Dihexa

Dihexa (N-hexanoic-Tyr-Ile-(6) aminohexanoic amide) is a synthetic peptide-based compound developed by Dr. Joseph Harding and colleagues at Washington State University. It was derived from structure-activity relationship studies of angiotensin IV (AngIV) and its receptor AT4R, which was subsequently identified as insulin-regulated aminopeptidase (IRAP). Through systematic modification, the team discovered that Dihexa acts as an extraordinarily potent agonist of the hepatocyte growth factor (HGF)/c-Met receptor signaling pathway; the primary neurotrophic system driving synaptogenesis, dendritic spine formation, and synaptic plasticity in the adult brain. In direct comparison, Dihexa is approximately 10 million times (seven orders of magnitude) more potent than BDNF at facilitating HGF/c-Met dimerization and downstream signaling. In animal models, Dihexa fully rescues cognitive deficits in scopolamine-induced amnesia models, aged rats with natural cognitive decline, and HGF-deficit models. It promotes new synapse formation (synaptogenesis) and augments dendritic spine density in the hippocampus and prefrontal cortex. Dihexa is orally bioavailable and crosses the blood-brain barrier, unusual for a peptide-based compound and critical for practical nootropic application. While the preclinical data is extraordinary, human clinical trial data is currently absent, and Dihexa remains an investigational compound.

Dihexa's primary mechanism is augmentation of HGF/c-Met receptor signaling in the brain. HGF (hepatocyte growth factor) is a pleiotropic growth factor that, when binding its receptor c-Met (a receptor tyrosine kinase), drives synaptogenesis, dendritic spine formation, neuronal survival, and synaptic plasticity — processes essential for learning and memory. Dihexa acts as an allosteric facilitator of HGF/c-Met dimerization, it dramatically enhances the ability of HGF to activate c-Met without being a direct c-Met agonist itself. This means Dihexa amplifies the endogenous neurotrophic signaling rather than replacing it. Downstream, c-Met activation triggers RAS/MAPK (promoting synaptic gene expression), PI3K/AKT (neuronal survival), and STAT3 (synaptic plasticity) cascades. In the hippocampus, this drives formation of new dendritic spines; the structural basis of new synaptic connections and memory formation. Dihexa also inhibits IRAP (insulin-regulated aminopeptidase), which may contribute to its cognitive effects by modulating neuropeptide processing (IRAP degrades vasopressin, oxytocin, and other memory-relevant peptides). The compound's ability to cross the BBB and achieve oral bioavailability is attributed to its lipophilic hexanoic acid modifications, which are uncommon in peptide pharmacology.