Dihexa (N-hexanoic-Tyr-Ile-(6)-aminohexanoic amide, PNB-0408) is a synthetic oligopeptide derived from angiotensin IV, engineered by researchers at Washington State University for cognitive enhancement and neuroprotection research. Chemical Name: N-hexanoic-Tyr-Ile-(6)-aminohexanoic amide Molecular Formula: C₂₇H₄₄N₄O₅ Molecular Weight: 504.28 Da Classification: Synthetic dipeptide derivative, nootropic agent - N-terminal: Hexanoic acid attached to tyrosine (increases lipophilicity) - C-terminal: Isoleucine linked to 6-aminohexanoic acid (protects against peptidases) - Core structure: Tyr-Ile dipeptide backbone These modifications enable blood-brain barrier penetration and oral bioavailability. Dihexa's procognitive effects stem from the hepatocyte growth factor (HGF) / c-Met receptor system: 1. High-affinity HGF binding (Kd ≈ 65 pM) 2. c-Met phosphorylation in presence of subthreshold HGF 3. Downstream activation: - PI3K/AKT pathway → neuronal survival - Synaptic plasticity signaling → new synapses and dendritic spines - Neurogenesis → new neurons, particularly in hippocampus In neurotrophic activity assays, Dihexa was found to be 7 orders of magnitude more potent than BDNF, making it one of the most powerful neurogenic compounds identified. | Model | Dose | Result | |-------|------|--------| | Scopolamine-impaired rats | 2 mg/kg oral | Restored spatial memory | | Aged rats | Chronic | Improved learning, increased spine density | | APP/PS1 Alzheimer's mice | Multiple oral doses | Enhanced neuronal density, reduced inflammation | - Dose: 0.5 mg/kg IP over 3 months - Restored tyrosine hydroxylase immunoreactivity to 100% - Complete recovery of motor function Effects blocked by HGF antagonist and c-Met shRNA, confirming HGF/c-Met dependency. - Half-life: 12.7 days (IV), 8.8 days (IP) in rats - BBB penetration: Confirmed via radiolabeled studies - Oral bioavailability: Yes (unique among peptide nootropics) | Application | Mechanism | Status | |-------------|-----------|--------| | Alzheimer's disease | Synaptogenesis, neuroprotection | Preclinical validated | | Parkinson's disease | Dopaminergic neuron protection | Preclinical validated | | Cognitive decline | Hippocampal neurogenesis | Preclinical validated | | Traumatic brain injury | Enhanced neural regeneration | Preliminary | | Vascular dementia | Synaptic repair | Preclinical | Fosgonimeton (ATH-1017) - phosphate prodrug of Dihexa developed by Athira Pharma for clinical trials in Alzheimer's and Parkinson's diseases. - Long half-life (12 days) may lead to accumulation - HGF/c-Met pathway activation has theoretical cancer implications - Long-term safety studies in humans not yet published - Well-tolerated in rodent studies - No significant adverse events in short-term trials - Store lyophilized at -20°C or below - Reconstitute with sterile water - Protect from light - Stable for extended periods when properly stored 1. McCoy et al. (2013) J Ph
Dihexa: Cognitive Enhancement Peptide Research Guide
Comprehensive overview of Dihexa (PNB-0408), an angiotensin IV-derived peptide studied for its potent procognitive and synaptogenic effects through HGF/c-Met pathway activation.