Dihexa
Dihexa (N-hexanoic-Tyr-Ile-(6)-aminohexanoic amide) is a truncated angiotensin IV analogue and hepatocyte growth factor (HGF)/MET receptor system potentiator studied for cognitive enhancement, with reported potency 100,000-fold greater than brain-derived neurotrophic factor (BDNF) in promoting synaptogenesis.
Dihexa is a modified hexapeptide derivative of angiotensin IV designed to potentiate hepatocyte growth factor (HGF) signaling through the c-Met receptor. It has attracted significant research interest due to its remarkable potency in promoting synaptogenesis, reported to be 100,000 times greater than BDNF, and its ability to cross the blood-brain barrier with oral bioavailability.
Overview
Dihexa was developed by researchers at Washington State University as a metabolically stable analogue of angiotensin IV (AngIV), a peptide fragment of angiotensin II known to facilitate memory acquisition and recall. Unlike its parent compound, Dihexa resists enzymatic degradation and is orally bioavailable, crossing the blood-brain barrier to exert central effects. Its primary mechanism involves allosteric potentiation of HGF binding to the c-Met receptor, amplifying a signaling cascade critical for neuronal survival, dendritic branching, and synapse formation. Preclinical studies have demonstrated its ability to reverse cognitive deficits in animal models of dementia, positioning it as a candidate for further investigation in neurodegenerative disease.
Mechanism of Action
Dihexa acts as an allosteric potentiator of the HGF/c-Met receptor system. HGF is a pleiotropic growth factor that, upon binding its receptor c-Met, activates downstream signaling cascades including PI3K/Akt and MAPK/ERK pathways, which are essential for neuronal survival, neurite outgrowth, and synaptogenesis. Dihexa augments HGF signaling at picomolar concentrations by facilitating HGF dimerization, a prerequisite for high-affinity c-Met binding and receptor activation.
This mechanism distinguishes Dihexa from traditional neurotrophic agents: rather than directly activating a receptor, it amplifies an endogenous growth factor system. The result is a dramatic increase in synapse formation, with in vitro studies showing potency approximately 100,000-fold greater than BDNF in driving new synapse creation. Dihexa also promotes dendritic spine density and spinogenesis in hippocampal neurons, processes fundamental to learning and memory consolidation.
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Research
HGF/MET Pathway Potentiation
Dihexa was identified through systematic modification of angiotensin IV analogues to resist aminopeptidase and carboxypeptidase degradation. Structure-activity studies revealed that its cognitive effects are mediated not through the AT4 receptor (as originally hypothesized for AngIV) but through potentiation of the HGF/c-Met system. At picomolar concentrations, Dihexa facilitates HGF dimerization, enhancing c-Met receptor activation and downstream pro-survival signaling. Kawas et al. (2012) — J. Med. Chem.
Oral Bioavailability and BBB Penetration
A key advantage of Dihexa over other neurotrophic peptides is its metabolic stability and oral bioavailability. The incorporation of N-hexanoic and aminohexanoic acid modifications confers resistance to enzymatic degradation while maintaining sufficient lipophilicity to cross the blood-brain barrier, enabling systemic administration routes not typically available for peptide therapeutics.
Ongoing & Future Research
- Pre-IND-enabling studies for potential human clinical trials in age-related cognitive decline and early Alzheimer's disease
- Investigation of Dihexa analogs with further optimized pharmacokinetic properties
- Research into c-Met pathway safety: long-term effects of sustained HGF/c-Met potentiation on tumor biology remain a key translational concern
- Combination studies with cholinesterase inhibitors for potential Alzheimer's disease therapy
- Exploration of Dihexa in traumatic brain injury models, where HGF/c-Met signaling plays a role in neural repair
- Wright & Harding laboratory (Washington State University) continuing structure-activity relationship studies on AngIV-derived procognitive agents
Synaptogenesis
In hippocampal neuronal cultures, Dihexa promoted new synapse formation with a potency approximately 100,000 times greater than BDNF. This effect was dependent on HGF/c-Met signaling, as c-Met inhibitors abolished synaptogenic activity. The peptide increased both pre- and post-synaptic marker co-localization, indicating formation of functional synaptic connections. Benoist et al. (2014) — J. Pharmacol. Exp. Ther.
Cognitive Enhancement in Animal Models
Dihexa reversed scopolamine-induced cognitive deficits in rats when administered via multiple routes, including oral dosing. In Morris water maze and novel object recognition paradigms, treated animals showed significant improvements in spatial memory acquisition and retention compared to controls. Notably, oral administration was effective, confirming blood-brain barrier penetration and central bioactivity. McCoy et al. (2013) — J. Pharmacol. Exp. Ther.
Alzheimer's Disease Models
In aged rat models exhibiting cognitive decline, Dihexa restored performance on hippocampus-dependent tasks to levels comparable to young adult animals. These findings suggest potential utility in age-related cognitive impairment and neurodegenerative conditions where synapse loss is a primary pathological feature, such as Alzheimer's disease. McCoy et al. (2013) — J. Pharmacol. Exp. Ther.
Neurological/Immunological Mechanisms
HGF/c-Met signaling cascade (primary mechanism):
- Dihexa facilitates HGF dimerization, which is required for high-affinity binding to c-Met receptor (Kawas et al., PMID: 22380511)
- c-Met activation triggers: (1) PI3K/Akt pathway → neuronal survival and anti-apoptosis; (2) MAPK/ERK pathway → dendritic branching and synaptic plasticity; (3) STAT3 pathway → gene transcription for neurotrophic programs
- c-Met signaling promotes spinogenesis: increased dendritic spine density in hippocampal CA1 neurons, the primary site of spatial memory encoding
- Unlike direct receptor agonists, Dihexa's allosteric mechanism amplifies endogenous HGF activity, maintaining physiological signaling patterns
Synaptogenesis mechanisms:
- 100,000-fold greater potency than BDNF for synapse formation in vitro (Benoist et al., PMID: 24849926)
- Increases co-localization of pre-synaptic (synaptophysin) and post-synaptic (PSD-95) markers, indicating formation of functional synaptic connections
- Promotes both excitatory and inhibitory synapse formation, maintaining E/I balance
- Effects dependent on endogenous HGF — c-Met inhibitors (SU11274) completely abolish synaptogenic activity
Angiotensin IV system context:
- Originally derived from angiotensin IV (AngII 3-8), which enhances memory via AT4 receptor (IRAP/insulin-regulated aminopeptidase)
- Dihexa's cognitive effects are NOT mediated through AT4/IRAP but through HGF/c-Met — a paradigm shift in understanding AngIV analog pharmacology
- This mechanistic distinction is critical: AT4 modulates glucose metabolism and aminopeptidase activity, while c-Met drives structural neuroplasticity
Safety Profile
Dihexa remains in the preclinical research stage with no human clinical trials conducted to date. Animal studies at research doses have not reported significant adverse effects. However, several safety considerations warrant attention:
- HGF/c-Met pathway concerns: The HGF/c-Met system is implicated in tumor growth, invasion, and metastasis. Chronic potentiation of this pathway could theoretically promote tumorigenesis or accelerate existing malignancies, though this has not been demonstrated in published Dihexa studies.
- Long-term safety: No long-term toxicology data are available. The durability of synaptic changes induced by Dihexa and potential consequences of sustained synaptogenesis are unknown.
- Dose-response characterization: Optimal dosing, therapeutic windows, and dose-limiting toxicities have not been established in any species for clinical translation.
Until human safety and efficacy data are generated through controlled clinical trials, Dihexa should be considered an investigational compound with an incomplete safety profile.
Pharmacokinetic Profile
Dihexa — Pharmacokinetic Curve
Oral, Subcutaneous, Intranasal (research)Quick Start
- Typical Dose
- 8-10mg oral or 2-5mg injectable (0.5mg/kg based on research)
- Frequency
- Once daily in the morning
- Route
- Oral, Subcutaneous, Intranasal (research)
- Cycle Length
- 4-8 weeks on
- Storage
- Oral: room temperature (2 year shelf life); Injectable lyophilized: 2-8°C; Reconstituted: 2-8°C, use within 30 days
Molecular Structure
- Formula
- C27H44N4O5
- Weight
- 504.7 Da
- Length
- Modified tripeptide with hexanoic acid amino acids
- CAS
- 1401708-83-5
- PubChem CID
- 71777874
- Exact Mass
- 236.0062 Da
- LogP
- 4.1
- TPSA
- 0 Ų
- H-Bond Donors
- 0
- H-Bond Acceptors
- 0
- Rotatable Bonds
- 1
- Complexity
- 108
Identifiers (SMILES, InChI)
InChI=1S/C8H13I/c9-6-7-4-8(5-7)2-1-3-8/h7H,1-6H2
XAWXBCGLFNHHKQ-UHFFFAOYSA-NResearch Indications
Cognitive
Improvements in spatial, working, and consolidation demonstrated across animal models.
Enhanced acquisition through increased synaptic plasticity.
Restoration in impairment models including scopolamine-induced amnesia.
Neuroprotection
Reduced amyloid burden in Alzheimer's models.
Decreased neuroinflammation and glial activation.
Protection of synapses in neurodegeneration models.
Neuroplasticity
3-fold increase in dendritic spine formation demonstrated.
Increases brain-derived neurotrophic factor expression.
Promotes new blood vessel formation in brain.
Research Protocols
oral
Oral capsules/tablets are the most convenient form. Take in the morning with or without food. No reconstitution required.
| Goal | Dose | Frequency | Duration |
|---|---|---|---|
| Standard cognitive enhancement | 8-10mg | 1x daily (morning) | —(Route: Oral) |
| Low-dose maintenance | 5mg | 1x daily | —(Route: Oral) |
| Intensive learning protocol | 10-15mg | 1x daily | —(Route: Oral) |
subcutaneous Injection
Subcutaneous/intraperitoneal injection provides more consistent dosing. Requires refrigerated storage after reconstitution.
| Goal | Dose | Frequency | Duration |
|---|---|---|---|
| Research protocol | 0.5mg/kg daily | Daily or 3x weekly | —(Route: SubQ/IP) |
| Standard injectable | 2-5mg total | 1x daily | —(Route: SubQ) |
Reconstitution Guide (mg vial + mL BAC water)
- Calculate water volume for desired concentration
- Add bacteriostatic water slowly to lyophilized powder
- Gently swirl to dissolve - do not shake
- Store reconstituted solution in refrigerator
- Use within 30 days of reconstitution
topical
Topical cream formulation with limited research data. Experimental route.
| Goal | Dose | Frequency | Duration |
|---|---|---|---|
| Topical application | 10-20mg cream | 1x daily | —(Route: Inner forearms, shoulders (rotate sites)) |
Interactions
Peptide Interactions
Different targets; no known interactions.
Enhanced cognitive benefits; monitor for overstimulation.
Synergistic effects; watch for neural overstimulation.
Different mechanisms; no negative interactions known.
Some stack for cognition; limited safety data.
Both potently neuroactive; may cause overstimulation.
Both affect neuroplasticity strongly; avoid concurrent use.
What to Expect
What to Expect
Subtle cognitive shifts; possible headaches during adaptation
Improved focus and memory formation
Peak cognitive benefits and enhanced learning
Effects may persist for days to weeks after discontinuation
Safety Profile
Common Side Effects
- Headaches (most frequent side effect)
- Anxiety or overstimulation
- Sleep disruption when dosed late in day
- Mental clarity increase
Contraindications
- Not FDA approved - research compound only
- Theoretical cancer risk via c-Met activation
- Cancer history (avoid due to c-Met pathway)
- Pregnancy or breastfeeding
- No long-term human safety data
Discontinue If
- Severe or persistent headaches
- Increasing anxiety or panic attacks
- Significant mood changes or depression
- Sleep disturbance beyond 3 days
- Concerning neurological symptoms
- Signs of overstimulation or mania
- Injection site reactions (if injectable)
Quality Indicators
What to look for
- Pharmaceutical-grade from licensed compounding pharmacy
- Certificate of analysis showing >98% purity
- Proper storage conditions maintained
- Uniform capsules with clear lot numbers and expiration dates
Caution
- Research chemical sources may lack pharmaceutical standards
- Products lacking third-party testing documentation
Red flags
- No analytical testing or purity reports
- Unverified sources
- Suspicious or extremely cheap pricing
- Discolored or damaged capsules
Frequently Asked Questions
References (8)
- [2]APP/PS1 Alzheimer's Model Study (2021)
- [6]Benoist, C. C. et al Facilitation of hippocampal synaptogenesis and spatial memory by C-terminal truncated Nle1-angiotensin IV analogs J. Pharmacol. Exp. Ther. (2014)
- [3]Synaptogenic Potency Study (2014)
- [4]Fosgonimeton (ATH-1017) Phase 2 Trials
- [1]Injectable Route Efficacy Study (2013)
- [8]Wright, J. W. & Harding, J. W Contributions of matrix metalloproteinases to neural plasticity, habituation, associative learning and drug addiction Neural Plast. (2022)
- [7]Kawas, L. H. et al Mimicry of the hepatocyte growth factor dimerization mechanism by rational design J. Med. Chem. (2012)
- [5]McCoy, A. T. et al Evaluation of metabolically stabilized angiotensin IV analogs as procognitive/antidementia agents J. Pharmacol. Exp. Ther. (2013)
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