N-Acetyl Semax

A free-acid N-acetylated analog of Semax, the Russian intranasal nootropic, capped at the N-terminus while retaining the native C-terminal carboxyl; the capped peptide itself has just two published papers, both chemistry-led, and no clinical record.

Also referenced as: NA-Semax, N-Acetyl Semax Free Acid, Acetyl-Semax, Ac-Semax, Ac-Met-Glu-His-Phe-Pro-Gly-Pro-OH

Also appears in: Neuroprotection

What is N-Acetyl Semax?

N-Acetyl Semax is the heptapeptide Semax (Met-Glu-His-Phe-Pro-Gly-Pro) carrying an acetyl group on its N-terminal methionine, with the native C-terminal carboxylic acid left intact — Ac-Met-Glu-His-Phe-Pro-Gly-Pro-OH, C39H53N9O11S, molecular weight roughly 856.0 (PubChem CID 172107353). The parent is a synthetic analog of the adrenocorticotropic hormone fragment ACTH(4-10), built from ACTH(4-7) plus a C-terminal Pro-Gly-Pro tail (C37H51N9O10S, molecular weight 813.93, CAS 80714-61-0), and it is a registered intranasal prescription drug in Russia.

Because the C-terminus is unmodified, the research market describes this as the “free acid” member of the acetylated Semax family, and it is a different molecule from N-Acetyl Semax Amidate, which replaces that terminal –OH with –NH2. Capping an N-terminus is a routine peptide-chemistry tactic against aminopeptidases, and it is the reason the capped forms are listed separately from plain Semax.

How it works

Only two published papers address the acetylated peptide itself: a metal-coordination study and a short proteolysis communication. Neither is a pharmacology study, and the only biological readout in either is a cell-viability assay. The mechanisms below belong to unmodified Semax, whose sequence N-Acetyl Semax retains:

• BDNF, trkB, and a specific brain binding site — tritium-labeled Semax bound rat basal forebrain membranes in a time-dependent, specific, reversible and calcium-dependent manner, with a dissociation constant of 2.4 ± 1.0 nM, and intranasal Semax at 50 and 250 µg/kg raised BDNF protein in the basal forebrain, but not the cerebellum, within three hours (Dolotov et al., Journal of Neurochemistry, 2006, 97 Suppl 1:82–86). In the hippocampus a single 50 µg/kg dose produced a 1.4-fold rise in BDNF protein and a 1.6-fold rise in trkB tyrosine phosphorylation (Dolotov et al., Brain Research, 2006, 1117(1):54–60)
• Neurotrophin gene induction in glia — in glial cultures from newborn rat basal forebrain, Semax raised BDNF mRNA roughly eightfold and NGF mRNA roughly fivefold within 30 minutes (Shadrina et al., Neuroscience Letters, 2001, 308(2):115–118)
• Monoaminergic modulation — striatal 5-HIAA tissue content rose 25% two hours after dosing and extracellular 5-HIAA rose to 180% over one to four hours, measured after intraperitoneal Semax at 0.15 mg/kg; Semax alone did not change dopamine, but given 20 minutes before amphetamine it sharply amplified amphetamine’s effect on extracellular dopamine and on locomotion (Eremin et al., Neurochemical Research, 2005, 30(12):1493–1500). FDA’s 2026 review treated that amphetamine interaction as an abuse-potential question rather than a therapeutic finding
• Enkephalin-degrading enzyme inhibition — Semax inhibited the enkephalin-degrading enzymes of human serum with an IC50 near 10 µM, more potently than the reference peptidase inhibitors tested alongside it (Kost et al., Bioorganicheskaia Khimiia, 2001, 27(3):180–183)
• What the acetyl cap is documented to change — capping the N-terminal amine removes copper’s primary anchor. The Cu(II) complex shifts from a CuN4 chromophore to a distorted CuN3O one with a more positive formal redox potential, and unlike unmodified Semax the acetylated peptide did not protect SH-SY5Y neuroblastoma cells against Cu(II) toxicity, which the authors attributed to the crucial role of the free N-terminal NH2. Zinc binding and zinc uptake were comparable for both forms (Magrì et al., Journal of Inorganic Biochemistry, 2016, 164:59–69)

The stability rationale for the capped forms rests on the parent’s metabolism. In rat blood and serum a bestatin-sensitive aminopeptidase removes the first and second N-terminal residues, Met then Glu, and accounts for roughly a third to a half of total degrading activity (Potaman et al., Biochemical and Biophysical Research Communications, 1991, 176(2):741–746); an inhibitor study put bestatin-sensitive activity as high as 66%, with puromycin covering about 33% and the ACE inhibitor lisinopril about 15% (Potaman et al., Peptides, 1993, 14(3):491–495). Replacing the N-terminal Met with Ala, Gly, or Thr measurably slowed aminopeptidase attack (Shevchenko et al., Bioorganicheskaia Khimiia, 2011, 37(4):475–482). Uniformly tritium-labeled Semax exposed to rat plasma membranes and basal forebrain cell cultures lost Met-Glu from one end and Gly-Pro from the other (Zolotarev et al., Amino Acids, 2006, 30(4):403–408).

That is the case for this particular variant, and it is a better case than the acetylated Selank analogs can make: Semax is attacked first at the N-terminus, so blocking that end addresses the dominant documented route. What the free acid leaves open is the loss of the C-terminal Gly-Pro — the route the amidated version is designed to close. A short Russian communication reports on the acetylated peptide’s proteolytic stability across biological media, indexed as “Stability of Semax acetyl to proteolysis in various biological media” (Shevchenko et al., Doklady Biological Sciences, 2013, 449:110–112). But that record carries no abstract, the full text is not openly available, and its title does not state which C-terminal form was tested — so neither the size of any advantage nor whether it was measured on the free acid at all can be checked against the source. Whether either terminal modification changes activity, exposure, or duration in a living animal has never been published.

Research status

The acetylated free acid has almost no research record of its own. A PubMed phrase search returns zero records for “N-acetyl semax” as of August 2026 — the phrase is not in the index — and exactly one record mentions “Ac-Semax,” the 2016 copper and zinc coordination study described above. Broadening the search to any pairing of Semax with acetylation returns only that study and the 2013 proteolysis note. ClinicalTrials.gov lists no registered study of Semax in any form.

The evidence usually cited for this compound belongs to unmodified Semax and is almost entirely Russian:

• Gusev et al. (1997) gave Semax to 30 patients in the acute period of hemispheric ischemic stroke and compared them with 80 patients on conventional therapy, using clinical rating scales, EEG mapping and somatosensory evoked potentials. The authors reported faster regression of general cerebral and focal deficits, especially motor ones, at daily doses of 12 mg in moderate strokes and 18 mg in severe strokes (Zhurnal Nevrologii i Psikhiatrii imeni S.S. Korsakova, 97(6):26–34). The comparison was not randomized or blinded
• Gusev, Martynov et al. (2018) followed 110 post-stroke patients split by rehabilitation timing and by whether they received semax, reporting higher plasma BDNF and faster Barthel index recovery in the semax subgroups (Zhurnal Nevrologii i Psikhiatrii imeni S.S. Korsakova, 118(3 Pt 2):61–68). Open-label, with no placebo arm
• Polunin et al. (2000) added Semax to standard therapy in optic nerve disease across three groups — nasal drops, endonasal electrophoresis, and control — and reported improvement in visual acuity, visual field, and the electrical sensitivity of the optic nerve (Vestnik Oftalmologii, 116(1):15–18)
• Negative results are part of the record. In an open-label study of 27 patients with motor neuron disease, 1% intranasal semax did not influence the course of chronic partial denervation on needle EMG or the clinical measures; only the total quality-of-life score improved, through emotional state and motivation (Serdiuk et al., Zhurnal Nevrologii i Psikhiatrii imeni S.S. Korsakova, 2007, 107(4):29–39)
• The analgesia study behind the compounding nomination also failed on its own terms. A single 0.5 mg/kg intranasal dose produced no change in pain characteristics, sensation or pain thresholds, or trigeminal somatosensory evoked potentials in patients with typical trigeminal neuralgia, and the authors concluded that semax does not exhibit analgesic activity by itself; in the 12 migraine subjects, 4 reported headache cessation at 90–120 minutes and the remaining 8 only partial relief (Koroleva et al., Bulletin of Experimental Biology and Medicine, 1996, 122:1107–1109). FDA characterized the study as small, unblinded, uncontrolled and insufficiently described

For its July 2026 meeting, FDA evaluated semax (free base) and semax acetate for the section 503A bulk drug substances list, on its own initiative after both nominations were withdrawn. The agency’s briefing document concluded that a balancing of the criteria weighed against adding either substance: neither was considered well characterized, no human pharmacokinetic study could be found for any route of administration, the only route discussed in the clinical literature was intranasal, no clinical immunogenicity or aggregation data existed, and the effectiveness evidence for the nominated uses — cerebral ischemia, migraine, and trigeminal neuralgia — was judged insufficient, with FDA-approved therapies already available for all three. FDA also set aside the Russian-language stroke literature, which had not been submitted with the verified English translation its regulations require. On July 24, 2026, the Pharmacy Compounding Advisory Committee nevertheless voted 8–5 to recommend inclusion for those uses. That vote is advisory rather than an agency action, final placement on the list would require separate rulemaking, no final FDA determination had been published at the time of writing, and none of the evaluation covered the N-acetylated analog.

Semax itself is registered in Russia and sold there as 0.1% and 1% nasal drops. Neither Semax nor any acetylated variant has ever been FDA-approved.

Common dosage forms

Research suppliers list N-Acetyl Semax as a lyophilized powder in sealed vials at small milligram fills for reconstitution, and as pre-mixed intranasal spray bottles. The nasal format mirrors the only route the parent’s human literature covers — FDA found no published clinical use of semax by any other route — and the rodent uptake work runs the same way: labeled Semax given intranasally to rats reached the brain within two minutes, with about 0.093% of the administered radioactivity per gram of brain tissue and roughly 80% of that still intact peptide rather than metabolites (Shevchenko et al., Bioorganicheskaia Khimiia, 2006, 32(1):64–70). Free-acid and amidated versions are routinely sold side by side under nearly identical names, and the compound is frequently packaged alongside the acetylated Selank analogs. Compounding nominations for the parent proposed intranasal spray and subcutaneous injection at 1,000 and 7,500 µg/mL, but no FDA-approved product exists, semax is not on the 503A bulks list, and the acetylated analog was not among the substances nominated or evaluated — so there is no licensed US compounding route for any of them. This section describes formats only and is not dosing guidance.

Key considerations

• Free acid versus amidate is one terminal group, and neither is documented. N-Acetyl Semax ends in a carboxyl (–COOH, C39H53N9O11S, molecular weight about 856.0, PubChem CID 172107353); N-Acetyl Semax Amidate ends in a carboxamide (–CONH2, C39H54N10O10S, about 855.0, CID 172638603) — an oxygen traded for a nitrogen plus a hydrogen, leaving the amidate roughly 1 Da lighter. Neither has been characterized in any published pharmacokinetic, efficacy, or immunogenicity study, so the stability advantages attributed to each are design rationale, not measured results. A 1 Da gap is also not something a low-resolution mass spectrometer reliably resolves.
• “Semax acetate” and “N-acetyl semax” are different substances. Semax acetate is the acetate salt of the unmodified peptide (C39H55N9O12S, molecular weight about 874.0, CAS 2828433-33-4); N-acetyl semax is a covalent modification of the peptide itself. FDA’s 2026 evaluation and the advisory committee vote that followed covered the free base and the acetate salt, not the acetylated analog. Copy that borrows the compounding news for the capped version is describing a different molecule.
• The one measured biological consequence of capping this peptide is a loss, not a gain. The single published biological comparison found that acetylation abolished Semax’s protection of neuroblastoma cells against copper toxicity, because the free N-terminal amine is what coordinates the metal (Magrì et al., 2016). Separately, the specific, saturable brain binding site that anchors the BDNF account of Semax has never been tested with the acetylated peptide, so whether the cap preserves it is unknown.
• Human safety data is thin, route-specific, and none of it involves this variant. FDA found no human pharmacokinetic data for semax by any route, no clinical immunogenicity or aggregation studies, and a single adverse-event report in FAERS — a consumer who reported ocular pain and burning after using 0.1% nasal drops bought online, with hospitalization and symptoms unresolved a year later. The agency also raised a bleeding-risk question from reported antithrombotic activity, and flagged immunogenicity risk from aggregation and peptide-related impurities for both injectable and nasal-spray presentations.
• Naming in this market is unreliable. “NA-Semax,” “N-Acetyl Semax,” “Semax Amidate,” and “N-Acetyl Semax Amidate” denote at least three different molecules and are used interchangeably by sellers. PubChem resolves the plain-language name “N-acetyl semax” to the amidate entry, while the free acid is indexed only under its written sequence. A certificate of analysis reporting the observed mass, or the sequence written out with its terminal group, is the only reliable way to establish which one a given vial contains.