Adamax (Dihexa)
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Adamax (Dihexa, PNB-0408, N-hexanoic-Tyr-Ile-(6) aminohexanoic amide) is a small molecule peptidomimetic derived from angiotensin IV and the related peptide Norleucine1-angiotensin IV (Nle1-AngIV). Dihexa was developed by Joseph Harding and colleagues at Washington State University through systematic optimisation of the hexapeptide Nle1-AngIV for blood-brain barrier penetration, oral bioavailability, and metabolic stability.
The pharmacological mechanism of Dihexa centres on hepatocyte growth factor (HGF) potentiation through its receptor c-Met (MET receptor tyrosine kinase). Published research by McCoy et al. (Journal of Pharmacology and Experimental Therapeutics, 2010) established that Dihexa and related AT4 receptor ligands potentiate HGF-driven c-Met activation at picomolar concentrations — a potency approximately 10^7-fold greater than HGF itself in some published assays, though this extraordinary potency has been subject to methodological scrutiny.
The AT4 receptor (proposed to be IRAP, insulin-regulated aminopeptidase, also known as leucocyte-derived arginine aminopeptidase LRAP) is the molecular target initially proposed for angiotensin IV and Nle1-AngIV, though more recent research has emphasised the HGF/c-Met potentiation mechanism as the primary pathway for cognitive effects.
Dihexa research protocol considerations: given the extraordinary potency claims (picomolar activity) in some published research, rigorous concentration-response characterisation is essential before interpreting biological effects. Prepare Dihexa stocks in DMSO at 10mM, then dilute serially in culture medium to cover a 9-10 log concentration range (1fM to 10µM) to properly characterise the concentration-response relationship. Include vehicle controls at matched DMSO concentration (less than 0.1% final) at every concentration tested.
For HGF/c-Met potentiation research: use hepatocyte growth factor (HGF) at its EC20 concentration (sub-maximal, allowing potentiation to be detected) in the presence of increasing Dihexa concentrations. Measure c-Met phosphorylation (pTyr1234/1235) by Western blot or AlphaScreen proximity assay, downstream Akt phosphorylation (Ser473), and ERK1/2 phosphorylation (Thr202/Tyr204) as the primary readouts. Include c-Met-selective inhibitor (crizotinib, 100nM) as a pathway-specificity control — if Dihexa effects are lost with crizotinib, this confirms c-Met dependence. For hippocampal synaptogenesis research, use primary rat hippocampal neurons (DIV7) treated for 72 hours, fixing and staining for synapsin-1 and PSD-95 to quantify pre- and post-synaptic puncta density by confocal microscopy. MW: 492.68 g/mol. CAS: 1417173-35-3. Prepare stocks in DMSO. Store lyophilised at -20°C. For laboratory and analytical research purposes only.
Dihexa and the IRAP hypothesis: the original AT4 receptor pharmacology framework proposed that angiotensin IV and related compounds including Dihexa act through IRAP (insulin-regulated aminopeptidase), an aminopeptidase N family member located primarily in GLUT4 storage vesicles in adipocytes and neurons. The hypothesis holds that IRAP inhibition by AT4 ligands protects endogenous neuropeptides (oxytocin, vasopressin, CCK) from degradation, amplifying their cognitive effects. Testing this mechanism with Dihexa requires: IRAP enzymatic activity assay using the fluorogenic substrate L-leucine-7-amido-4-methylcoumarin (LeuAMC), measuring inhibition of LeuAMC cleavage by recombinant IRAP in the presence of increasing Dihexa concentrations; and comparison with the established IRAP inhibitor HFI-419 as a positive control. For the c-Met potentiation mechanism, use a hepatocyte scatter assay (HGF-driven cell scattering is a classic c-Met activation endpoint) — Dihexa at picomolar concentrations alongside sub-threshold HGF concentrations should potentiate cell scattering in MDCK or HepG2 cells if the published potentiation mechanism is operative in the specific cell model. MW: 492.68 g/mol. CAS: 1417173-35-3. Prepare stocks in DMSO. Store lyophilised at -20°C. For laboratory and analytical research purposes only.
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