Semax vs Selank: Two Russian Heptapeptides with Different Parent Sequences

Semax and Selank share a C-terminal Pro-Gly-Pro device and little else. Neither has an established receptor. What the published research shows.

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Semax and Selank are the two best-known members of a Russian series of short regulatory peptides, and they are built on the same structural idea: a short endogenous fragment that plasma enzymes destroy quickly, extended at the C-terminus with the tripeptide Pro-Gly-Pro to slow that cleavage.

Beyond that shared device the two have different parent sequences, different proposed mechanisms, and separate literatures that were never designed to be read against each other. They also share a problem that dominates both pages: neither has an established receptor, and the evidence base for both sits largely outside the indexed Western clinical literature.

What they are

PropertySemaxSelank
Development codeNot establishedTP-7
Compound typeSynthetic heptapeptideSynthetic heptapeptide
Peptide familyAdrenocorticotropic hormone (ACTH) fragment analogues; proline-containing regulatory peptidesTuftsin analogues; proline-containing regulatory peptides
Primary targetNo single molecular receptor is established; reported activity is described through neurotrophin signalling rather than a characterised binding site.No high-affinity receptor is established. The best-characterised molecular interactions are inhibition of plasma enkephalin-degrading enzymes and allosteric modulation of GABA binding to brain membrane preparations.
Secondary targetsNot establishedNot established
Receptor familyThe parent hormone ACTH acts at melanocortin receptors; no corresponding receptor interaction has been established for this fragment analogue.Tuftsin, the parent tetrapeptide, is a ligand at the neuropilin-1 and Fc-receptor-associated pathways of innate immunity; no corresponding receptor interaction has been established for this analogue.
Agonist / antagonistNot establishedNot established; reported as a positive allosteric modulator of GABA binding in membrane preparations rather than as a receptor agonist or antagonist.
Highest research phaseControlled clinical studies conducted and published in the Russian Federation; no phase-designated Western development programme exists.A randomised comparative clinical study published in the Russian Federation; no phase-designated Western development programme exists.
Regulatory status (United States)Not approved. Semax has not been approved by the U.S. Food and Drug Administration for any indication, and no marketing application for it is on record in the United States.Not approved. Selank has not been approved by the U.S. Food and Drug Administration for any indication, and no marketing application for it is on record in the United States.
Human trials publishedYesYes

Every value in this table is read from the two compounds’ own library entries when the site is built, so it cannot disagree with them. Nothing here ranks one compound against the other.

Semax is a synthetic heptapeptide, MEHFPGP — the ACTH(4-7) tetrapeptide Met-Glu-His-Phe extended by Pro-Gly-Pro. CAS registry number 80714-61-0, PubChem CID 9811102, UNII I5FAL2585H, molecular weight 813.9 g/mol for the free peptide. It is registered as a pharmaceutical product in the Russian Federation and is not approved by the U.S. Food and Drug Administration for any indication.

Selank is a synthetic heptapeptide, TKPRPGP — the immunoglobulin-derived tetrapeptide tuftsin, Thr-Lys-Pro-Arg, extended by the same Pro-Gly-Pro tripeptide. CAS registry number 129954-34-3, PubChem CID 11765600, UNII TS9JR8EP1G, molecular weight 751.9 g/mol for the free peptide. It too is registered as a pharmaceutical product in the Russian Federation and is not approved by the FDA. The development designation TP-7 appears throughout the older literature, including in papers that never use the name Selank.

So both are four-residue natural fragments carrying the same three-residue extension. The four residues are where they diverge completely: one derives from a pituitary hormone, the other from an antibody.

Receptor and mechanistic differences

Neither compound has an established receptor, and this is the central fact for both. Neither entry in this library carries a binding constant at a named target, because none has been published. What exists is a downstream literature on one side and a pair of unreconciled biochemical proposals on the other.

Semax is described through neurotrophin signalling. In rodent work the peptide raises expression of brain-derived neurotrophic factor and its receptor TrkB in the hippocampus [7], and alters neurotrophin gene expression across several brain regions [9]. Genome-wide work in rat focal ischaemia describes changes in immune and vascular gene sets [14], and later transcriptomic work reports compensation of a disrupted gene expression profile a day after experimental ischaemia [23]. Every one of these is a statement about what changed after exposure, not about what the peptide binds.

Selank has two mechanistic proposals that have not been reconciled. The older is enzymatic: the peptide inhibits enkephalin-degrading enzymes in human plasma, which would raise the half-life of endogenous enkephalins [1]. The newer is receptor-adjacent: radioligand work on brain cell membranes describes positive allosteric modulation of GABA binding, with an interaction at the benzodiazepine binding site that is not additive [18]. Separate work reports effects on the expression of genes involved in GABAergic neurotransmission, in rodents and in a human neuroblastoma cell line [15, 16].

These are not the same kind of claim as each other, let alone the same as Semax's. One is enzyme inhibition, one is allosteric modulation at a ligand-gated ion channel, and Semax's is a change in growth-factor gene expression. The compounds are grouped by origin and by structural device, not by mechanism.

Parent fragment
Semax — ACTH(4-7), from adrenocorticotropic hormone. Selank — tuftsin, from the heavy chain of immunoglobulin G.
Shared device
Both carry a C-terminal Pro-Gly-Pro tripeptide that slows enzymatic cleavage of the parent fragment.
Established receptor
Neither. No binding constant at a named receptor is published for either compound.
Proposed mechanism
Semax — neurotrophin and gene-expression changes [7, 9]. Selank — enkephalin-degrading enzyme inhibition [1] and allosteric modulation of GABA binding [18].
Regulatory position
Both are registered pharmaceutical products in the Russian Federation. Neither is approved in the United States for any indication.
Research literature
Both are predominantly Russian-language or Russian-origin, with a substantial rodent component and a thin indexed clinical component.

What the research compares

No study has compared Semax with Selank. There is no head-to-head clinical trial and no head-to-head animal study in the indexed literature. The two are marketed together in some supplier listings, and a combined preparation exists as a catalogue item, but no published trial of the combination was identified.

The nearest thing to a comparison is a 2024 study that examined Semax alongside another ACTH(4-10) analogue in a rodent stress model — and the comparator there was Melanotan II, not Selank [22]. That paper is useful for what it shows about the ACTH-analogue series, and it does not touch the tuftsin side of this pair at all.

There is a structural reason the comparison is thin beyond the accident of who studied what. The two compounds have no shared target to be compared at. Where two GLP-1 receptor agonists can be placed on one potency axis, and two hexapeptide secretagogues can be placed on another, Semax and Selank have no common axis — one has no characterised receptor at all and the other has two disputed molecular interactions.

A further limitation applies to both sides equally. Much of the clinical literature for both compounds is published in Russian-language journals, and the studies indexed in PubMed are frequently available only as abstracts in English. Where this page cites clinical work, it reports what the indexed record states and no more.

What the human research shows for each

Human clinical research

Results from pharmaceutical clinical trials describe the investigational material and populations used in those studies and should not be interpreted as establishing the effects of research-grade materials offered for laboratory use.

Semax — a stroke literature

The indexed clinical record for Semax is concentrated in cerebrovascular disease. Effectiveness in the acute period of hemispheric ischaemic stroke was reported in a clinical and electrophysiological study [4], and mechanisms of a neuroprotective effect in the acute period of ischaemic stroke were investigated separately [5]. Later work examined the compound in the prevention of disease progression and exacerbations in patients with cerebrovascular insufficiency [6], and a 2018 report addressed efficacy at different stages of ischaemic stroke [17].

Limitations. These are studies conducted and published in the Russian Federation, indexed in English largely as translated titles and abstracts. No phase-designated Western development programme exists for this compound, there is no registrational dataset, and the trial designs, endpoints and analysis populations are not fully retrievable from the indexed record. That is a statement about what can be verified, not a judgement about what was done.

Selank — a narrower clinical record

The indexed clinical record for Selank is smaller. Efficacy and possible mechanisms of action in the therapy of generalised anxiety disorder were reported in a study described as a new peptide anxiolytic [10].

Limitations. A single indexed clinical report, published in the Russian Federation, with no phase-designated Western development programme and no published human pharmacokinetic dataset in the indexed English-language literature. What the compound does in human plasma over time is not a published quantity.

What the two human records have in common

Both are registered pharmaceutical products in one country and approved nowhere else. Both lack a Western registrational programme. Neither has a published human pharmacokinetic dataset in the indexed English-language literature. And for both, the bulk of what is asserted about them in general circulation rests on rodent work rather than on the clinical studies above.

What the animal research shows for each

Animal research

The rodent literatures are the substantial part of the evidence base for both compounds, and they are separate rather than comparative.

Semax in rodents. Intranasal administration was reported to regulate BDNF and TrkB expression in the rat hippocampus [7], and neurotrophin gene expression was altered across rat brain regions after administration [9]. In a rat model of focal cerebral ischaemia, the peptide affected expression of genes related to the immune and vascular systems [14], and brain protein expression profiling in a rat ischaemia model was reported as consistent with a protective effect [20]. Transcriptomic work in 2024 reported that ACTH-like peptides compensated a disrupted rat brain gene expression profile a day after experimental ischaemia [23], and antidepressant-like and antistress effects of Semax and Melanotan II were compared in male rodents [22].

Selank in rodents. Effects on behavioural reactions and on plasma enkephalin-degrading enzyme activity were reported in mice with differing behavioural phenotypes [2], and the peptide was examined alongside short tuftsin-family peptides in the regulation of adaptive behaviour under stress [3]. Intranasal administration was reported to regulate BDNF expression in the rat hippocampus [11] — the one endpoint on which the two compounds' rodent literatures actually overlap. Transcriptomic responses of rat hippocampus and spleen cells to single and chronic administration were characterised [12], as was expression of inflammation-related genes in mouse spleen [13]. Later work reported protection against ethanol-induced memory impairment with regulation of BDNF [19] and attenuation of aversive signs of morphine withdrawal in rats [21].

The one genuine overlap, and its limits. Both compounds have a rodent report of altered hippocampal BDNF expression after intranasal administration [7, 11]. Those are two separate studies by different groups using different designs, not a comparison, and a shared downstream marker is weak evidence of a shared mechanism — BDNF expression changes in response to a very wide range of interventions.

Findings described in this section were observed in animals. Nothing in them establishes anything about humans.

What the in vitro research shows for each

In vitro research

Semax. Degradation of the ACTH(4-10) analogue was characterised in the presence of rat basal forebrain cell cultures and plasma membranes, identifying the cleavage products and the order in which they appear [8]. That work is the basis for the claim that the Pro-Gly-Pro extension slows degradation relative to the parent fragment — a claim about enzyme kinetics, not about activity.

Selank. Inhibition of enkephalin-degrading enzymes in human plasma was reported as a possible mechanism of anxiolytic action [1]. Separately, radioligand work on brain cell membranes described positive allosteric modulation of GABA binding, with a non-additive interaction at the benzodiazepine site [18], and gene-expression work in a human neuroblastoma cell line examined GABAergic genes under GABA, Selank and olanzapine [16].

No in vitro study has characterised the two peptides against each other, and there is no shared assay in which they could be placed: one is described by its degradation kinetics and downstream gene expression, the other by enzyme inhibition and allosteric modulation.

Research status of each

Semax is registered as a pharmaceutical product in the Russian Federation. Controlled clinical studies have been conducted and published there; no phase-designated Western development programme exists, and it is not approved by the FDA for any indication.

Selank is registered as a pharmaceutical product in the Russian Federation. Its highest indexed clinical evidence is a randomised comparative clinical study published there; no phase-designated Western development programme exists, and it is not approved by the FDA for any indication.

For both compounds, registration in one jurisdiction attaches to a specific manufactured pharmaceutical product under that jurisdiction's regulatory system. It does not transfer to any other country, and it says nothing about research-grade material supplied for laboratory use.

Frequently Asked Questions

What is the difference between Semax and Selank?
The parent fragment each is built from. Semax is MEHFPGP — the ACTH(4-7) tetrapeptide from adrenocorticotropic hormone, extended by Pro-Gly-Pro. Selank is TKPRPGP — the tetrapeptide tuftsin, a fragment of the heavy chain of immunoglobulin G, extended by the same Pro-Gly-Pro tripeptide. One derives from a pituitary hormone and the other from an antibody; the shared three residues are a stability device rather than a shared pharmacology.
What does the Pro-Gly-Pro extension do?
It slows enzymatic cleavage. Both parent tetrapeptides are cleaved quickly in plasma, and the added tripeptide is the structural device that extends their survival. For Semax the degradation products and the order in which they appear were characterised in rat basal forebrain cell cultures and plasma membranes [8]. It is a claim about enzyme kinetics, not about activity.
Do either of them have an identified receptor?
No. Neither compound has a published binding constant at a named receptor. Semax is described downstream, through changes in neurotrophin signalling and gene expression [7, 9]. Selank has two mechanistic proposals that have not been reconciled: inhibition of enkephalin-degrading enzymes in human plasma [1], and positive allosteric modulation of GABA binding on brain cell membranes [18].
Have Semax and Selank been compared in a study?
No head-to-head study exists, in humans or in animals. The nearest published comparison examined Semax alongside another ACTH(4-10) analogue in a rodent stress model, and the comparator there was Melanotan II rather than Selank [22]. There is also no shared characterised target at which the two could be compared.
Are they approved anywhere?
Both are registered as pharmaceutical products in the Russian Federation. Neither is approved by the U.S. Food and Drug Administration for any indication, and no marketing application for either is on record in the United States. Registration in one jurisdiction attaches to a specific manufactured product under that jurisdiction's regulatory system and does not transfer.
What does the clinical literature actually cover?
For Semax, mainly cerebrovascular disease: the acute period of hemispheric ischaemic stroke [4, 5], prevention of progression in cerebrovascular insufficiency [6], and efficacy at different stages of ischaemic stroke [17]. For Selank, a single indexed clinical report on generalised anxiety disorder [10]. Both literatures are published in the Russian Federation and indexed in English largely as translated titles and abstracts.
Is there any overlap between their animal literatures?
One endpoint. Both have a rodent report of altered hippocampal brain-derived neurotrophic factor expression after intranasal administration [7, 11]. Those are separate studies by different groups with different designs, not a comparison, and a shared downstream marker is weak evidence of a shared mechanism — BDNF expression changes in response to a very wide range of interventions. Findings in animals establish nothing about humans.
Is there published research on the two used together?
No published trial of the combination was identified, in humans or in animals, although a combined preparation exists as a catalogue item. Nothing in the literature cited on this page addresses the two administered together.

References

  1. The inhibitory effect of Selank on enkephalin-degrading enzymes as a possible mechanism of its anxiolytic activity Bulletin of Experimental Biology and Medicine; 2001. PMID 11550013
  2. Effects of Selank on behavioral reactions and activities of plasma enkephalin-degrading enzymes in mice with different phenotypes of emotional and stress reactions Bulletin of Experimental Biology and Medicine; 2002. PMID 12432865 doi:10.1023/a:1015582302311
  3. Selank and short peptides of the tuftsin family in the regulation of adaptive behavior in stress Neuroscience and Behavioral Physiology; 2003. PMID 14969422 doi:10.1023/a:1025988519919
  4. [Effectiveness of semax in acute period of hemispheric ischemic stroke (a clinical and electrophysiological study)] Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova; 1997. PMID 11517472
  5. [Investigation of mechanisms of neuro-protective effect of semax in acute period of ischemic stroke] Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova; 1999. PMID 10358912
  6. [Semax in prevention of disease progress and development of exacerbations in patients with cerebrovascular insufficiency] Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova; 2005. PMID 15792140
  7. Semax, an analog of ACTH(4-10) with cognitive effects, regulates BDNF and trkB expression in the rat hippocampus Brain Research; 2006. PMID 16996037 doi:10.1016/j.brainres.2006.07.108
  8. Degradation of the ACTH(4-10) analog Semax in the presence of rat basal forebrain cell cultures and plasma membranes Amino Acids; 2006. PMID 16773243 doi:10.1007/s00726-006-0328-8
  9. Neurotrophin gene expression in rat brain under the action of Semax, an analogue of ACTH 4-10 Neuroscience Letters; 2007. PMID 17353092 doi:10.1016/j.neulet.2007.02.042
  10. [Efficacy and possible mechanisms of action of a new peptide anxiolytic selank in the therapy of generalized anxiety disorders and neurasthenia] Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova; 2008. PMID 18454096
  11. Intranasal administration of the peptide Selank regulates BDNF expression in the rat hippocampus in vivo Doklady Biological Sciences; 2008. PMID 18841804 doi:10.1134/s0012496608040066
  12. Transcriptomic response of rat hippocampus and spleen cells to single and chronic administration of the peptide selank Doklady Biochemistry and Biophysics; 2010. PMID 20380151 doi:10.1134/s1607672910010023
  13. Expression of inflammation-related genes in mouse spleen under tuftsin analog Selank Regulatory Peptides; 2011. PMID 21609736 doi:10.1016/j.regpep.2011.05.001
  14. 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. PMID 24661604 doi:10.1186/1471-2164-15-228
  15. Selank Administration Affects the Expression of Some Genes Involved in GABAergic Neurotransmission Frontiers in Pharmacology; 2016. PMID 26924987 doi:10.3389/fphar.2016.00031
  16. GABA, Selank, and Olanzapine Affect the Expression of Genes Involved in GABAergic Neurotransmission in IMR-32 Cells Frontiers in Pharmacology; 2017. PMID 28293190 doi:10.3389/fphar.2017.00089
  17. [The efficacy of semax in the tretament of patients at different stages of ischemic stroke] Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova; 2018. PMID 29798983 doi:10.17116/jnevro20181183261-68
  18. Peptide-based Anxiolytics: The Molecular Aspects of Heptapeptide Selank Biological Activity Protein and Peptide Letters; 2018. PMID 30255741 doi:10.2174/0929866525666180925144642
  19. Selank, Peptide Analogue of Tuftsin, Protects Against Ethanol-Induced Memory Impairment by Regulating of BDNF Content in the Hippocampus and Prefrontal Cortex in Rats Bulletin of Experimental Biology and Medicine; 2019. PMID 31625062 doi:10.1007/s10517-019-04588-9
  20. Brain Protein Expression Profile Confirms the Protective Effect of the ACTH(4-7)PGP Peptide (Semax) in a Rat Model of Cerebral Ischemia-Reperfusion International Journal of Molecular Sciences; 2021. PMID 34201112 doi:10.3390/ijms22126179
  21. Selank, a Peptide Analog of Tuftsin, Attenuates Aversive Signs of Morphine Withdrawal in Rats Bulletin of Experimental Biology and Medicine; 2022. PMID 36322304 doi:10.1007/s10517-022-05624-x
  22. 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 European Journal of Pharmacology; 2024. PMID 39442746 doi:10.1016/j.ejphar.2024.177068
  23. ACTH-like Peptides Compensate Rat Brain Gene Expression Profile Disrupted by Ischemia a Day After Experimental Stroke Biomedicines; 2024. PMID 39767736 doi:10.3390/biomedicines12122830

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