Semax and Selank: A Comparative Research Review of the Two Regulatory Heptapeptides, Their ACTH(4-10) and Tuftsin Origins and Their Distinct Mechanisms

By Peptide Insider Research Team · 12 min read · Last updated 10 September 2026

Semax and selank are two synthetic regulatory heptapeptides developed at the Institute of Molecular Genetics of the Russian Academy of Sciences from different natural templates: the semax peptide (Met-Glu-His-Phe-Pro-Gly-Pro) is a fragment analog of adrenocorticotropic hormone, ACTH(4-7), stabilised by a C-terminal Pro-Gly-Pro tail, whereas the selank peptide (Thr-Lys-Pro-Arg-Pro-Gly-Pro) is the immunopeptide tuftsin extended by the same Pro-Gly-Pro motif [1,2]. Sharing a laboratory of origin, a seven-residue length and a stabilising tripeptide, they are frequently catalogued together, yet their pharmacology and research histories are largely separate. This review compares them side by side — structure, mechanism, evidence by domain and catalogue notation — and states plainly where head-to-head data do and do not exist. All content is provided strictly for research reference.

Introduction

Both peptides belong to a design philosophy articulated by Igor Ashmarin and colleagues in the 1980s and 1990s: take a short endogenous fragment with a documented behavioural or immunological activity, remove residues that confer hormonal side-activity, and append a proline-rich C-terminus to slow proteolysis [1,3]. For Semax the parent was ACTH(4-10), reported to influence attention and learning in animals without stimulating corticosteroid release; truncation to ACTH(4-7) plus Pro-Gly-Pro gave a molecule far more resistant to blood enzymes than the natural fragment [3]. For Selank the parent was tuftsin (Thr-Lys-Pro-Arg), an IgG-derived tetrapeptide characterised as a phagocytosis stimulator; the same extension produced a compound with anxiolytic-like activity in rodent conflict tests [2,4].

The result is a pair of structural cousins that are pharmacologically distinct: Semax is discussed chiefly as a neurotrophin-inducing, ischaemia-responsive peptide, Selank as an anxiolytic-like, GABA-modulating and immunoregulatory one. Catalogues listing a "seemax" or "semax and selank" pair group by lineage, not mechanism, and each evidence base must be read on its own terms.

Biological background: two parent peptides, one stabilising motif

The melanocortin fragment. ACTH is a 39-residue pro-opiomelanocortin product whose N-terminal region, ACTH(1-24), carries adrenal steroidogenic activity, while the internal core ACTH(4-10) (Met-Glu-His-Phe-Arg-Trp-Gly) is shared with α-, β- and γ-melanocyte-stimulating hormones. This core had been studied since the 1970s for effects on attention and avoidance learning independent of adrenal output [1,3]. Semax retains only its first four residues and lacks the His-Phe-Arg-Trp pharmacophore needed for high-affinity melanocortin receptor binding, so its actions are not generally attributed to MC1–MC5 agonism [1,5].

The immunoglobulin fragment. Tuftsin is generated by enzymatic cleavage of the CH2 domain of IgG heavy chain (residues 289–292) and has been characterised as a stimulator of macrophage and neutrophil phagocytosis, chemotaxis and antigen processing [2]. Early behavioural work reported that tuftsin and related short peptides altered adaptive behaviour under conflict stress in rodents, motivating the search for a more stable analog [4].

The Pro-Gly-Pro tail. The tripeptide Pro-Gly-Pro is itself a bioactive collagen-derived fragment. In both Semax and Selank it functions primarily as a protease-resistant C-terminus, and studies of Semax degradation by rat blood enzymes reported that the intact heptapeptide persists far longer than ACTH(4-10) and that the resulting metabolites (including Glu-His-Phe-Pro-Gly-Pro and Pro-Gly-Pro) retain partial activity [3]. Selank metabolism similarly yields Pro-Gly-Pro and shorter fragments, which some authors have proposed contribute to its observed effects [4,6].

Compound structure and mechanism of action

Semax: neurotrophin induction and transcriptomic modulation

The most consistently replicated molecular observation for Semax is rapid induction of neurotrophins. In primary rat glial cultures, Shadrina and colleagues reported an approximately eight-fold rise in BDNF mRNA and a five-fold rise in NGF mRNA within 30 minutes of exposure, followed by a decline over several hours [7]. In vivo, Dolotov and co-workers observed that a single intranasal exposure in rats increased hippocampal BDNF protein about 1.4-fold, exon III BDNF transcript about three-fold, and TrkB phosphorylation about 1.6-fold, in parallel with improved conditioned-avoidance performance [5]. Genome-wide studies in permanent and transient middle cerebral artery occlusion (MCAO) models have extended this picture: Medvedeva et al. reported that the immune response was the biological process most affected by Semax after focal ischaemia, with immunoglobulin and chemokine transcripts prominent among upregulated genes, together with vascular-development genes [8,9]; Filippenkov et al. identified 394 differentially expressed genes at 24 hours after transient MCAO, with suppression of inflammation-related transcripts and activation of neurotransmission-related transcripts [10], later corroborated at the protein level by reduced MMP-9, c-Fos and active JNK and increased active CREB in subcortical tissue [11].

Selank: GABAergic gene expression, enkephalin kinetics and cytokines

Selank's behavioural profile in rodents resembles that of benzodiazepines in several tests, which prompted mechanistic studies of the GABAergic system. Volkova et al. compared the expression of 84 neurotransmission-related genes in rat frontal cortex after intranasal Selank or GABA and reported that 45 genes changed at one hour and 22 at three hours, with a positive correlation between the Selank- and GABA-induced expression patterns — findings the authors interpreted as consistent with allosteric modulation of GABA_A receptor function rather than direct agonism [12]. A follow-up in IMR-32 neuroblastoma cells found that Selank did not itself alter GABA-receptor subunit mRNA but did modify the transcriptional response to olanzapine, again pointing to a modulatory rather than primary ligand role [13]. A second, independent line of work concerns endogenous opioid peptides: in the clinical study by Zozulya and colleagues, Selank exposure was associated with an increased half-life of leu-enkephalin in serum, which the authors attributed to inhibition of enkephalin-degrading enzymes [14]. A third strand is immunological, inherited from tuftsin: Uchakina et al. reported that Selank at 10^-7 M suppressed IL-6 gene expression in peripheral blood cell cultures and shifted the Th1/Th2 cytokine balance in serum over a 14-day study [15].

Nomenclature and catalogue variants

Because both compounds were developed and named in Russia and later entered international research catalogues through transliteration, the same molecules appear under many labels. The table below lists the variants that recur in catalogue listings and search data, with their correct referent, so that researchers can reconcile entries.

Catalogue or search variant	Refers to	Note
semax peptide · peptide semax · peptides semax	Semax (ACTH(4-7)-PGP)	Word-order variants of the same compound
na-semax · na semax peptide · N-acetyl Semax	N-terminally acetylated Semax	Acetylation of the Met1 amine; sometimes further amidated ("NA-Semax amidate"). Published mechanistic data are almost entirely on unmodified Semax
seemax	Semax	Common misspelling
selank peptide · selank peptides	Selank (Thr-Lys-Pro-Arg-Pro-Gly-Pro)	Singular/plural variants
selenk	Selank	Common misspelling
N-acetyl Selank amidate	Acetylated, C-amidated Selank	Catalogue derivative; no peer-reviewed comparison with parent Selank located
semax and selank · semax selank peptide	Both compounds listed as a pair	Lineage grouping only — no combination study has been published

Evidence by research domain

Research domain	Compound	Typical models	Reported findings	Evidence maturity
Neurotrophin signalling	Semax	Rat glial culture; rat hippocampus	Rapid BDNF/NGF mRNA induction; increased BDNF protein and TrkB phosphorylation [5,7]	Replicated preclinical
Cerebral ischaemia transcriptomics	Semax	Rat pMCAO and tMCAO	Immune, vascular and neurotransmission gene-set shifts; reduced MMP-9, c-Fos, JNK; increased CREB [8–11]	Replicated preclinical
Clinical stroke literature	Semax	Russian open and comparative studies	Faster regression of focal deficits reported in 1997; higher plasma BDNF and Barthel-index improvement in 2018 rehabilitation cohort [16,17]	Limited clinical (non-blinded, single country)
Behavioural stress models	Selank	Wistar rats; C57BL/6 and BALB/c mice	Antistress and anxiolytic-like activity in conflict paradigms, strain-dependent [4]	Preclinical
GABAergic gene expression	Selank	Rat frontal cortex; IMR-32 cells	Expression pattern correlated with GABA; modulatory rather than agonist profile [12,13]	Preclinical, mechanistic
Immune and cytokine modulation	Selank	Human PBMC culture; patient serum	IL-6 transcript suppression in vitro; Th1/Th2 shift [15]	Small clinical + in vitro
Clinical anxiety literature	Selank	Active-comparator study (n = 62)	Anxiolytic effect comparable to medazepam; leu-enkephalin half-life increased [14]	Limited clinical (active comparator, no placebo)
Head-to-head or combination	Both	—	No published study located	None

Neurotrophins and ischaemia (Semax)

The neurotrophin data are the strongest part of the Semax literature, reproduced across culture, healthy-animal and ischaemia models by more than one group. The transcriptomic studies are notable for breadth: Semax exposure after MCAO was associated with coordinated changes in immunoglobulin, chemokine, interferon, vascular-development and neurotransmission gene sets [8–10], framed by the authors as "neuroimmune crosstalk"; the initiating target remains unidentified.

Clinical stroke reports (Semax)

Semax has been registered in Russia since the 1990s and its clinical literature is Russian-language. Gusev and colleagues described faster regression of focal motor and general cerebral symptoms in acute hemispheric stroke in 1997 [16], and in 2018 reported sustained plasma BDNF elevation and greater Barthel-index gains in Semax-exposed subgroups of 110 rehabilitation patients [17]. Neither study was placebo-controlled or blinded to contemporary standards, and none has been published outside Russia.

Anxiety-related and GABAergic research (Selank)

Kozlovskaya et al. compared Selank with ten tuftsin-family peptides across rats and mice sorted by emotional reactivity and reported antistress activity that depended on strain and on the specific degradation fragments generated [4]. The 2008 comparative clinical study in generalised anxiety disorder and neurasthenia reported anxiolytic effects comparable to the benzodiazepine medazepam, with additional anti-asthenic activity, but the design lacked a placebo arm and the abstract does not confirm blinding [14]. The GABAergic gene-expression work of 2016–2017 provides a plausible mechanism but does not constitute receptor-binding proof [12,13].

Immunomodulation (Selank)

Selank's tuftsin heritage is reflected in the cytokine literature. The 2008 immunology report combined an in vitro PBMC experiment with serum analysis in patients and concluded that Selank behaves as an immunomodulator that shifts Th1/Th2 balance [15]. Expression work in mouse spleen has since reported time-dependent changes in chemokine and cytokine genes after Selank exposure, though these datasets are smaller than the Semax ischaemia series [6].

Side-by-side comparison

Feature	Semax	Selank
Sequence	Met-Glu-His-Phe-Pro-Gly-Pro	Thr-Lys-Pro-Arg-Pro-Gly-Pro
Parent molecule	ACTH(4-10) / melanocortin core	Tuftsin (IgG-derived tetrapeptide)
Stabilising motif	C-terminal Pro-Gly-Pro	C-terminal Pro-Gly-Pro
Principal mechanistic theme	BDNF/NGF induction; ischaemia transcriptome modulation	GABAergic gene-expression modulation; enkephalinase inhibition; cytokine shift
Best-replicated model	Rat MCAO transcriptomics	Rodent conflict/anxiety paradigms
Clinical literature	Russian stroke studies (1997–2018)	Russian GAD/neurasthenia studies (2008–2015)
Common derivatives	N-acetyl Semax (NA-Semax), NA-Semax amidate	N-acetyl Selank amidate
Combination data	None published

Limitations and research considerations

• Geographic concentration. Essentially all clinical data for both peptides originate from Russian institutions, several of which were involved in the compounds' development; independent replication outside that setting is absent.
• Design limitations. Clinical reports are open-label or active-comparator studies with small samples and without confirmed blinding [14,16,17]; effect sizes should be read as hypothesis-generating.
• Undefined primary target. Neither compound has a validated high-affinity receptor. Semax's melanocortin-receptor affinity is low given the truncated pharmacophore [1,5], and Selank's GABAergic profile is inferred from expression correlations rather than binding assays [12,13].
• Derivative gap. N-acetylated and amidated catalogue variants of both peptides lack published comparative pharmacology; results obtained with the parent sequences should not be assumed to transfer.
• No combination study. Despite frequent co-listing, no peer-reviewed experiment has examined Semax and Selank together, so no statement about additive, synergistic or antagonistic interaction is supported.

Where to source for research

Both heptapeptides are available as lyophilised research-grade material. Laboratories comparing suppliers typically look for a lot-specific certificate of analysis (HPLC purity, mass-spectrometry identity), clear labelling of parent sequence versus N-acetylated derivative, and research-use-only terms. Catalogue listings for Semax and Selank can be found at Short Chain Aminos, BioPep, Catalyst Research and Apex Research Services. Peptide Insider's supplier evaluation guide and suppliers directory outline the documentation researchers generally request before purchase.

Frequently asked research questions

Are semax and selank the same peptide?

No. Semax is derived from the ACTH(4-10) melanocortin core and Selank from the IgG fragment tuftsin. They share only the C-terminal Pro-Gly-Pro stabilising motif and a seven-residue length. Their mechanistic literatures — neurotrophin induction for Semax, GABAergic and cytokine modulation for Selank — are largely separate [1,2].

What is the semax peptide studied for?

The semax peptide is studied chiefly for rapid induction of BDNF and NGF in glial cultures and rat hippocampus, and for broad transcriptomic changes after experimental cerebral ischaemia, including suppression of inflammatory transcripts and increased active CREB. Russian clinical reports in stroke exist but are not placebo-controlled [5,7–11,16,17].

What is the selank peptide studied for?

The selank peptide is studied for anxiolytic-like activity in rodent conflict tests, for gene-expression changes in rat frontal cortex that correlate with those of GABA, for slowed degradation of leu-enkephalin, and for cytokine modulation including IL-6 suppression in vitro. One active-comparator clinical study in anxiety exists [4,12,14,15].

Is there any study combining semax and selank?

No peer-reviewed study has examined the two peptides together. Catalogue pairings and "semax selank peptide" listings reflect shared laboratory origin and structure, not combination data. Any claim of additive or synergistic effects is unsupported by the published literature and should be treated as a hypothesis awaiting experimental test.

What is na-semax or N-acetyl Semax?

NA-Semax is Semax with an acetyl group on the N-terminal methionine; an amidated version is also catalogued. These derivatives were introduced to alter stability, but published mechanistic and transcriptomic data were generated with unmodified Semax, and no head-to-head pharmacology comparing parent and acetylated forms has been located.

Why are "seemax" and "selenk" found in catalogues?

Both are misspellings that arose during transliteration from Russian and propagated through search engines and vendor listings. "Seemax" refers to Semax and "selenk" to Selank. Researchers reconciling catalogue entries should confirm the amino-acid sequence on the certificate of analysis rather than relying on the label.

How mature is the clinical evidence for each?

Both compounds are registered in Russia and have Russian-language clinical reports, but these are small, open or active-comparator studies without confirmed blinding and without independent replication elsewhere. Preclinical mechanistic data — particularly Semax's neurotrophin and ischaemia transcriptomics — are more extensively replicated than the clinical findings [14,16,17].

Works Cited

1. Ashmarin IP, Nezavibatko VN, Myasoedov NF, et al. A nootropic adrenocorticotropin analog 4-10-semax (15 years experience in its design and study). Zh Vyssh Nerv Deiat Im I P Pavlova. 1997;47(2):420-430. PMID: 9173745.
2. Kolomin T, Shadrina M, Slominsky P, Limborska S, Myasoedov N. A new generation of drugs: synthetic peptides based on natural regulatory peptides. Neurosci Med. 2013;4:223-252. DOI: 10.4236/nm.2013.44035.
3. Potaman VN, Alfeeva LY, Kamensky AA, Nezavibatko VN. N-terminal degradation of ACTH(4-10) and its synthetic analog semax by the rat blood enzymes. Biochem Biophys Res Commun. 1991;176(2):741-746. PMID: 1851003.
4. Kozlovskaya MM, Kozlovskii II, Val'dman EA, Seredenin SB. Selank and short peptides of the tuftsin family in the regulation of adaptive behavior in stress. Neurosci Behav Physiol. 2003;33(9):853-860. DOI: 10.1023/A:1025988519919.
5. 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(1):54-60. PMID: 16996037.
6. Kolomin T, Shadrina M, Andreeva L, Slominsky P, Limborska S, Myasoedov N. Expression of inflammation-related genes in mouse spleen under tuftsin analog Selank. Regul Pept. 2011;170(1-3):18-23. PMID: 21609731.
7. Shadrina MI, Dolotov OV, Grivennikov IA, et al. Rapid induction of neurotrophin mRNAs in rat glial cell cultures by Semax, an adrenocorticotropic hormone analog. Neurosci Lett. 2001;308(2):115-118. DOI: 10.1016/S0304-3940(01)01994-2.
8. Medvedeva EV, Dmitrieva VG, Limborska SA, et al. Semax, an analog of ACTH(4-7), regulates expression of immune response genes during ischemic brain injury in rats. Mol Genet Genomics. 2017;292(3):635-653. DOI: 10.1007/s00438-017-1297-1.
9. 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. DOI: 10.1186/1471-2164-15-228.
10. 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(6):681. PMID: 32580520.
11. Filippenkov IB, Stavchansky VV, Glazova NY, et al. The peptide drug ACTH(4-7)PGP (Semax) suppresses mRNA transcripts encoding proinflammatory mediators induced by reversible ischemia of the rat brain. Int J Mol Sci. 2021;22(12):6179. PMID: 34201112.
12. Volkova A, Shadrina M, Kolomin T, et al. Selank administration affects the expression of some genes involved in GABAergic neurotransmission. Front Pharmacol. 2016;7:31. PMID: 26924987.
13. Filatova E, Kasian A, Kolomin T, et al. GABA, Selank, and olanzapine affect the expression of genes involved in GABAergic neurotransmission in IMR-32 cells. Front Pharmacol. 2017;8:89. DOI: 10.3389/fphar.2017.00089.
14. Zozulia AA, Neznamov GG, Siuniakov TS, et al. Efficacy and possible mechanisms of action of a new peptide anxiolytic selank in the therapy of generalized anxiety disorders and neurasthenia. Zh Nevrol Psikhiatr Im S S Korsakova. 2008;108(4):38-48. PMID: 18454096.
15. Uchakina ON, Uchakin PN, Miasoedov NF, et al. Immunomodulatory effects of selank in patients with anxiety-asthenic disorders. Zh Nevrol Psikhiatr Im S S Korsakova. 2008;108(5):71-75. PMID: 18577961.
16. Gusev EI, Skvortsova VI, Miasoedov NF, et al. Effectiveness of semax in acute period of hemispheric ischemic stroke (a clinical and electrophysiological study). Zh Nevrol Psikhiatr Im S S Korsakova. 1997;97(6):26-34. PMID: 11517472.
17. Gusev EI, Martynov MYu, Kostenko EV, Petrova LV, Bobyreva SN. The efficacy of semax in the treatment of patients at different stages of ischemic stroke. Zh Nevrol Psikhiatr Im S S Korsakova. 2018;118(3 Pt 2):61-68. PMID: 29798983.
18. Kaplan AYa, Kochetova AG, Nezavibathko VN, Rjasina TV, Ashmarin IP. Synthetic ACTH analogue Semax displays nootropic-like activity in humans. Neurosci Res Commun. 1996;19(2):115-123. DOI: 10.1002/(SICI)1520-6769(199609)19:2<115::AID-NRC171>3.0.CO;2-B.

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