on a proposed connection between the AT4 receptor system and hepatocyte growth factor (HGF) / c-Met receptor signaling. This is described as a hypothesis examined in cell and rodent models, and some of the primary papers proposing this mechanism have since been subject to retraction or a notice of concern, as detailed above.
Has dihexa been tested in humans?
No clinical trial of dihexa in humans is indexed in the sources reviewed for this article. The rodent and cell-based studies cited here do not constitute clinical evidence, and dihexa is not approved or labeled for any human use.
Why were some of the dihexa papers retracted?
A 2025 retraction notice in the Journal of Pharmacology and Experimental Therapeutics addressed image handling issues identified in figures from a 2012 paper describing the HGF/Met mechanism (Kawas et al., 2012), following an institutional investigation. A separate 2021 notice of concern applies to the 2013 paper describing dihexa's development and rodent behavioral testing (McCoy et al., 2013), which has not itself been retracted.
Is dihexa regulated as a controlled substance?
Based on the FDA's published bulk drug substance resources reviewed for this article, dihexa does not appear on or among substances currently being evaluated for the Section 503A bulk drug substances list, and no DEA scheduling applies to it in the sources checked. It is not an approved drug product.
What form does Homegrown Peptides supply dihexa in?
Dihexa is supplied as a lyophilized powder for laboratory reconstitution, consistent with the other research compounds in this catalog. See the reconstitution guide linked above for general bench technique.
References
- McCoy AT, Benoist CC, Wright JW, et al. "Evaluation of Metabolically Stabilized Angiotensin IV Analogs as Procognitive/Antidementia Agents." J Pharmacol Exp Ther. 2013. PubMed
- McCoy AT, et al. Full text. J Pharmacol Exp Ther. 2013. PMC
- Wright JW, Stubley L, Pederson ES, et al. "Contributions of the Brain Angiotensin IV-AT4 Receptor Subtype System to Spatial Learning." J Neurosci. 1999. PubMed
- Wright JW, Kawas LH, Harding JW. "The Development of Small Molecule Angiotensin IV Analogs to Treat Alzheimer's and Parkinson's Diseases." Prog Neurobiol. 2015. PubMed
- Kawas LH, McCoy AT, Yamamoto BJ, et al.. Retraction notice to "Development of Angiotensin IV Analogs as Hepatocyte Growth Factor/Met Modifiers" [J Pharmacol Exp Ther 340 (2012) 539-548]. J Pharmacol Exp Ther. 2025. PubMed 40312092.
- "Notice of Concern: McCoy AT, Benoist CC, Wright JW, et al. (2013) Evaluation of Metabolically Stabilized Angiotensin IV Analogs as Procognitive/Antidementia Agents." J Pharmacol Exp Ther. 2021. PubMed
- PubChem. "Dihexa." National Center for Biotechnology Information. PubChem compound record
- U.S. Food and Drug Administration. "Bulk Drug Substances Used in Compounding Under Section 503A of the FD&C Act." FDA.gov
Research use only. Homegrown Peptides products are for laboratory research and are not for human or animal use. Nothing in this article is medical advice.
