Semax – Synthetic ACTH(4–10) Analog with Neurotropic and Nootropic Properties

Chemical Identity

Chemical Name: L-Methionyl-L-α-glutamylhistidyl-L-phenylalanyl-L-prolylglycyl-L-proline
Synonyms: Semax; MEHFPGP; ACTH(4–10) analog
Molecular Formula: C₃₇H₅₁N₉O₁₀S
Molecular Weight: 813.93 g/mol
CAS Number: 80714-61-0
Sequence: Met-Glu-His-Phe-Pro-Gly-Pro
Structure Type: Synthetic heptapeptide derived from the adrenocorticotropic hormone (ACTH) fragment (4–10)

Pharmacological Classification

Semax is a **non-hormonal neuropeptide** and analog of ACTH(4–10), developed to exhibit **neuroprotective**, **nootropic**, and **neurorestorative** properties without glucocorticoid stimulation. It is approved in Russia for use in stroke, optic nerve ischemia, cognitive disorders, and neurodegeneration.

Mechanism of Action

• BDNF Induction: Upregulates brain-derived neurotrophic factor and TrkB receptor signaling, especially in hippocampal and cortical neurons.
• Monoamine Modulation: Enhances dopaminergic and serotonergic tone via regulation of tyrosine hydroxylase and monoamine oxidase expression.
• NF-κB Suppression: Inhibits pro-inflammatory cytokines (e.g., TNF-α, IL-1β), particularly in ischemic or oxidative injury.
• NRF2 Antioxidant Pathway: Increases expression of endogenous antioxidant enzymes (e.g., SOD2, GPx, catalase).
• Neurovascular Support: Improves angiogenesis, neurogenesis, and mitochondrial stabilization in damaged neural tissue.
• Epigenetic Remodeling: Alters expression of neuroplasticity- and stress-related genes via chromatin and histone modifications.

Neurotropic Signaling Summary

Target Pathway	Effect of Semax	Receptor or System
BDNF/TrkB	Upregulation of neurotrophic signaling	TrkB (tyrosine kinase receptor)
NF-κB	Suppression of inflammatory transcription	Non-GPCR intracellular pathway
NRF2	Antioxidant gene activation	Nuclear transcription factor
Dopamine/Serotonin Systems	Elevated monoaminergic tone	Transporter modulation and synthesis control

β-Arrestin Recruitment

Semax is not a GPCR agonist and does not exhibit β-arrestin recruitment. Its mechanism is nuclear, enzymatic, and transcriptional rather than membrane-receptor-mediated.

Pharmacokinetics (Non-Dosing)

• Route: Intranasal (primary), subcutaneous (investigational)
• Bioavailability: ~65–75% via intranasal administration
• Plasma Half-Life: ~20 minutes (short); however, downstream effects persist 12–24 hours
• Distribution: Rapid CNS penetration via olfactory epithelium
• Excretion: Primarily renal via peptidase-cleaved fragments

Biological Effects

Improves cognitive function, learning, attention, and memory. Promotes recovery after ischemic stroke and traumatic brain injury. Enhances neuronal survival, angiogenesis, and synaptogenesis. Reduces anxiety and stress markers in preclinical models without sedation.

Stability and Storage

• Form: Lyophilized acetate salt
• Solubility: Water, PBS, or dilute acidic buffers (pH 4.5–6.0)
• Storage: –20°C (lyophilized); 4°C reconstituted (≤14 days)
• Handling: Avoid light, moisture, and freeze-thaw cycles

References

1. Dolotov OV, et al. J Neurochem. 2006;97(Suppl 1):82–86.
2. Andreeva LA, et al. Neurosci Behav Physiol. 2014;44(3):267–271.
3. Gulyás B, et al. Cell Mol Neurobiol. 2020;40(5):689–705.
4. Ashmarin IP, et al. Physiol Behav. 1995;57(4):819–823.
5. PubChem CID 9811102 – Semax. PubChem