Encyclopedia

Dihexa is a small-molecule peptide derivative of angiotensin IV, developed at Washington State University as a potentiator of hepatocyte growth factor (HGF) signaling through the c-Met receptor, reported to drive synaptogenesis at extremely low concentrations in preclinical assays. It has zero completed human clinical trials, and its two foundational research papers have serious, disclosed integrity issues: one carries a formal Expression of Concern and the other was retracted in 2025. It is not FDA-approved.

Dihexa (N-hexanoic-Tyr-Ile-(6) aminohexanoic amide, development code PNB-0408) is a metabolically stabilized peptidomimetic derived from angiotensin IV, designed to act as an allosteric potentiator of HGF binding to its c-Met receptor rather than a direct receptor agonist. The original in vitro synaptogenesis assays (McCoy et al. 2013; Benoist et al. 2014, both from the same Washington State University research group) reported activity at picomolar concentrations, described in secondary sources as many orders of magnitude more potent than BDNF at the same in vitro endpoint -- a claim that reflects a narrow molar comparison at one assay endpoint, not a validated measure of clinical potency. This evidence base has a major integrity caveat: the McCoy 2013 paper carries a published Expression of Concern, and the Benoist 2014 follow-up paper was formally retracted in 2025. An independent 2021 replication by an unrelated group (Sun et al.) provides some supporting evidence from outside the original lab, but Dihexa has no completed human clinical trials. A related compound advancing the same HGF/c-Met mechanism into clinical development, fosgonimeton (ATH-1017), has completed phase 1 human pharmacokinetic and safety studies -- this is a distinct, separately-developed molecule and its human data should not be read as clinical validation of dihexa itself.

Mechanism of Action

Reported to act as an allosteric potentiator of hepatocyte growth factor (HGF) binding to its receptor tyrosine kinase, c-Met, amplifying endogenous HGF signaling rather than acting as a direct agonist. In preclinical models this HGF/c-Met potentiation is proposed to drive synaptogenesis (new dendritic spine and synapse formation). Reported potency claims versus BDNF derive from a narrow in vitro comparison and should not be read as an indicator of relative clinical effect.