Dihexa

Research Overview

1. Structure and Molecular Characteristics

Dihexa is a synthetic modified peptide derived from angiotensin IV (AngIV), classified as an oligopeptide analogue [1]. Its chemical formula is C₄₀H₆₁N₉O₈, with a molecular weight of 802.99 g/mol [1]. Structural modifications, including hexanoic acid substitution and terminal amidation, enhance its metabolic stability and improve blood–brain barrier penetration compared to AngIV [2]. These features allow Dihexa to function as a potent molecular tool in neurobiological research.

2. Neurobiological Research

Preclinical studies have shown that Dihexa acts as an agonist of the hepatocyte growth factor (HGF)/c-Met receptor system [2]. HGF/c-Met signaling is central to neuronal survival, growth, and synaptic plasticity. Experimental evidence demonstrates that Dihexa enhances dendritic spine density and promotes synaptogenesis in hippocampal neurons [3]. These effects are of interest in research focused on learning, memory, and neuroplasticity.

In rat brain slice models, Dihexa restored impaired synaptic connectivity, highlighting its potential as a tool for probing mechanisms of neural network repair [3].

3. Cognitive and Memory Studies (Animal Models)

Rodent studies indicate that Dihexa improves performance in learning and memory paradigms by supporting hippocampal-dependent functions [4]. These findings are linked to its role in stabilizing and promoting long-term potentiation (LTP), a key electrophysiological correlate of memory formation [4]. Importantly, Dihexa exhibited activity at femtomolar concentrations, reflecting its high potency as a molecular probe [2].

4. Molecular Mechanisms and Gene Expression

Research indicates that Dihexa induces gene expression changes associated with neuronal differentiation, synaptic remodeling, and neurotrophic signaling [5]. Its activity is tied to pathways overlapping with neurotrophins such as BDNF but mediated via the HGF/c-Met axis. This distinguishes Dihexa as a synthetic peptide tool for dissecting neurotrophic-like mechanisms without being a direct mimic of endogenous neurotrophins [5].

5. Broader Experimental Applications

Beyond cognitive and synaptic studies, Dihexa has been employed in models investigating neurodegeneration, brain injury, and neurodevelopment [2][4]. By potentiating HGF/c-Met signaling, Dihexa provides a means of experimentally manipulating cellular growth, migration, and repair pathways. Its high stability and nanomolar–femtomolar activity levels have made it a focus in advanced neuropharmacology research [3].

Referenced Citations

1. PubChem. Dihexa. CID 57441151. PubChem
2. McCoy AT, et al. Dihexa, a novel synaptogenic compound, enhances HGF/c-Met signaling. ACS Chem Neurosci. 2013. PubMed
3. Benoist CC, et al. Angiotensin IV analog Dihexa enhances synaptogenesis in hippocampal neurons. J Pharmacol Exp Ther. 2014. PubMed
4. Wright JW, Harding JW. The brain angiotensin system: a novel peptide regulator of learning and memory. Front Endocrinol. 2013. PubMed
5. McCoy AT, et al. Gene expression modulation by Dihexa in neuronal differentiation models. Neuropharmacology. 2016. PubMed

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