Dihexa

Dihexa (N-hexanoic-Tyr-Ile-(6) aminohexanoic amide; development code PNB-0408; CAS 1401708-83-5) is an orally active, blood-brain-barrier-permeable synthetic hexapeptide derived from the endogenous hexapeptide angiotensin IV (Ang IV). It was developed in the laboratory of Joseph Harding at Washington State University as a metabolically stabilized analog designed to retain Ang IV’s procognitive activity while overcoming the parent peptide’s short half-life and poor BBB permeability. The compound has been characterized in rat and mouse cognitive-research models — principally scopolamine-induced cognitive impairment, aged-rat cognitive decline, and the APP/PS1 transgenic Alzheimer’s disease model — with reported effects on hippocampal synaptogenesis, dendritic spine density, and Morris water maze performance.

The most consistent mechanistic finding in the published Dihexa research literature is that the compound’s procognitive and synaptogenic effects are not mediated by the classical AT₄ receptor, despite Dihexa’s structural origin as an Ang IV derivative. In a 2014 study published in the Journal of Pharmacology and Experimental Therapeutics, Benoist and colleagues used the HGF/c-Met dimerization antagonist Hinge to block Dihexa’s effects in scopolamine-impaired rats, demonstrating that the procognitive activity requires functional hepatocyte growth factor (HGF) / mesenchymal-epithelial transition factor (c-Met) receptor signaling [3]. Subsequent work by Sun and colleagues in the APP/PS1 mouse model identified downstream PI3K/AKT pathway activation as a major component of the mechanism, with the PI3K inhibitor wortmannin reversing Dihexa’s anti-inflammatory and anti-apoptotic effects [5]. The HGF/c-Met framing places Dihexa in a different mechanism class from classical Ang IV / AT₄ agonists.

Dihexa has not been investigated in human clinical trials. The published research base is entirely preclinical (rat and mouse studies plus rat hippocampal neuron culture work). Dihexa is not approved by the FDA, EMA, or any other regulatory authority for any indication, and is not in active regulatory development as a drug candidate. Researchers should interpret the rodent amount protocols summarized below as scientific reference for the published model systems, not as guidance for any other context.

Important Note on the Evidence Base

Important note on the evidence base: The Dihexa research literature is entirely preclinical — rodent behavioral models, in vitro hippocampal neuron culture, and mechanistic work characterizing HGF/c-Met-dependent signaling. There are no human clinical trials of Dihexa itself. Readers researching the broader hepatocyte growth factor / c-Met pathway for cognitive indications should be aware that Fosgonimeton (development code ATH-1017), a structurally distinct small-molecule prodrug developed by Athira Pharma as an HGF positive modulator, has been investigated in three clinical trials in dementia indications. The Phase 2 ACT-AD trial (NCT04491006) in mild-to-moderate Alzheimer’s disease failed its primary endpoint in June 2022. The Phase 2 SHAPE trial (NCT04831281) in Parkinson’s disease dementia and dementia with Lewy bodies failed its primary endpoint in December 2023. The Phase 2/3 LIFT-AD trial (NCT04488419), evaluating once-daily subcutaneous fosgonimeton 40 mg versus placebo in 312 participants with mild-to-moderate Alzheimer’s disease over 26 weeks, failed its primary endpoint (Global Statistical Test composite of ADAS-Cog11 and ADCS-ADL23) and its key secondary endpoints when results were announced in September 2024. Fosgonimeton and Dihexa are different molecules with different chemical structures and different pharmacokinetic profiles, but they share the HGF/c-Met pathway as their proposed primary mechanism class. The fosgonimeton clinical history is not direct evidence about Dihexa, but it is relevant context for any reader evaluating the HGF/c-Met pathway as a research target for cognitive applications.

Mechanism of Action

Dihexa was designed to retain the procognitive activity of angiotensin IV while overcoming the parent peptide’s metabolic instability and poor blood-brain-barrier permeability. The published mechanistic literature has converged on the HGF/c-Met receptor system as the primary molecular target, with downstream effects on dendritic synaptogenesis and PI3K/AKT signaling.

Structural origin and rationale. Angiotensin IV (Val¹-Tyr²-Ile³-His⁴-Pro⁵-Phe⁶) is an endogenous hexapeptide fragment of the renin-angiotensin system, historically considered a metabolite of angiotensin II but subsequently shown to have independent procognitive activity in rodent models. Ang IV itself is metabolically unstable and crosses the blood-brain barrier poorly. In a 2011 study, Benoist and colleagues established that the procognitive core of Nle¹-Ang IV resides in its three N-terminal residues (Nle-Tyr-Ile), and that C-terminally truncated tetrapeptides and tripeptides retained scopolamine-reversal activity in the Morris water maze [1]. The McCoy 2013 paper extended this work by introducing N- and C-terminal modifications designed to enhance metabolic stability and hydrophobicity, ultimately producing Dihexa (N-hexanoic-Tyr-Ile-(6) aminohexanoic amide) as an orally active, BBB-permeable analog [2].

HGF/c-Met receptor system — the primary mechanism class. Despite Dihexa’s structural derivation from Ang IV, mechanistic studies have established that the compound does not act through the classical AT₄ receptor (insulin-regulated aminopeptidase, IRAP). The Benoist 2014 study used the HGF/MET dimerization antagonist Hinge to block Dihexa’s procognitive activity in scopolamine-impaired rats, with oral Dihexa (2 mg/kg/day) reversing the scopolamine-induced Morris water maze deficit when administered alone but losing effect when co-administered with Hinge [3]. The same study showed that Dihexa potentiates HGF-stimulated c-Met phosphorylation and downstream signaling at concentrations consistent with high-affinity binding. The Wright and Harding 2015 review in the Journal of Alzheimer’s Disease situated the HGF/c-Met system more broadly as a candidate cognitive-research target, summarizing the receptor’s roles in neurogenesis, synaptic plasticity, and neuroprotection [4].

Dendritic spinogenesis and synaptogenesis. The most quantitatively striking effect reported in the Dihexa literature is on dendritic spine density in rat hippocampal neuron cultures. McCoy and colleagues reported that 5-day treatment of dissociated rat hippocampal neurons with Dihexa increased dendritic spine density approximately three-fold compared to vehicle control (~41 spines per 50 µm of dendrite versus ~15 spines), with the increase reflecting both new spine formation and increased spine-head width consistent with synaptic maturation [2]. Subsequent work has reported that the spinogenic effect requires HGF/c-Met activation and is blocked by the same Hinge antagonist that blocks the procognitive effect in vivo [3].

PI3K/AKT signaling in the APP/PS1 mouse model. Sun and colleagues extended the mechanistic work to the APP/PS1 transgenic Alzheimer’s disease mouse model. After three months of intragastric Dihexa administration (1.44 or 2.88 mg/kg), the APP/PS1 mice showed restored Morris water maze performance, increased neuronal cell counts and synaptophysin expression on Nissl staining, reduced microglial and astrocyte activation, decreased pro-inflammatory cytokines (IL-1β, TNF-α) and increased anti-inflammatory IL-10. The mechanistic core of the finding was that Dihexa activated the PI3K/AKT signaling pathway in the brains of the APP/PS1 mice, and that the PI3K inhibitor wortmannin reversed Dihexa’s anti-inflammatory and anti-apoptotic effects [5]. The Sun 2021 work positions PI3K/AKT as a downstream signaling node coupling HGF/c-Met receptor activation to the cognitive and anti-inflammatory readouts characterized in the broader Dihexa literature.

Available Forms

Omnix Peptides supplies Dihexa in a single research format. Each lot is independently characterized by HPLC and LC–MS, with a batch-specific Certificate of Analysis available on the product page.

• Dihexa Capsules 10 mg, 30-count — oral capsule format. The capsule format reflects the orally active, BBB-permeable design that distinguishes Dihexa from its parent peptide angiotensin IV; the published rodent literature has used intragastric (oral) and oral gavage administration as the primary delivery route.

Dihexa is classified under the Cognitive & Neurological research category. For research framed around different cognitive mechanism classes, see the Semax hub (a heptapeptide derived from ACTH_4-10 with proposed BDNF-mediated mechanisms — the closest cognitive-category neighbor in the catalog, though a different mechanism class). For broader cognitive-landscape research adjacent to the growth-hormone axis, see the CJC-1295 no-DAC hub.

Amount in the Published Research Literature

The following administration ranges describe the protocols used in the peer-reviewed rodent literature on Dihexa. They are reported here for research-reference purposes only and do not constitute administration recommendations of any kind. Dihexa has not been investigated in human clinical trials, and no human-equivalent amount translation has been published in the peer-reviewed literature.

McCoy 2013 — scopolamine and aged-rat cognitive protocols. The McCoy 2013 paper, which introduced and characterized Dihexa as the metabolically stabilized lead from the Harding laboratory’s Ang IV-analog series, used scopolamine-induced cognitive impairment in young rats and natural cognitive decline in aged rats as the primary Morris water maze readouts. Oral Dihexa at 2 mg/kg/day reversed the scopolamine-induced spatial learning deficit, with treated rats performing indistinguishably from non-impaired controls. The aged-rat cohort showed improved Morris water maze performance with the same oral protocol, though with greater variability reflecting the heterogeneous baseline cognitive status of the aged-rat population. The in vitro hippocampal-neuron-culture spine-density work used Dihexa concentrations across a wide range, with effects observed at picomolar concentrations [2].

Benoist 2014 — HGF/c-Met mechanism-confirmation protocol. The Benoist 2014 mechanism-confirmation study replicated the 2 mg/kg/day oral Dihexa protocol from McCoy 2013 in scopolamine-impaired rats, with the addition of intracerebroventricular Hinge co-administration to block HGF/c-Met dimerization. Oral Dihexa reversed the scopolamine deficit by day 7 of training; Hinge co-administration eliminated the effect, confirming the HGF/c-Met dependence [3].

Sun 2021 — APP/PS1 transgenic mouse protocol. The Sun 2021 study used the APP/PS1 transgenic mouse model of Alzheimer’s disease, with intragastric administration of Dihexa at 1.44 mg/kg or 2.88 mg/kg once daily for three months (six to nine months of age in the APP/PS1 cohort). Both amounts restored Morris water maze performance relative to vehicle-treated APP/PS1 controls; the 2.88 mg/kg amount produced the larger effect on neuroinflammatory cytokine markers and PI3K/AKT pathway activation [5]. The intragastric administration route used in Sun 2021 reflects the BBB-permeability and oral-bioavailability profile characterized for Dihexa in the McCoy 2013 pharmacokinetic work.

Researchers planning protocols are referred to the original primary literature cited in the References section for full methodological detail, including vehicle composition (the Sun 2021 vehicle was 10% DMSO, 40% PEG300, 5% Tween-80, 45% saline), administration timing relative to behavioral testing, and outcome assessment timepoints.

Frequently Asked Questions

References

1. 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. J Pharmacol Exp Ther. 2011;339(1):35-44. doi:10.1124/jpet.111.182220 · PubMed: 21719467
2. McCoy AT, Benoist CC, Wright JW, et al. Evaluation of metabolically stabilized angiotensin IV analogs as procognitive/antidementia agents. J Pharmacol Exp Ther. 2013;344(1):141-154. doi:10.1124/jpet.112.199497 · PubMed: 23055539
3. Benoist CC, Kawas LH, Zhu M, et al. The procognitive and synaptogenic effects of angiotensin IV-derived peptides are dependent on activation of the hepatocyte growth factor/c-met system. J Pharmacol Exp Ther. 2014;351(2):390-402. doi:10.1124/jpet.114.218735 · PubMed: 25187433
4. Wright JW, Harding JW. The brain hepatocyte growth factor/c-Met receptor system: a new target for the treatment of Alzheimer’s disease. J Alzheimers Dis. 2015;45(4):985-1000. doi:10.3233/JAD-142814 · PubMed: 25649658
5. 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 Sci. 2021;11(11):1487. doi:10.3390/brainsci11111487 · PubMed: 34827486

For Research Use Only. The products described on this page are sold strictly for in vitro laboratory research and are not intended for human or animal consumption, diagnostic use, or therapeutic use. The published research summarized above is provided as scientific reference material. Nothing on this page constitutes medical advice, a therapeutic claim, or a recommendation for any use outside of a properly resourced and ethically reviewed research setting.