Dihexa (PNB-0408; N-hexanoic-Tyr-Ile-(6) aminohexanoic
amide)

The Discovery

The Forgotten Angiotensin Connection

How two WSU scientists found cognitive power in an ancient hormone

In the 1990s, Joseph Harding and John Wright at Washington State University were studying the renin-angiotensin system. Most researchers focused on blood pressure control. But Wright and Harding noticed something odd: angiotensin IV seemed to sharpen memory in animal brains. It was counterintuitive. Why would a blood-regulating peptide enhance cognition?

Year after year, they tested angiotensin IV in cognitive tasks. Rats learned faster. Memory improved. The effect was consistent and surprising. But there was a major problem: angiotensin IV broke down too quickly in the body. It couldn't cross the blood-brain barrier. Its natural form was useless for therapy.

The scientists faced a choice. Give up, or redesign the molecule. They chose to redesign it. Starting in the early 2000s, they began systematic structure-activity relationship studies. Which parts of the angiotensin IV sequence were essential? Which could be modified? They methodically tested variants, searching for stability and brain penetration.

The Breakthrough

An Insanely Active Molecule Emerges

Dihexa shows 10 million times the synapse-building power of BDNF

In 2012-2013, McCoy and the WSU team synthesized a radically modified angiotensin IV analog. They added hexanoic acid chains to both termini. They replaced some amino acids with metabolically stable variants. The result was dihexa—a compound no longer recognizable as an angiotensin, but built on its skeleton.

Testing began immediately. Dihexa crossed the blood-brain barrier. It survived stomach acid. It resisted enzymatic breakdown. When they administered it orally to rats, cognitive enhancement followed. Scopolamine, a drug that erases memory, no longer worked. The rats remembered despite the challenge drug. In aged animals showing natural cognitive decline, dihexa restored lost memory capacity. Something remarkable was happening.

But the researchers wanted to understand the mechanism. They tested whether the old AT4 receptor was responsible. It wasn't. Something else was driving the effect. Through clever pharmacological experiments, they discovered the true target: hepatocyte growth factor. Dihexa bound HGF with extraordinary affinity. Sixty-five picomolar. The binding was tighter than most antibodies achieve. This binding potentiated HGF signaling at the c-Met receptor on brain cells. And when c-Met activated, something magical happened: neurons sprouted new dendritic spines. Synapses multiplied.

The Trials

From Laboratory Success to Real-World Testing

Translating stunning preclinical results into clinical promise

The WSU team's findings attracted attention from neuroscientists worldwide. Here was a small peptide that rewired the brain with stunning efficiency. It boosted memory in aged animals. It reversed drug-induced memory loss. It was orally active—a huge advantage over intravenous growth factors. M3 Biotechnology, founded to commercialize the technology, began planning clinical trials.

But preclinical success doesn't guarantee human efficacy. The jump from rats to people is enormous. Rats live two years. Humans live eighty. Rat brains are simpler. Human brains contain orders of magnitude more complexity. Dosing strategies that work in animals often fail in humans. Side effects emerge. Efficacy shrinks. Every researcher knew these sobering statistics.

M3 Biotechnology pursued development of related compounds, particularly fosgonimeton, designed for clinical trial advancement. The strategy was sound: validate the HGF/c-Met mechanism in human patients. Start with mild cognitive impairment or Alzheimer's disease—conditions with huge unmet need. Measure cognitive outcomes. Safety remained paramount. The researchers had seen promising compounds fail due to unexpected toxicity.

Meanwhile, the internet and biohacker communities discovered dihexa research online. Some people obtained the compound through research chemical suppliers and self-administered it. Enthusiastic anecdotal reports emerged. But anecdotes aren't evidence. Placebo is powerful. Expectation shapes perception. The scientific community watched with cautious skepticism.

The Crisis

The Translation Obstacle and the Hype-Science Tension

Bridging the gap between preclinical promise and clinical reality

By 2018, dihexa faced a critical challenge: it remained in preclinical development. No human clinical trials had been published. The animal data was remarkable, but animal data is inherently limited. Rodent models of Alzheimer's don't fully replicate human disease. Their brains don't develop tau tangles and amyloid plaques with human complexity. They don't suffer decades of cognitive decline. They live two years, not eighty.

The regulatory pathway loomed large. The FDA demands extensive preclinical toxicology, pharmacokinetics, and biodistribution data before approving human trials. Months of studies. Millions of dollars. Risk assessments. Manufacturing standards. Quality control. GMP compliance. The process is lengthy by design—to protect human subjects. But the length and expense meant that promising compounds often stalled.

Meanwhile, the online nootropics community had created a problem. Dihexa was being sold as a supplement. People bought it from research chemical suppliers. Social media influencers touted it as a cognitive enhancer. Reddit communities swapped dosing protocols. Blog posts claimed miraculous memory restoration. This hype disconnected from rigorous science created a dangerous divide. People expected fast results. Science required patience. People wanted universal dosing. Science knew responses vary. The enthusiasm, while understandable, clouded the actual scientific picture.

Joseph Harding and his team faced a dilemma. They had discovered something genuinely promising. But premature hype could damage credibility. If uncontrolled self-experimentation led to adverse events, regulatory scrutiny would intensify. They had to maintain scientific rigor while public excitement mounted.

The Legacy

A Paradigm Shift in Neuroplasticity Science

How dihexa changed our understanding of brain growth and aging

Despite remaining in preclinical stages, dihexa revolutionized how neuroscientists think about neuroregeneration. Before dihexa, most researchers pursued big-name growth factors like BDNF and NGF. These are powerful but hard to deliver and produce side effects. Dihexa suggested a radically different approach: identify natural growth factor partners, then design small peptides that amplify their signals.

The HGF/c-Met axis became a focus of intense research after dihexa's mechanism was published. Scientists worldwide began investigating how to manipulate this pathway. Other groups designed HGF mimetics. Researchers explored c-Met signaling in neuroinflammation, brain injury, and neurodegenerative disease. Dihexa opened doors that were previously locked.

For cognitive aging specifically, dihexa provided a proof-of-concept: age-related decline is reversible. Aged animals showed recovered memory and learning when treated with dihexa. This challenged the assumption that cognitive aging was inevitable and unchangeable. If a small molecule could restore cognitive function in old rats, perhaps human cognitive aging wasn't a one-way street. This philosophical shift—from passive acceptance to active reversal—shaped research priorities for the next decade.

Today, dihexa remains a research tool and symbol of possibility. Clinical trials with fosgonimeton and related compounds may eventually translate the promise to human patients. But even if dihexa itself never reaches the clinic, its scientific legacy endures. It demonstrated that small peptides can achieve exquisite molecular specificity. It showed that brain growth is possible at any age. It proved that angiotensin IV—an old, humble blood-pressure hormone—contained hidden secrets. Most importantly, it inspired a generation of researchers to think differently about neuroregeneration.