Dihexa

What it is

Dihexa (PNB-0408; N-hexanoic-Tyr-Ile-(6) aminohexanoic amide) is a small-molecule analogue of angiotensin IV, developed by chemically modifying the Nle-Tyr-Ile core of an angiotensin IV analogue for metabolic stability, oral activity, and blood-brain barrier entry. Although it keeps a modified tyrosine-isoleucine core, it is described in the literature as a small-molecule drug candidate rather than a peptide drug in the strict sense. It appears only in preclinical cognition and neurodegeneration research, has no published human trials, and is not an approved medicine in any market.

How it works

Its originating laboratory proposed that dihexa acts as a hepatocyte growth factor (HGF) mimetic, dimerising with endogenous HGF to activate the c-Met receptor and promote new synapse formation, and a later mouse study linked its effects to PI3K/AKT signalling. A central 2014 paper supporting the HGF/c-Met mechanism was retracted in 2025, so the mechanism is not established.

Regulatory status

1. Cosmetic ingredient
2. Research compound
3. In clinical trials
4. Approved medicine

Not approved as a medicine by the FDA or the EMA. Some are registered in individual countries. Supplied for laboratory research only.

What published research is studying

• Spatial learning and memory in scopolamine-impaired and aged rats
• Cognition and neuroinflammation in APP/PS1 Alzheimer's model mice
• Protection of sensory hair cells from aminoglycoside toxicity in zebrafish
• Motor and cognitive deficits in a Huntington's disease-like rat model

Key findings

1. 01

   In rat studies, dihexa was reported to be orally active and blood-brain barrier permeant, with antidementia activity in scopolamine-impaired and aged rat models and marked synaptogenic activity; the journal published a notice of concern about this paper in 2021.

   McCoy AT et al., J Pharmacol Exp Ther 2013
2. 02

   In larval zebrafish, dihexa protected lateral line hair cells from neomycin and gentamicin, with optimal protection at a concentration of 1 µM, and the effect was attenuated by the HGF antagonist 6-AH.

   Uribe PM et al., Front Cell Neurosci 2015
3. 03

   In APP/PS1 Alzheimer's model mice, dihexa restored Morris water maze performance, reduced astrocyte and microglia activation and IL-1β and TNF-α levels, and its anti-inflammatory and anti-apoptotic effects were reversed by the PI3K inhibitor wortmannin.

   Sun X et al., Brain Sci 2021
4. 04

   In a randomised study of 40 rats exposed to the mitochondrial toxin 3-nitropropionic acid and followed for 5 weeks, PNB-0408 did not protect against the resulting weight, motor, and cognitive deficits.

   Wells RG et al., J Huntingtons Dis 2024

How strong is the evidence?

Common questions