Semax: A Research Overview

Introduction

Semax (Met-Glu-His-Phe-Pro-Gly-Pro; MEHFPGP) is a synthetic heptapeptide derived from the adrenocorticotropic hormone (ACTH) fragment spanning positions 4 through 10 of the native hormone sequence, with a C-terminal Pro-Gly-Pro tripeptide appended by design. Pharmacologically classified as a noncorticotropic melanocortin analog, Semax has been the subject of sustained investigation in Russian and international research programs since the 1980s — principally centered on melanocortin receptor pharmacology and the compound's reported interactions with BDNF and NGF neurotrophin signaling systems. This article provides an educational reference overview of Semax's chemical identity, pharmacological classification, and regulatory history, based on published primary literature.

Background

Melanocortins are a family of peptide hormones — including ACTH and the melanocyte-stimulating hormones (MSH) — produced from the precursor protein proopiomelanocortin (POMC). Research conducted in the 1970s and 1980s established that the ACTH(4-10) core fragment retained behavioral and neuromodulatory activities distinct from the endocrine functions of full-length ACTH [1]. This observation motivated a program at the Institute of Molecular Genetics, Russian Academy of Sciences, to develop a stabilized analog suitable for extended in vivo study. Semax belongs to the same Russian neuropeptide cluster as Selank, another POMC-adjacent peptide developed at overlapping institutions during the same research era.

A research group led by Academician Igor Ashmarin and Academician Nikolai Myasoedov synthesized Semax in the early 1980s by incorporating the minimal active melanocortin tetrapeptide core (ACTH(4-7): Met-Glu-His-Phe) and appending a Pro-Gly-Pro tripeptide to the C-terminus [1]. The Pro-Gly-Pro extension was incorporated specifically to confer resistance to carboxypeptidase-mediated proteolysis, thereby extending the molecule's biological half-life relative to the unmodified ACTH(4-10) sequence. The subsequent decades of published research have focused largely on two interrelated pharmacological axes: melanocortin receptor engagement and BDNF/NGF neurotrophin pathway interactions.

Chemistry and Structure

Semax has the amino acid sequence Met-Glu-His-Phe-Pro-Gly-Pro (one-letter code: MEHFPGP). The N-terminal methionine (Met) corresponds to position 4 of the native ACTH sequence. The histidine residue (His) at position 3 of the heptapeptide confers an atypically high affinity for copper(II) ions, as characterized in a 2015 study by Tabbì and colleagues, which reported that Semax coordinates divalent copper through an amino-terminal copper- and nickel-binding (ATCUN) motif [2]. This chelating capacity was reported to attenuate copper-induced cytotoxicity in neuroblastoma cell lines in vitro [2].

The Pro-Gly-Pro C-terminal tripeptide does not correspond to any portion of the native ACTH sequence; it was introduced by design as a protease-resistant stabilizing tail. A 1993 study by Inozemtseva and colleagues confirmed that carboxypeptidase activity is substantially attenuated on the Semax sequence relative to the unmodified fragment [3]. The molecular weight of Semax is approximately 812 daltons.

An N-terminally acetylated derivative, N-Acetyl Semax, has also been characterized in the research literature. Acetylation of the methionine alpha-amine alters the copper coordination geometry and modifies the peptide's interaction with melanocortin receptor subtypes, as documented by Levitskaya and colleagues [4].

Pharmacological Classification

Semax is classified as a noncorticotropic melanocortin analog. The melanocortin receptor family comprises five G-protein-coupled receptor subtypes (MC1R through MC5R). The ACTH(4-10) fragment and its analogs engage melanocortin receptors in the central nervous system without the corticotropic endocrine activity associated with full-length ACTH.

Published binding studies, including the 2006 work by Dolotov and colleagues in the Journal of Neurochemistry, characterized Semax's interaction with BDNF protein levels in rat basal forebrain tissue — reporting specific binding and associated changes in BDNF concentrations [5]. The molecular details of these interactions are covered in the Semax mechanism of action article. A companion Brain Research publication from the same group reported approximately 1.4-fold changes in BDNF protein and approximately 3-fold changes in BDNF mRNA in hippocampal tissue, along with elevated trkB receptor phosphorylation [6]. Shadrina and colleagues (2001) reported the most pronounced in vitro neurotrophin response in the published literature: approximately eightfold elevation of BDNF mRNA and fivefold elevation of NGF mRNA in neonatal rat glial cultures [7].

The monoaminergic pharmacology of Semax was characterized by Eremin and colleagues (2005), who reported that Semax administration in rodents was associated with altered dopamine and serotonin metabolism in the striatum, frontal cortex, and hippocampus [8]. The researchers attributed these observations to downstream effects of melanocortin receptor engagement rather than direct monoaminergic receptor activity.

Regulatory Status

In the Russian Federation, Semax received registration from the Russian Ministry of Health in 1994 following a clinical development program that included phase I and phase II trials conducted between 1990 and 1996 [1]. The approved formulation is a nasal spray solution. Semax is listed on the Russian List of Vital and Essential Drugs, as documented in the review by Deigin and colleagues (2022) in Pharmaceutics [9].

Outside the Russian Federation, Semax has not received regulatory authorization for human therapeutic use. In the United States, the European Union, Canada, and Australia, the compound is classified as a research material. The European Medicines Agency's centralized database of authorized medicines does not include Semax, and the FDA has not reviewed the compound for any indication. Research-grade Semax from SpartaLabs is supplied with batch-specific certificates of analysis for verified research applications.

Discovery History

The scientific lineage of Semax begins with work on the behavioral neuropharmacology of ACTH fragments in the 1970s, when multiple research groups established that short peptides derived from the ACTH sequence could influence learning and memory in rodent models independently of adrenal effects. The academic program at the Institute of Molecular Genetics of the Russian Academy of Sciences formalized this direction in the late 1970s and early 1980s.

The synthesis of Semax and the characterization of its in vivo behavioral effects were documented in a 1997 review by Ashmarin, Nezavibatko, and Myasoedov, published in the Russian journal Zhurnal Vysshei Nervnoi Deyatelnosti, which surveyed 15 years of work from initial design through clinical registration [1]. The English-language peer-reviewed literature grew substantially from 2001 onward, centering on the BDNF/NGF neurotrophin axis and melanocortin receptor pharmacology as the primary mechanistic frameworks.

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. Tabbì G, Magrì A, Giuffrida A, Lanza V, Pappalardo G, Naletova I, Nicoletti VG, Attanasio F, Rizzarelli E. 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. DOI: 10.1016/j.jinorgbio.2014.09.014

3. 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

4. Levitskaya NG, Sebentsova EA, Andreeva LA, Alfeeva LY, Kamenskii AA, Myasoedov NF. Semax and analogs: physiological activity and comparison of pharmacological properties. In: Heptapeptides in Neuropeptidology. Moscow: Nauka; 2009. [Secondary reference; see primary data in Dolotov OV et al., J Neurochem 2006]

5. 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

6. 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

7. 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

8. 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

9. 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