Dihexa

Overview

Dihexa (PNB-0408) is a small-molecule hexapeptide-like analog of angiotensin IV developed at Washington State University by the Harding/Wright group as a preclinical candidate for Alzheimer's disease and cognitive decline. It is NOT FDA-approved and has never been tested in human clinical trials. The often-quoted claim that it is 'roughly ten million times more potent than BDNF' refers to EC50 comparisons in an in vitro dendritic spine assay, not clinical efficacy.

Mechanism of Action

Dihexa binds with high affinity to hepatocyte growth factor (HGF) and facilitates HGF/c-Met receptor dimerization and activation at otherwise subthreshold HGF concentrations, downstream of which it drives dendritic spine formation and hippocampal synaptogenesis. It does not appear to act through classical angiotensin (AT1/AT2/AT4/IRAP) receptors despite being derived from angiotensin IV. The compound was designed for oral bioavailability and blood-brain barrier penetration; the HGF/c-Met pathway it engages is the same pathway that c-Met proto-oncogene signaling uses in peripheral tissues.

Research Summary

Preclinical rodent studies (McCoy et al., JPET 2013) showed that oral dihexa reversed scopolamine-induced memory deficits and improved Morris water maze performance in aged rats at low doses. Sun et al. (Brain Sci 2021) reported that dihexa rescued cognitive impairment in the APP/PS1 Alzheimer's mouse model via PI3K/AKT signaling. A 2014 paper on HGF/c-Met-dependent synaptogenesis from the same group (Benoist et al., JPET 2014, PMID 25187433) was retracted in 2025 and should not be cited as primary evidence. Dihexa was licensed to M3 Biotechnology (renamed Athira Pharma in 2019); Athira's clinical program pivoted to the related analog fosgonimeton (ATH-1017), whose Phase 2/3 LIFT-AD trial failed its primary endpoint in 2024 and was discontinued. No human clinical trial of dihexa itself has been conducted or published.

Dosing Information

Reported Side Effects

• No human safety data — all listed effects are theoretical or anecdotal
• Headache and overstimulation reported anecdotally by self-experimenters
• Theoretical blood pressure effects from the angiotensin-derived scaffold (not clinically demonstrated)
• Completely unknown long-term effects

Research References

• Evaluation of metabolically stabilized angiotensin IV analogs as procognitive/antidementia agents (McCoy et al., J Pharmacol Exp Ther, PMID 23055539) (2013)
• The Brain Hepatocyte Growth Factor/c-Met Receptor System: A New Target for the Treatment of Alzheimer's Disease (Wright & Harding, J Alzheimers Dis, PMID 25649658) (2015)
• AngIV-Analog Dihexa Rescues Cognitive Impairment and Recovers Memory in the APP/PS1 Mouse via the PI3K/AKT Signaling Pathway (Sun et al., Brain Sci, PMID 34827486) (2021)