Semax: The ACTH(4-10) Analog in the Research Literature

Research-use-only context. This article summarizes published third-party scientific literature and laboratory practice. It is not medical advice, not a therapeutic or performance claim, and not a usage guide. US Prime Peptides products are supplied strictly for in vitro laboratory research and are not for human or veterinary use.

This article surveys the published literature on Semax, a seven-residue synthetic analog of the ACTH(4-10) region, sorted by model system: receptor-binding and cell-culture work, rodent gene-expression studies, the metal-coordination chemistry, and the Russian clinical record. It also covers the N-acetyl amidate variant and the US regulatory position.

Semax is ACTH(4-7) joined to the tripeptide Pro-Gly-Pro

Semax is the heptapeptide Met-Glu-His-Phe-Pro-Gly-Pro (one-letter code MEHFPGP), molecular formula C37H51N9O10S, molecular weight about 813.9 daltons, PubChem CID 9811102, CAS 80714-61-0. The first four residues are positions 4 to 7 of adrenocorticotropic hormone, the region of the parent hormone that does not stimulate the adrenal cortex; the C-terminal Pro-Gly-Pro is a glyproline cap that was added to slow enzymatic breakdown. The design came from the Institute of Molecular Genetics of the Russian Academy of Sciences in Moscow, and the majority of the primary literature is from that institute and its collaborators.

The methionine at position 1 is the residue most prone to oxidation in storage, and the histidine at position 3 gives the chain a metal-binding site that has been characterized in detail (see below). A 2006 Bioorganicheskaia Khimiia paper by Shevchenko and colleagues used Semax labeled with tritium on the C-terminal proline to follow it in rats and reported rapid enzymatic cleavage, with the tripeptide Pro-Gly-Pro the dominant labeled species in tissue samples. A companion 2006 paper from Zolotarev and colleagues, using evenly tritiated peptide in the presence of nerve cells, reported His-Phe-Pro-Gly-Pro and Pro-Gly-Pro as the main breakdown products, which points to N-terminal aminopeptidase attack as the main degradation route.

Semax is not an approved drug in the United States. It holds a marketing registration in the Russian Federation, where it was first registered as a medicinal product in the 1990s, which is why most of the human-use literature is in Russian-language journals. A research vial is a laboratory chemical documented by a certificate of analysis, not by any clinical record. The Semax 10 mg and Semax 30 mg listings show the lot-matched certificate format, with identity by mass spectrometry and purity by HPLC on each lot.

Binding sites and BDNF: the core cell and tissue findings

The most-cited mechanistic result is a 2006 Journal of Neurochemistry paper by Dolotov and colleagues, which reported that tritiated Semax bound to membranes isolated from rat basal forebrain in a time-dependent, specific and reversible manner. Binding required calcium ions, and the authors reported a dissociation constant of about 2.4 nanomolar and a maximal binding capacity of about 33 femtomoles per milligram of membrane protein. In the same study, a sandwich immunoassay showed higher brain-derived neurotrophic factor (BDNF) protein in basal forebrain tissue three hours after exposure, with no change in cerebellum. No receptor for Semax has been cloned or identified.

A second 2006 paper from the same group, in Brain Research, measured the hippocampal BDNF/TrkB system in rats and reported a 1.4-fold rise in BDNF protein, a 1.6-fold rise in TrkB tyrosine phosphorylation, and roughly 3-fold and 2-fold increases in exon III BDNF mRNA and TrkB mRNA. Earlier work by Dolotov in Doklady Biological Sciences (2003) reported BDNF expression changes in several rat brain regions, and a 2010 Journal of Molecular Neuroscience paper by Shadrina and colleagues compared the time course of NGF and BDNF transcripts in rat hippocampus, frontal cortex and retina and reported region- and time-specific patterns.

In pure cell culture, Grivennikov and colleagues (2008, Restorative Neurology and Neuroscience) used primary cultures of rat basal forebrain and reported roughly 1.5- to 1.7-fold higher survival of cholinergic neurons, an increase in choline acetyltransferase activity at 100 nanomolar, no change in the number of GABAergic neurons, and no effect on glial proliferation across 1 nanomolar to 10 micromolar. The same paper confirmed the stability of the peptide in culture medium by HPLC.

Transcriptome and proteome work in rat ischemia models

A large block of the modern literature is genome-wide expression profiling in rat models of cerebral ischemia, almost all from the Institute of Molecular Genetics in Moscow. The first, by Medvedeva and colleagues in BMC Genomics (2014), used permanent middle cerebral artery occlusion and microarrays, and reported that more than half of the genes whose expression changed in the presence of Semax were immune-related, with immunoglobulin and chemokine genes forming the largest groups; 24 vascular-system genes were altered at 3 hours and 12 at 24 hours. A 2017 follow-up in Molecular Genetics and Genomics extended the immune-gene analysis.

Filippenkov and colleagues (2020, Genes) switched to a transient occlusion model and RNA-Seq, identifying 394 differentially expressed genes at 24 hours relative to saline; they described suppression of inflammation-related transcripts and activation of neurotransmission-related transcripts, the opposite of the pattern produced by ischemia alone. Sudarkina and colleagues (2021, International Journal of Molecular Sciences) then measured proteins in the same model and reported higher active CREB in subcortical structures, lower MMP-9 and c-Fos in the adjacent cortex, and lower active JNK in both. Papers from 2023 to 2025 extend the comparison to related ACTH-like peptides.

Two caveats apply. The studies share one laboratory, one peptide source and one set of models, so they are internally consistent but not independently replicated. And expression profiling shows which transcripts moved, not why; the authors themselves describe the mechanism as not fully understood.

Monoamine, metal-coordination and enzyme chemistry

Eremin and colleagues (2005, Neurochemical Research) measured monoamine metabolites in rodent striatum and reported a 25 percent rise in tissue 5-hydroxyindoleacetic acid two hours after Semax, an extracellular rise to about 180 percent of baseline over one to four hours by microdialysis, and no change in dopamine or its metabolites when the peptide was given alone. The histidine-containing N-terminus also makes Semax a copper and zinc ligand. Tabbi and colleagues (2015, Journal of Inorganic Biochemistry) characterized three copper(II) complex species, with a four-nitrogen planar species dominant above pH 5, and reported lower copper-induced toxicity by MTT assay in SH-SY5Y neuroblastoma and RBE4 endothelial cells when Semax was present.

Kost and colleagues (2001, Bioorganicheskaia Khimiia) reported that both Semax and Selank inhibited enkephalin-degrading enzymes in human serum, and the 2006 Zolotarev paper attributed the Semax effect mainly to aminopeptidases. A 2025 Bulletin of Experimental Biology and Medicine paper by Kolbaev and colleagues examined intracellular calcium dynamics in cultured rat brain neurons exposed to the peptide. Behavioral rodent studies, including a 2024 European Journal of Pharmacology chronic-stress study by Inozemtseva and colleagues that measured sucrose preference, adrenal mass and hippocampal BDNF, complete the preclinical record. For the tuftsin-derived relative, see Semax vs Selank and the Selank research overview.

The N-acetyl Semax amidate variant, explained chemically

N-acetyl Semax amidate is Semax with two terminal modifications: an acetyl group on the N-terminal methionine amine and an amide in place of the C-terminal proline carboxylic acid. Acetylation removes the positive charge on the N-terminus and blocks the free amine that aminopeptidases recognize, and amidation removes the negative charge at the C-terminus. The combined effect is a molecule with the same seven-residue backbone, a mass about 41 daltons higher (plus 42 for acetyl, minus 1 for the amide), different HPLC retention, and no free N-terminal amine for metal coordination. A guide to reading those caps on a label is in How to Read a Peptide Sequence.

The published chemistry of the acetylated form comes from Magri and colleagues (2016, Journal of Inorganic Biochemistry). They showed that acetylation changes the copper(II) complex from a four-nitrogen chromophore to a nitrogen-three/oxygen chromophore with a weak methionine sulfur contact, shifts the redox potential to a more positive value, and makes the complex reactive toward ascorbate. In their SH-SY5Y assay, the acetylated peptide no longer reduced copper-induced toxicity, which the authors attributed to the loss of the free N-terminus. Zinc binding was comparable for both forms. A 2013 Doklady Biological Sciences note by Shevchenko and colleagues examined the proteolytic stability of acetyl-Semax in biological media, which is the stated reason for the cap. Searches of PubMed for the doubly modified acetyl-amidate form itself return no biological characterization; the vendor name describes a chemical structure, not a studied compound. The N-Acetyl Semax Amidate liquid spray 10 mg listing documents the labeled mass and lot certificate for that structure, and the identity line on a certificate for this variant should show the modified mass, not 813.9.

The human record and the regulatory position

Human-use data exist because of the Russian registration, and they are almost entirely in Russian-language journals. A 2018 paper by Gusev and colleagues in Zhurnal Nevrologii i Psikhiatrii imeni S.S. Korsakova followed 110 adults after ischemic stroke, divided into early and late rehabilitation groups with and without Semax, and reported plasma BDNF levels, a motor-performance scale and the Barthel index over the study period. Lebedeva and colleagues (2018, Bulletin of Experimental Biology and Medicine) reported functional MRI measures of the default mode network in healthy volunteers, and a 2020 Doklady Biological Sciences paper by Panikratova and colleagues applied a connectomic analysis to Semax and Selank. These are open or small comparative designs, none is a blinded, placebo-controlled registration trial, and none has been replicated outside Russia.

Semax is not approved by the FDA and is not an approved medicine in the European Union. In the United States it is sold as a research chemical, and the paperwork that matters for a laboratory buyer is the lot-matched certificate: identity by mass spectrometry at the expected mass, HPLC purity, net peptide content, endotoxin and sterility. Because methionine can oxidize, an early-eluting shoulder on the chromatogram is worth checking against the certificate's impurity list (see How to Read an HPLC Chromatogram).

Frequently Asked Questions

What is Semax and where did it come from?

Semax is the synthetic heptapeptide Met-Glu-His-Phe-Pro-Gly-Pro, built from positions 4 to 7 of ACTH with a Pro-Gly-Pro cap. It was designed at the Institute of Molecular Genetics of the Russian Academy of Sciences, and most of its primary literature comes from that institute.

Is Semax an approved drug in the United States?

No. Semax is not approved by the FDA and has no US monograph. It holds a Russian medicinal registration dating to the 1990s, which is why its human-use studies are mostly published in Russian-language journals. In the US it is sold strictly as a research chemical.

What does the research say Semax does to BDNF?

Two 2006 papers from the Dolotov group reported higher BDNF protein in rat basal forebrain and a 1.4-fold rise in rat hippocampal BDNF with increased TrkB phosphorylation and mRNA. These are rodent tissue measurements from a single laboratory; the binding site that would explain them has not been cloned or identified.

What is N-acetyl Semax amidate?

It is Semax with an acetyl group on the N-terminus and an amide at the C-terminus, which removes both terminal charges and blocks aminopeptidase attack. The 2016 Magri paper showed the acetyl cap changes the copper chemistry and removed the cell-protection seen with the free amine; the doubly modified form itself has no published biological characterization.

Citations

1. Dolotov OV, Karpenko EA, Seredenina TS, et al. Semax, an analogue of adrenocorticotropin (4-10), binds specifically and increases levels of brain-derived neurotrophic factor protein in rat basal forebrain. J Neurochem. 2006;97 Suppl 1:82-86. PMID 16635254
2. Dolotov OV, Karpenko EA, Inozemtseva LS, et al. Semax, an analog of ACTH(4-10) with cognitive effects, regulates BDNF and trkB expression in the rat hippocampus. Brain Res. 2006;1117:54-60. PMID 16996037
3. Dolotov OV, Seredenina TS, Levitskaya NG, et al. The heptapeptide SEMAX stimulates BDNF expression in different areas of the rat brain in vivo. Dokl Biol Sci. 2003;391:292-295. PMID 14556513
4. Shadrina M, Kolomin T, Agapova T, et al. Comparison of the temporary dynamics of NGF and BDNF gene expression in rat hippocampus, frontal cortex, and retina under Semax action. J Mol Neurosci. 2010;41:30-35. PMID 19662538
5. Grivennikov IA, Dolotov OV, Zolotarev YA, et al. Effects of behaviorally active ACTH (4-10) analogue - Semax on rat basal forebrain cholinergic neurons. Restor Neurol Neurosci. 2008;26:35-43. PMID 18431004
6. Medvedeva EV, Dmitrieva VG, Povarova OV, et al. The peptide semax affects the expression of genes related to the immune and vascular systems in rat brain focal ischemia: genome-wide transcriptional analysis. BMC Genomics. 2014;15:228. PMID 24661604
7. Filippenkov IB, Stavchansky VV, Denisova AE, et al. Novel Insights into the Protective Properties of ACTH(4-7)PGP (Semax) Peptide at the Transcriptome Level Following Cerebral Ischaemia-Reperfusion in Rats. Genes (Basel). 2020;11:681. PMID 32580520
8. Sudarkina OY, Filippenkov IB, Stavchansky VV, et al. Brain Protein Expression Profile Confirms the Protective Effect of the ACTH(4-7)PGP Peptide (Semax) in a Rat Model of Cerebral Ischemia-Reperfusion. Int J Mol Sci. 2021;22:6179. PMID 34201112
9. Eremin KO, Kudrin VS, Saransaari P, et al. Semax, an ACTH(4-10) analogue with nootropic properties, activates dopaminergic and serotoninergic brain systems in rodents. Neurochem Res. 2005;30:1493-1500. PMID 16362768
10. Tabbi G, Magri A, Giuffrida A, et al. Semax, an ACTH4-10 peptide analog with high affinity for copper(II) ion and protective ability against metal induced cell toxicity. J Inorg Biochem. 2015;142:39-46. PMID 25310602
11. Magri A, Tabbi G, Giuffrida A, et al. Influence of the N-terminus acetylation of Semax, a synthetic analog of ACTH(4-10), on copper(II) and zinc(II) coordination and biological properties. J Inorg Biochem. 2016;164:59-69. PMID 27586814
12. Shevchenko KV, Nagaev IY, Andreeva LA, Shevchenko VP, Myasoedov NF. Stability of Semax acetyl to proteolysis in various biological media. Dokl Biol Sci. 2013;449:110-112. PMID 23652441
13. Shevchenko KV, Nagaev IY, Alfeeva LY, et al. Kinetics of Semax penetration into the brain and blood of rats after its intranasal administration [in Russian]. Bioorg Khim. 2006;32:64-70. PMID 16523722
14. Zolotarev YA, Dadayan AK, Dolotov OV, et al. Evenly tritium-labeled peptides and their in vivo and in vitro biodegradation [in Russian]. Bioorg Khim. 2006;32:183-191. PMID 16637290
15. Kost NV, Sokolov OY, Gabaeva MV, et al. Semax and selank inhibit the enkephalin-degrading enzymes from human serum [in Russian]. Bioorg Khim. 2001;27:180-183. PMID 11443939
16. Inozemtseva LS, Yatsenko KA, Glazova NY, et al. Antidepressant-like and antistress effects of the ACTH(4-10) synthetic analogs Semax and Melanotan II on male rats in a model of chronic unpredictable stress. Eur J Pharmacol. 2024;984:177068. PMID 39442746
17. Kolbaev SN, et al. The Effect of Peptide Semax, an ACTH(4-10) Analogue, on Intracellular Calcium Dynamics in Rat Brain Neurons. Bull Exp Biol Med. 2025;179:416-420. PMID 41171324
18. Gusev EI, Martynov MY, Kostenko EV, Petrova LV, Bobyreva SN. The efficacy of semax in the treatment of patients at different stages of ischemic stroke [in Russian]. Zh Nevrol Psikhiatr Im S S Korsakova. 2018;118(3 Pt 2):61-68. PMID 29798983
19. Lebedeva IS, et al. Effects of Semax on the Default Mode Network of the Brain. Bull Exp Biol Med. 2018;165:653-656. PMID 30225715
20. Panikratova YR, et al. Functional Connectomic Approach to Studying Selank and Semax Effects. Dokl Biol Sci. 2020;490:9-11. PMID 32342318

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