Dihexa

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We currently track a single listing for this compound. When a second vendor is added the rows are ordered by measured $/mg, and the flags for testing and shipping are computed from the data shown. Each row carries its own verification date.

(2S,3S)-N-(6-amino-6-oxohexyl)-2-[[(2S)-2-(hexanoylamino)- 3-(4-hydroxyphenyl)propanoyl]amino]-3-methylpentanamide

L-Isoleucinamide, N-(1-oxohexyl)-L-tyrosyl-N-(6-amino-6-oxohexyl)-

OC1=CC=C(C[C@H](NC(CCCCC)=O)C(N[C@H](C(NCCCCCC(N)=O)=O) [C@@H](C)CC)=O)C=C1

Only two standard amino acids — tyrosine and isoleucine — flanked by two six-carbon groups: an N-terminal hexanoyl cap and a C-terminal 6-aminohexanoic acid (Ahx) residue, amidated. The name Dihexa refers to those two hexyl units. This is why the compound is described as a small molecule or oligopeptide rather than a peptide in the usual sense.

Hexanoic acid (C6H12O2) + Tyr (C9H11NO3) + Ile (C6H13NO2) + 6-aminohexanoic acid (C6H13NO2) sums to C27H49N3O9. Removing three waters for the three amide bonds gives C27H43N3O6; converting the C-terminal carboxyl to a carboxamide gives C27H44N4O5 at 504.67 g/mol. The SMILES above resolves to the same count: Tyr 9C + Ile 6C + hexanoyl 6C + aminohexanamide 6C = 27C.

This is the single most consequential practical fact about the compound and it separates Dihexa from almost everything else in the category.

Dihexa is hydrophobic. It does not dissolve in water, and it does not dissolve in bacteriostatic water. Reconstitution requires dimethyl sulfoxide (DMSO).

Dissolves in DMSO at approximately 1 mg/mL. Adding water to a DMSO stock can cause the solution to turn cloudy; brief sonication — on the order of two seconds — typically clears it. Suppliers of the material sell DMSO alongside it for this reason, and the original pharmacology work prepared Dihexa in DMSO where the comparator peptides were prepared in water.

Standard peptide reconstitution guidance does not apply. Anyone working from a generic bacteriostatic-water protocol will fail to get the compound into solution.

Dihexa derives from angiotensin IV (AngIV), and specifically from the Nle1-AngIV analog series (Nle-Tyr-Ile-His-Pro-Phe). The design problem being solved was metabolic stability: Nle1-AngIV has a reported serum half-life of under 2 minutes, which makes it unusable as a systemic agent.

The Dihexa modification places a six-carbon group at each end — the N-terminal hexanoyl cap and the C-terminal aminohexanoic amide.

Both termini are therefore protected from the peptidases that destroy the parent compound, and the added hydrophobicity supports passage across the blood-brain barrier.

Dihexa is reported to bind hepatocyte growth factor (HGF) with high affinity and to potentiate HGF signalling at its receptor c-Met.

The described consequence is augmented rather than independent signalling: the compound acts on an existing growth factor pathway rather than functioning as a receptor agonist in its own right.

Downstream effects reported in preclinical models include neuronal differentiation, dendritic branching, spinogenesis and synaptic plasticity, with activity reported at very low concentrations.

The foundational characterisation paper for this compound. Rat models unless noted.

Nle1-AngIV (parent) < 2 min N-Acetyl-Nle-Tyr-Ile-His 115 ± 7.6 min D-Nle-Tyr-Ile 225 ± 23.7 min Dihexa 335.5 ± 9.5 min GABA-Tyr-Ile 946 ± 234 min

Both N-terminal and C-terminal modification independently extend half-life; Dihexa combines the two.

Co-infusion of [3H]Dihexa with [14C]inulin as a vascular space marker. Dihexa concentrated above blood levels in every region examined — prefrontal cortex, hippocampus, hypothalamus, striatum, thalamus, midbrain, brain stem and cerebellum.

Terminal elimination half-life reported at 12.68 days following intravenous administration, with a large volume of distribution.

Rat liver microsomes: intrinsic clearance 2.72 µL/min/mg, half-life 509.4 minutes — characterized as very low phase I metabolism.

Scopolamine (70 nmol) used to induce deficits. Dihexa improved performance by intracerebroventricular (0.1 and 1.0 nmol), intraperitoneal (0.25 and 0.50 mg/kg) and oral (2.0 mg/kg) routes.

High-dose groups were indistinguishable from vehicle controls across testing days, and day-9 probe trials showed increased time in the target quadrant. Oral administration also improved performance in 24-month-old rats.

5-day treatment vehicle 15 spines / 50 µm Nle1-AngIV 32 spines / 50 µm Dihexa 41 spines / 50 µm

vehicle 17.4 spines / 50 µm Nle1-AngIV 22.6 spines / 50 µm Dihexa 23.9 spines / 50 µm

control 7 spines / 50 µm Nle1-AngIV 11 spines / 50 µm Dihexa 11 spines / 50 µm

New spines colocalized with presynaptic markers VGLUT1 and synapsin and postsynaptic marker PSD-95 at percentages comparable to controls. Whole-cell patch clamp showed increased frequency of AMPA-mediated miniature excitatory postsynaptic currents — 1.6-fold for Dihexa, 1.7-fold for Nle1-AngIV — without change to amplitude, rise time or decay time. The interpretation offered is an increase in the number of functional synapses rather than a change in the properties of individual synapses.

A distinct and less widely known application, and one that follows directly from the HGF mechanism.

In work generating functional hepatic cells from human pluripotent stem cells, Dihexa was used as part of a small-molecule cocktail replacing expensive recombinant growth factors at the hepatic specification step.

Vitamin C 10 µg/mL Dihexa 0.1 µM Forskolin 10 µM

This substituted for BMP2 (20 ng/mL) and FGF4 (30 ng/mL), and reported 95.5% efficiency by HNF4α+/AFP+ staining — comparable to the growth-factor control.

Dihexa also appeared at 0.1 µM in the hepatoblast expansion cocktail and in the final maturation medium.

The logic is consistent with the stated mechanism: if Dihexa potentiates HGF signalling at c-Met, it can stand in for HGF in a differentiation protocol that would otherwise require the recombinant growth factor. (Pan et al., Stem Cell Research & Therapy, 2022)

Dihexa is an investigational compound. It has not been approved by the FDA or any other regulatory agency for any indication, and there are no completed human clinical trials establishing efficacy or safety. All data described above derive from in vitro work and animal models.

Material supplied for laboratory use is a research chemical. It is not a drug, food, cosmetic, or dietary supplement, has not been evaluated by the FDA, and is not intended for human or veterinary use.