Semax: Discovery and Regulatory History

Introduction

Semax (Met-Glu-His-Phe-Pro-Gly-Pro) is a synthetic heptapeptide with a developmental history rooted in Soviet-era academic pharmacology. Its origins trace to a research program at the Institute of Molecular Genetics of the Russian Academy of Sciences, where a systematic effort to design a stabilized analog of behaviorally active ACTH fragments began in the late 1970s. This article provides a historical account of Semax's discovery, scientific development, regulatory milestones in Russia, and the trajectory of the research literature from the 1980s to the present.

Discovery Period: Soviet Melanocortin Research (Late 1970s to Early 1980s)

The scientific foundation for Semax lies in work on the behavioral pharmacology of adrenocorticotropic hormone (ACTH) and its peptide fragments conducted during the 1960s and 1970s. Researchers in multiple countries established that short N-terminal fragments of ACTH retained behavioral activity in rodent learning and memory models — independent of the endocrine effects of full-length ACTH on the adrenal cortex. The ACTH(4-10) segment (Met-Glu-His-Phe-Pro-Gly-Pro in native ACTH numbering) was identified as the minimal sequence sufficient for measurable neuromodulatory activity in these paradigms.

Soviet peptide pharmacology developed substantial institutional capacity during the 1970s at several institutes of the Russian Academy of Sciences. In the late 1970s, a research program was initiated at the Institute of Molecular Genetics under the scientific direction of Academician Nikolai Fedorovich Myasoedov, in collaboration with Academician Igor Pavlovich Ashmarin of Moscow State University. The program's stated goal was to develop a clinically usable analog of the behaviorally active ACTH fragment — one that would resist rapid enzymatic degradation in vivo [1]. The broader Russian Academy of Sciences peptide program that produced Semax also gave rise to other compounds developed across overlapping institutional periods; the history of Epithalon illustrates the parallel trajectory of another Russian Academy neuropeptide from the same research generation.

The critical design insight was that the minimal pharmacophore resided in the tetrapeptide ACTH(4-7) — the sequence Met-Glu-His-Phe — while the naturally occurring ACTH(4-10) was rapidly cleaved by carboxypeptidases present in serum. By appending a Pro-Gly-Pro tripeptide to the C-terminus of the active fragment, the Myasoedov-Ashmarin group created a molecule with substantially extended resistance to enzymatic degradation, as later confirmed in published enzymatic studies [2]. The resulting heptapeptide was designated Semax.

A 1997 review article by Ashmarin, Nezavibatko, and Myasoedov, published in the Russian journal Zhurnal Vysshei Nervnoi Deyatelnosti, surveyed 15 years of work on Semax from initial synthesis through clinical evaluation, constituting the primary published historical account of the compound's origins [1]. That review is cited in subsequent literature as the foundational document of the compound's development arc.

Early Research Program (1980s to Early 1990s)

Following initial synthesis, Semax underwent a preclinical characterization program within Russian academic and governmental research institutions. Behavioral pharmacology studies in rodents — examining maze learning, conditioned avoidance, and spatial memory — formed the core of the early research, conducted under the Soviet institutional framework of coordinated academic-government research programs.

The first systematic enzymatic degradation studies were conducted in this period, establishing that Semax's Pro-Gly-Pro C-terminal tail conferred the intended protease resistance. Inozemtseva and colleagues reported in 1993 in the journal Peptides that rat serum carboxypeptidase activity was substantially reduced on the Semax sequence relative to the unmodified ACTH/MSH(4-10) fragment [2]. This study, published in a Western peer-reviewed journal, represented an early point of contact between the Russian Semax research program and the international scientific literature.

During the same period, synthesis methods for Semax were refined to yield material suitable for clinical evaluation. The compound was formulated as a nasal spray solution — an administration route selected for the preclinical program and carried forward into clinical development. The synthesis methodology and current analytical verification standards for research-grade material are documented in the Semax sourcing and quality article.

Regulatory Milestones

Semax completed phase I and phase II clinical trials within the Russian regulatory system between 1990 and 1996. The compound received registration from the Russian Ministry of Health in 1994, becoming an approved pharmaceutical in the Russian Federation — one of a small number of synthetic peptides developed within the Russian Academy of Sciences system to reach clinical registration [1, 3]. The approved formulation is the nasal spray product.

A review of Russian peptide pharmaceutical development published in Pharmaceutics (2022) by Deigin and colleagues documented Semax's regulatory history and its listing on the Russian List of Vital and Essential Drugs, a governmental register of pharmaceuticals considered fundamental to the national formulary [3]. The review noted that Semax's preclinical and clinical data base reflected the institutional priorities of the Soviet and post-Soviet academic research infrastructure, where neuropeptide pharmacology received sustained governmental support. The SpartaLabs Semax product page includes batch-specific analytical documentation for researchers sourcing the compound for preclinical use.

Outside the Russian Federation, Semax has not received regulatory authorization for human therapeutic use. The compound is not included in the European Medicines Agency's centralized authorization database, and the United States Food and Drug Administration has not reviewed or approved Semax for any indication. In the United States and European Union, Semax occupies the status of a research-use-only material — a characterization that reflects the regulatory pathways available in those jurisdictions for a compound with a Russian-origin clinical data base. The international research community continues to generate published literature that expands the mechanistic characterization of the compound.

Published Research Landscape: 2000 to the Present

The English-language scientific literature on Semax grew substantially from 2001 onward, as members of the Institute of Molecular Genetics research group published findings from molecular mechanistic studies in Western peer-reviewed journals. A cluster of publications between 2001 and 2010 established the BDNF/NGF neurotrophin axis as the primary molecular framework through which Semax's preclinical pharmacology has been interpreted.

Shadrina and colleagues (2001) published the first English-language characterization of neurotrophin mRNA induction by Semax in glial cell cultures in Neuroscience Letters [4]. The approximately eightfold BDNF mRNA elevation and fivefold NGF mRNA elevation reported in that study became the foundational quantitative reference for subsequent mechanistic work. The Dolotov group subsequently published multiple papers in Brain Research and the Journal of Neurochemistry (2006) reporting BDNF protein and trkB receptor changes in rat hippocampus and basal forebrain [5, 6]. These publications established the compound's visibility in the international neuropeptide literature and provided mechanistic hypotheses that guided subsequent research.

Eremin and colleagues contributed monoaminergic pharmacology data (Neurochemical Research, 2005), characterizing dopamine and serotonin turnover across multiple brain regions as downstream effects of melanocortin receptor engagement [7]. Agapova and colleagues (Neuroscience Letters, 2007) provided the in vivo neurotrophin gene expression dataset across multiple brain regions, establishing the region-specificity of the transcriptional response [8].

A genome-wide transcriptional study published in BMC Genomics in 2014 by Medvedeva and colleagues represented a methodological advance in the Semax literature, applying high-throughput mRNA sequencing to characterize the full transcriptional response in an ischemia model [9]. The review by Kolomin, Shadrina, and Myasoedov published in Neuroscience and Medicine in 2013 synthesized two decades of published research, providing a consolidated English-language account of the Russian peptide research program [1].

More recent publications have extended the Semax research program into new mechanistic territory. Filippenkov and colleagues (2021, International Journal of Molecular Sciences) characterized hippocampal gene expression patterns in a stress model, framing Semax within the broader melanocortin antistress pharmacology literature [10]. Inozemtseva and colleagues (2024, European Journal of Pharmacology) published a chronic stress model study comparing Semax and Melanotan-II as representative noncorticotropic melanocortins, including hippocampal BDNF protein measurements as a primary outcome [11]. Liu and colleagues (2025, British Journal of Pharmacology) reported the first published characterization of Semax's interaction with the mu-opioid receptor gene Oprm1, demonstrating activity in a murine spinal cord injury model through a USP18 deubiquitinase mechanism — a pharmacological axis not previously described for the compound [12].

Active Research Frontier

As of the mid-2020s, the published Semax literature comprises several dozen peer-reviewed English-language publications and a substantially larger Russian-language body of work. The English-language corpus reflects an evolving mechanistic understanding — from the initial behavioral observations in Soviet-era rodent studies, through the molecular characterization of the BDNF/NGF neurotrophin pathway interactions, to genome-wide and multi-system analyses in the 2010s and 2020s.

The research program remains centered at Russian institutions, primarily the Institute of Molecular Genetics of the Russian Academy of Sciences, with an increasing number of international collaborative publications. The 2025 British Journal of Pharmacology paper by Liu and colleagues demonstrates that investigators outside the original Russian program are now contributing novel mechanistic insights. As the published literature on melanocortin pharmacology and BDNF/NGF neurotrophin biology continues to advance, Semax occupies a defined place as the most extensively characterized noncorticotropic ACTH(4-10) analog in the peer-reviewed literature.

References

1. Kolomin T, Shadrina M, Slominsky P, Limborska S, Myasoedov N. A new generation of drugs: synthetic peptides based on natural regulatory peptides. Neuroscience & Medicine. 2013;4:223–252. DOI: 10.4236/nm.2013.44035

2. Inozemtseva LS, Dolotov OV, Zolotarev YA, Dolotova OS, Andreeva LA, Myasoedov NF. Degradation of ACTH/MSH(4-10) and its synthetic analog semax by rat serum enzymes: an inhibitor study. Peptides. 1993;14(4):745–50. PMID: 8392718. DOI: 10.1016/0196-9781(93)90104-U

3. Deigin VI, Poluektova EA, Beniashvili AG, Kozin SA, Poluektov YM. Development of peptide biopharmaceuticals in Russia. Pharmaceutics. 2022;14(4):716. PMCID: PMC9030433. DOI: 10.3390/pharmaceutics14040716

4. Shadrina MI, Dolotov OV, Grivennikov IA, Slominsky PA, Andreeva LA, Inozemtseva LS, Limborska SA, Myasoedov NF. Rapid induction of neurotrophin mRNAs in rat glial cell cultures by Semax, an adrenocorticotropic hormone analog. Neurosci Lett. 2001;308(2):115–8. PMID: 11457573. DOI: 10.1016/S0304-3940(01)01994-2

5. Dolotov OV, Karpenko EA, Seredenina TS, Inozemtseva LS, Levitskaya NG, Zolotarev YA, Kamensky AA, Grivennikov IA, Engele J, Myasoedov NF. Semax, an analog of ACTH(4-10) with cognitive effects, regulates BDNF and trkB expression in the rat hippocampus. Brain Res. 2006;1117(1):54–60. PMID: 16996037. DOI: 10.1016/j.brainres.2006.07.108

6. Dolotov OV, Karpenko EA, Inozemtseva LS, Seredenina TS, Levitskaya NG, Zolotarev YA, Kamensky AA, Grivennikov IA, Engele J, Myasoedov NF. 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 1:82–6. PMID: 16635254. DOI: 10.1111/j.1471-4159.2006.03658.x

7. Eremin KO, Kudrin VS, Saransaari P, Oja SS, Grivennikov IA, Myasoedov NF, Rayevsky KS. Semax, an ACTH(4-10) analogue with nootropic properties, activates dopaminergic and serotoninergic brain systems in rodents. Neurochem Res. 2005;30(12):1493–500. PMID: 16362768. DOI: 10.1007/s11064-005-8826-8

8. Agapova TY, Agniullin YV, Shadrina MI, Shram SI, Kolomin TA, Myasoedov NF, Slominsky PA, Limborska SA. Neurotrophin gene expression in rat brain under the action of Semax, an analogue of ACTH 4-10. Neurosci Lett. 2007;417(2):201–5. PMID: 17353092. DOI: 10.1016/j.neulet.2007.02.042

9. Medvedeva EV, Dmitrieva VG, Povarova OV, Limborska SA, Skvortsova VI, Myasoedov NF, Dergunova LV. 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. PMCID: PMC3987924. DOI: 10.1186/1471-2164-15-228

10. Filippenkov IB, Stavchansky VV, Glazova NYu, Sebentsova EA, Remizova JA, Valieva LV, Levitskaya NG, Myasoedov NF, Limborska SA, Dergunova LV. Antistress action of melanocortin derivatives associated with correction of gene expression patterns in the hippocampus of male rats following acute stress. Int J Mol Sci. 2021;22(18):10054. PMID: 34576218. PMCID: PMC8469576. DOI: 10.3390/ijms221810054

11. Inozemtseva LS, Poletaeva DA, Dolotov OV, Grivennikov IA, Myasoedov NF. 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. 2025;984:177068. PMID: 39442746. DOI: 10.1016/j.ejphar.2024.177068

12. Liu Y, Chen X, Zhang Y, Wang H, Li Z, Wu J, et al. Semax peptide targets the μ opioid receptor gene Oprm1 to promote deubiquitination and functional recovery after spinal cord injury in female mice. Br J Pharmacol. 2025. PMID: 40692165. DOI: 10.1111/bph.70122