Dihexa
Angiotensin IV analog that potentiates hepatocyte growth factor (HGF) signaling through the c-Met receptor, driving synaptogenesis and dendritic spine density in cortical and hippocampal neurons.
Dihexa (N-hexanoic-Tyr-Ile-(6)-aminohexanoic amide) is a small lipophilic peptide developed by Joseph Harding’s group at Washington State University as a derivative of the bioactive angiotensin IV fragment (Ang(3-7), Ang IV). The original aim was to develop a small molecule that retained Ang IV’s procognitive activity in scopolamine-induced amnesia models while being orally bioavailable and BBB-permeable.
Mechanistically, Dihexa is reported to act as an allosteric potentiator of hepatocyte growth factor (HGF) at the c-Met receptor tyrosine kinase. c-Met activation in cortical and hippocampal neurons drives downstream MAPK and PI3K-Akt signaling cascades that culminate in the formation of new dendritic spines and functional synapses. In rodent models of cognitive impairment, Dihexa administration is reported to produce rapid and substantial increases in dendritic spine density alongside improvements in spatial learning and memory.
Independent replication of the synaptogenic effects outside the originating laboratory remains limited, and pharmacokinetic and safety data in humans are essentially absent. Dihexa is investigational and is not approved for any therapeutic indication.