Dihexa: Molecular Structure

Molecular Structure and Properties#

Dihexa (PNB-0408) is a small synthetic oligopeptide with the systematic name N-hexanoic-Tyr-Ile-(6)-aminohexanoic amide. It has a molecular weight of 504.66 Da, molecular formula C27H44N4O5, and CAS number 1401708-83-5. Unlike most neuropeptides which are linear chains of amino acids, dihexa is a highly modified dipeptide derivative designed for metabolic stability and oral bioavailability.

Chemical Structure#

Dihexa's structure consists of three principal components:

• N-terminal hexanoic acid cap: A six-carbon aliphatic acid provides metabolic stability by protecting the N-terminus from aminopeptidase degradation. This cap replaces the valine-tyrosine N-terminal portion of the parent angiotensin IV hexapeptide.
• Central dipeptide core: Tyrosine-isoleucine (Tyr-Ile), which retains the pharmacophore essential for HGF binding activity derived from the angiotensin IV sequence.
• C-terminal 6-aminohexanoic amide: A non-natural amino acid modification that provides resistance to carboxypeptidase degradation and an amide C-terminus. The six-carbon spacer maintains the spatial orientation needed for receptor interaction.

Design Rationale#

Dihexa was developed through systematic modification of angiotensin IV and its analog Nle1-AngIV (Norleucine1-angiotensin IV). The parent angiotensin IV hexapeptide (Val-Tyr-Ile-His-Pro-Phe) possesses procognitive activity but is rapidly degraded by peptidases in vivo and cannot cross the blood-brain barrier.

The design strategy involved:

1. Minimal pharmacophore identification: Determining that the Tyr-Ile dipeptide core was sufficient for HGF binding activity
2. N-terminal capping: Replacing the N-terminal amino acids with a hexanoic acid chain to prevent aminopeptidase degradation while maintaining lipophilicity for membrane permeability
3. C-terminal modification: Substituting the C-terminal His-Pro-Phe tripeptide with 6-aminohexanoic amide to resist carboxypeptidase activity

Pharmacokinetics#

Oral Bioavailability#

Dihexa is one of the few peptide-derived compounds with meaningful oral bioavailability. Approximately 38% of the compound is absorbed when administered orally, which is remarkably high for a peptide-derived molecule. This oral bioavailability is attributed to the compound's small size (504.66 Da, well below the typical oral bioavailability threshold of approximately 500-600 Da for peptidomimetics), metabolic stability provided by the N- and C-terminal modifications, and sufficient lipophilicity for transcellular absorption.

Blood-Brain Barrier Permeability#

Studies using radiolabeled dihexa administered via carotid cannula demonstrated that dihexa concentrates in multiple brain regions, confirming BBB permeability. Brain concentrations sufficient for pharmacological activity were achieved after oral administration in rats, consistent with the behavioral improvements observed in the Morris water maze.

Metabolic Stability#

Unlike native angiotensin IV (half-life of minutes), dihexa demonstrates prolonged stability in plasma due to resistance to aminopeptidases and carboxypeptidases. The exact plasma half-life has not been reported in published literature, but the behavioral studies suggest a duration of action sufficient for once-daily oral dosing in animal models.

HGF Binding Pharmacology#

Dihexa's primary molecular target is hepatocyte growth factor (HGF), not a traditional receptor. The compound binds to HGF and modulates its interaction with the c-Met receptor tyrosine kinase in a concentration-dependent manner:

• Picomolar to nanomolar range: Augments HGF-dependent c-Met activation and cell scattering. At these concentrations, dihexa does not independently activate c-Met but potentiates the activity of subthreshold HGF concentrations.
• Micromolar range: Inhibits HGF dimerization, suggesting that at higher concentrations, dihexa may interfere with normal HGF processing.

This dual mechanism distinguishes dihexa from direct receptor agonists or antagonists; it functions as an allosteric modulator of a growth factor rather than a receptor ligand.

Structural Comparison with Related Compounds#

• vs. Angiotensin IV (VYIHPF): Dihexa retains only the Tyr-Ile core from the parent hexapeptide. The modifications reduce molecular weight from approximately 774 Da to 505 Da while dramatically improving metabolic stability and oral bioavailability.
• vs. Nle1-AngIV: The norleucine-substituted angiotensin IV analog was the immediate precursor to dihexa in the drug design process. Nle1-AngIV shares the HGF/c-Met potentiation mechanism but lacks oral bioavailability and BBB permeability.
• vs. Traditional nootropic peptides: Most nootropic peptides (semax, selank, cerebrolysin fragments) are longer polypeptides requiring intranasal or subcutaneous administration. Dihexa's small size and oral activity are distinctive among cognitive peptides.

Physicochemical Properties#

• Solubility: Soluble in DMSO and ethanol; limited aqueous solubility at neutral pH
• Stability: Store as lyophilized powder at -20 degrees C for long-term storage. Reconstituted solutions should be stored at 2-8 degrees C and used within a limited timeframe
• Appearance: White to off-white lyophilized powder

Related Reading#

• Dihexa overview and research guide
• Peptides similar to Dihexa
• Dihexa research evidence