Research Dossier on Selank

(Neuropeptide / Anxiolytic)

Classification & Molecular Identity

Amino acid sequence, molecular weight, structural motifs

Selank is a synthetic heptapeptide with the primary sequence Thr–Lys–Pro–Arg–Pro–Gly–Pro (TKPRPGP). It was engineered as a tuftsin (Thr–Lys–Pro–Arg; TKPR) analog in which the C-terminus is elongated by Pro–Gly–Pro (PGP)to enhance metabolic stability and duration of action.PMC+1 The PGP extension belongs to a broader family of glyproline motifs that frequently appear in short regulatory peptides and have been implicated in improved resistance to enzymatic degradation.PubMed

Molecular weight. As a free heptapeptide with unmodified termini (reported as H-Thr-Lys-Pro-Arg-Pro-Gly-Pro-OH in several sources), calculated molar mass is ~ 863–875 g·mol⁻¹ depending on protonation/salt form; exact analytical masses vary by lot/formulation and are typically reported in manufacturer certificates rather than primary literature. (Peer-reviewed reports customarily emphasize sequence and biological targets over exact mass cataloging.)SCIRP Files

Structural motif rationale. Tuftsin (TKPR) is an immunomodulatory tetrapeptide derived from the IgG heavy chain; appending PGP creates a chimeric, glyproline-stabilized tuftsin analog with reported anxiolytic, neuroactive, and immunomodulatory signals in preclinical and small clinical investigations.mostwiedzy.pl

Discovery history (lab, year, species)

Selank emerged from Russian peptide-neuroscience and “regulatory peptide” programs in the late 1990s–2000s as a putative anxiolytic/antistress analog of tuftsin with CNS activity and minimal sedation. Early behavioral pharmacology in rodents showed anxiolytic-like effects, modulation of stress-induced behaviors, and interactions with GABAergicsignaling.PubMed A subsequent stream of experimental work examined gene-expression effects relevant to GABAergicand inflammatory pathways, together with exploratory human evaluations in anxiety/neurasthenia cohorts.PMC+1

Endogenous vs synthetic origin

• Endogenous: Selank is not endogenous. Its parent concept derives from tuftsin, an endogenous TKPR fragment of the IgG heavy chain involved in phagocyte activation.mostwiedzy.pl

• Synthetic: Selank is produced by solid-phase peptide synthesis; reported studies used laboratory-grade material (quality verified by HPLC/MS in methods sections) and pharmaceutical intranasal formulations in Russian clinical practice literature.PubMed

Homologs, analogs, derivatives

• Tuftsin (TKPR): immunomodulatory tetrapeptide; parent template for Selank.PubMed

• Semax (MEHFPGP): a distinct glyproline heptapeptide (ACTH4-10 analog) co-developed in the same research tradition, frequently used as a mechanistic/comparative control in neuropeptide studies.PubMed

• Shorter Selank fragments and glyproline cores have been explored for activity and stability.ScienceDirect

Historical Development & Research Trajectory

Key milestones in discovery and study

1. Stress/adaptive behavior (2003): Selank and tuftsin-family peptides modulated adaptive behavior and stress responses in rodent paradigms, supporting an anxiolytic-like pharmacology distinct from benzodiazepine sedation.PubMed

2. Gene-expression links (2011–2013): Selank and fragments altered inflammation-related gene expression in mouse spleen and other tissues, hinting at immunomodulatory actions.ScienceDirect

3. GABAergic hypothesis (2016): In human lymphoblast-derived SH-SY5Y/neuronal cell models, Selank produced early transcriptional changes overlapping with GABA administration, suggesting allosteric modulation of GABAergic signaling rather than direct orthosteric action.PMC

4. Clinically relevant interactions (2017): In rats, Selank enhanced diazepam’s anxiolytic effect under chronic mild stress and showed single-agent anxiolysis; authors proposed GABA_A system engagement consistent with prior gene-expression work.PMC

5. BDNF and cognition under ethanol stress (2019): In an aging-plus-ethanol rat model, Selank attenuated memory disturbances; hippocampal/prefrontal BDNF findings implicated neurotrophin mechanisms.PubMed

6. Human exploratory trials (2008–2015): Small controlled/observational studies in generalized anxiety disorder (GAD) and neurasthenia suggested anxiolysis on psychometric scales and potential synergy with benzodiazepines; methods typically lacked modern large-scale RCT rigor.PubMed+1

Paradigm shifts and controversies

• From classic receptor binding to network modulation: Early attempts to identify a classic single receptor target gave way to transcriptomic and functional evidence for GABAergic allosteric effects, monoamine metabolism shifts, and immune-gene modulation—consistent with a systems-level anxiolytic mechanism but leaving the primary molecular target unresolved.PMC+1

• Clinical evidence gap: While multiple Russian-language or regionally published studies report efficacy in anxiety conditions, randomized, double-blind, placebo-controlled trials with modern CONSORT reporting are limited; dose, duration, and population generalizability remain uncertain.PubMed

Evolution of scientific interest

Investigations progressed from behavioral pharmacology to molecular (gene-expression, GABA-related) and then to combined pharmacology with benzodiazepines or antipsychotics (olanzapine), reflecting an interest in adjunctive as well as stand-alone anxiolysis.PMC+1

Mechanisms of Action

Primary and secondary receptor interactions

• Direct orthosteric receptor: Not established. Multiple groups have failed to demonstrate strong classical receptor binding (e.g., benzodiazepine site occupancy) at physiologically relevant concentrations; instead, Selank affects the interaction of GABA with GABA_A receptors—consistent with allosteric modulation or membrane-level effects—but does not robustly alter mRNA for GABAergic genes in some neuronal lines.PMC

• GABA_A-related modulation: Comparative transcriptomics in cortical neurons showed early gene-expression shifts 1 h after Selank administration, partially overlapping with GABA; authors argued for GABAergic system involvement without direct orthosteric action.PMC

• Monoaminergic influences: Older rat work in PCPA-pretreated models points to serotonin metabolismnormalization by Selank (tuftsin did not replicate), implicating 5-HT pathways as secondary mechanisms under depletion stress.ResearchGate

• Neurotrophin/BDNF axis: In aging + ethanol models, Selank’s protection against memory impairment was accompanied by BDNF modulation in hippocampus and prefrontal cortex, suggesting neuroplasticity-relevant effects.PubMed

• Immunomodulation: Expression analyses in spleen and other tissues indicated downstream changes in inflammation-related genes after Selank or fragments, in line with tuftsin lineage biology.ScienceDirect

Synthesis: The most consistent picture is that Selank modulates inhibitory tone (GABAergic) and stress/inflammatory gene networks, with neurotrophin and monoamine contributions—without a single, validated orthosteric receptor target.

Intracellular signaling pathways

• GABAergic network: Transcriptome responses (at ~1 h) include synaptic transmission, ion-channel, and neurotransmission genes; similarity to GABA’s early expression profile supports pathway crosstalk.PMC

• Inflammation-related gene programs: Selank/fragments altered NF-κB-adjacent and other immune-gene transcripts in mouse spleen, consistent with the tuftsin ancestry.ScienceDirect

• Neurotrophin signaling: BDNF changes under ethanol stress point to plasticity effects; whether Selank engages TrkB-dependent cascades directly or secondarily via reduced stress/inflammation is Not established.PubMed

CNS vs peripheral effects

• CNS focus: Behavioral anxiolysis, dendritic spine protection (reported for related ultra-short peptides), and GABA-network modulation place Selank’s primary research interest in CNS.PMC

• Peripheral/immune: Tuftsin lineage and spleen gene findings indicate peripheral immune modulation may accompany CNS effects.ScienceDirect

Hormonal, metabolic, immune interactions

• Stress-axis modulation is often inferred from behavioral normalization in rodent stress paradigms; direct HPAhormone profiling with Selank remains sparse.

• Immune: Gene-expression shifts and tuftsin analog biology align with immunomodulation, but dose–exposure relationships and immunological endpoints in humans are Not established.ScienceDirect

Evidence grading (A–C)

• A (replicated preclinical signals): Anxiolytic-like effects in stress models; GABA_A-related modulation in expression assays; BDNF-linked cognitive protection under ethanol stress.PubMed+2PMC+2

• B (translational indications): Small, controlled human studies suggest comparable anxiolysis to benzodiazepines with possibly distinct tolerability; adjunctive benefits with diazepam in rodents support combination hypotheses.PubMed+1

• C (uncertain mechanisms): A single primary receptor has not been identified; full PK/PD characterization and dose-response mapping in humans are Not established.

Pharmacokinetics & Stability

ADME profile

• Absorption/route: Many laboratory and clinical-practice reports describe intranasal (IN) use; however, formal PK for Selank in humans or animals is sparse in peer-reviewed journals. Some regional/legacy sources claim rapid brain access and high nasal bioavailability, but these are not consistently documented in indexed, peer-reviewed PK papers. Status: Not established.

• Distribution: As a 7-mer, Selank is expected to have limited plasma half-life and rapid renal clearance if systemic; nose-to-brain transport is plausible by analogy to other neuropeptides but specific Selank tissue distribution studies with modern analytics are lacking. Status: Not established.

• Metabolism & excretion: Likely peptidase-mediated degradation to small fragments and amino acids; details in vivo are unknown.

• Elimination half-life: Frequently cited review articles mention very short in-vitro half-life (minutes), but high-quality in vivo t½ data are not available in indexed journals. Status: Not established.SCIRP

Bottom line: Selank’s PK profile remains poorly defined in the peer-reviewed literature. Most conclusions on onset/duration rely on pharmacodynamic observations rather than rigorous PK parameters.

Stability in vitro & in vivo

• In vitro: Stable across short experimental windows used in gene-expression and cell-viability assays.

• In vivo (functional): Behavioral and gene-expression effects arise after single or short-course dosing, but without quantitative exposure measurements.

Storage/reconstitution considerations

Peer-reviewed sources do not report standardized CMC/stability datasets for research-grade Selank; standard small-peptide handling is assumed (cold chain, minimize freeze–thaw).

Preclinical Evidence

Behavioral pharmacology and anxiety paradigms

• Stress/adaptive behavior: Selank and tuftsin-family peptides modulated stress coping in rats (e.g., open-field/elevated plus maze/readouts of adaptive behavior).PubMed

• Diazepam interaction: Under unpredictable chronic mild stress, Selank alone reduced anxiety, while Selank + diazepam produced the most pronounced anxiolysis—supporting combinational strategies and GABA_A pathway involvement. Investigational dosing used in study: rat dosing regimens specified by author; behavioral outcomes at day-14/21.PMC

Molecular/transcriptomic studies

• Neurotransmission genes: Within 1 h of administration, Selank changed expression of GABA-related and neurotransmission genes in cultured neurons; profile overlapped with GABA, supporting GABAergic crosstalk. Investigational concentrations used in study; time-course: 1–3 h.PMC

• GABA_A gene expression with antipsychotics: In neuroblastoma IMR-32 cells, Selank did not directly alter GABAergic mRNAs but modulated the expression response to GABA and olanzapine, suggesting receptor-levelinteraction rather than gene induction.PMC

Neurotrophin and cognition under ethanol stress

• Aging + ethanol model: Selank prevented ethanol-induced memory/attention disturbances and was associated with BDNF content regulation in hippocampus/prefrontal cortex—consistent with neurotrophin-mediatedplasticity. Investigational dose used in study: 0.3 mg·kg⁻¹ day⁻¹ i.p. × 7 days in 9-month-old rats.PubMed

Inflammation/immune-gene modulation

• Mouse spleen & fragments: Selank and fragments altered inflammation-related gene expression dynamics, pointing to immune pathway effects consistent with tuftsin lineage biology. Investigational dosing (in vitro/in vivo) varies by model.ScienceDirect

Neuroimaging/functional connectivity (human experimental)

• Resting-state fMRI (healthy volunteers, n=52): A connectomic approach examined acute effects of Selank (and Semax) on amygdala and DLPFC functional connectivity. Results indicated region-specific FC changes consistent with anxiolytic and executive network modulation; the study was exploratory and not linked to clinical outcomes. Investigational intranasal exposure used in study; single-session imaging paradigm.PubMed

Dose ranges tested (illustrative; all investigational)

• Rodent behavioral: Doses typically 0.1–1.0 mg·kg⁻¹ i.p. or intranasal in stress/anxiety paradigms (study-specific).

• Ethanol/aging model: 0.3 mg·kg⁻¹ day⁻¹ i.p. for 7 days protected cognition and modulated BDNF.PubMed

• In-vitro: Low- to mid-micromolar concentrations over 1–24 h in gene-expression and cytoprotection assays (model-dependent).PMC

Comparative efficacy/safety (preclinical)

• Efficacy: Consistent anxiolytic-like signals and molecular shifts supportive of GABAergic, neurotrophin, and immune crosstalk.

• Safety: Preclinical reports note absence of classic benzodiazepine adverse profiles (sedation, myorelaxation, dependence) in rodent testing; however, translation to humans is not established by modern RCTs.

Limitations

• Heterogeneity of paradigms and regional concentration of research groups; exposure metrics (PK) largely missing.

• Receptor target remains uncertain, complicating SAR and in-silico design efforts.

Human Clinical Evidence

Controlled/observational trials

• GAD and neurasthenia (2008; 62 participants): A comparative clinical study evaluated selank vs medazepamover several weeks in GAD/neurasthenia using Hamilton, Zung, and CGI scales; anxiolytic effects were similarbetween agents, with reports of antiasthenic/psychostimulant features in the Selank arm. Investigational regimen used in study: clinical intranasal dosing per protocol (regional preparation); small sample size; limited modern CONSORT reporting.PubMed

• Combination therapy optimization (2015): A pragmatic study reported that adding Selank to benzodiazepinesimproved outcomes in anxiety-spectrum disorders relative to benzodiazepine monotherapy. Methodological limitations: non-blinded/limited randomization details.PubMed

• Functional connectivity (2020; healthy volunteers): Acute fMRI changes in amygdala/DLPFC networks were reported after intranasal Selank, consistent with anxiolytic network modulation; clinical endpoints were not part of this protocol.PubMed

Clinical interpretation caveats

• Trials are small and often single-center; placebo control and blinding are variably reported; dose and exposureverification (PK) are absent. Accordingly, generalizable efficacy and safety conclusions cannot be drawn at this time.

Registered trials

• As of this writing, no large, modern randomized, placebo-controlled Selank trials with posted results are indexed in ClinicalTrials.gov; regional approvals/uses are described in reviews but lack cross-jurisdictional regulatory evaluation. Status: Not established.

Safety signals/adverse events (human)

• Peer-reviewed human studies report good short-term tolerability in small cohorts, without benzodiazepine-like sedation or dependence signals; however, systematic adverse-event capture and long-term safety data are insufficient. Status: Unknown/Not established.PubMed

Comparative Context

Related peptides/approaches

• Tuftsin (TKPR): immunomodulatory tetrapeptide; ancestral to Selank.PubMed

• Semax (MEHFPGP): glyproline heptapeptide (ACTH4-10 analog) with overlapping neuroprotective/nootropicclaims; frequently co-studied with Selank in molecular and imaging paradigms.PubMed

• GABAergic modulators: Benzodiazepines produce orthosteric allosteric modulation at BZ sites on GABA_Areceptors with well-defined sedation/myorelaxation profiles—a different pharmacologic picture than Selank’s transcriptomic/allosteric inferences.MDPI

Advantages (research perspective)

• Compact heptapeptide that engages GABAergic, neurotrophin, and immune gene networks without clear benzodiazepine-like sedation in preclinical work.

• Adjunctive potential suggested by diazepam enhancement in rodent stress models.PMC

Disadvantages/constraints

• PK unknowns (bioavailability, t½, brain exposure, metabolism) hinder dose–exposure–response translation.

• Lack of modern RCTs limits conclusions on efficacy/safety in humans.

• Primary molecular target remains elusive, complicating rational SAR optimization.

Research category placement

Selank is best positioned as a research tool and candidate for anxiolytic-adjunct and neuroimmune modulation studies, particularly for probing GABAergic allosteric networks, BDNF-linked plasticity under stressors, and immune-geneexpression effects.

Research Highlights

• Sequence-defined tuftsin analog with PGP extension (TKPRPGP) and glyproline lineage—a design intended to improve stability and duration.PMC

• GABAergic modulation without canonical orthosteric binding: rapid gene-expression shifts overlap with GABA; synergy with diazepam in rodent stress paradigms.PMC+1

• BDNF-linked cognitive protection in aging + ethanol stress.PubMed

• Immunomodulatory transcripts altered in spleen, consistent with tuftsin ancestry.ScienceDirect

• Human exploratory data suggest anxiolysis comparable to benzodiazepines in small cohorts—with uncertaingeneralizability.PubMed

Conflicting/uncertain evidence.

• Definitive receptor target(s) and PK remain unresolved; human RCTs are few/dated; claims of high intranasal bioavailability are insufficiently documented in indexed PK literature.SCIRP

Potential Research Applications (no clinical claims; research-use framing)

1. GABAergic allostery mapping

   • Pair Selank with GABA_A receptor subunit-selective modulators and BZ-site antagonists; use electrophysiology and single-cell RNA-seq to dissect subunit-specific network consequences vs diazepam.PMC

2. Stress and neurotrophin plasticity

   • In aging/ethanol or chronic-stress models, quantify BDNF/TrkB signaling, dendritic spine metrics, and behavior under Selank±BZDs to determine whether neurotrophin shifts are primary or secondary.PubMed

3. Neuroimmune crosstalk

   • Validate spleen/brain inflammatory-gene effects in infection or sterile-inflammation models; track microglial and astrocyte responses.

4. Translational PK/PD groundwork

   • Execute quantitative PK (e.g., LC-MS/MS, capLC-HRMS) after intranasal and parenteral dosing in rodents/large animals; measure nose-to-brain transport metrics (e.g., DTE/DTP) and brain:plasma ratios to enable exposure–response modeling.

5. Human experimental medicine

   • In healthy volunteers, combine pharmacodynamic tasks (e.g., threat reactivity, emotional conflict) with resting-state/task fMRI and EEG to correlate FC changes with behavioral endpoints following singleSelank exposures.PubMed

Safety & Toxicology

Preclinical

Rodent studies broadly report tolerability at investigational doses and absence of benzodiazepine-like sedation or myorelaxation; however, standardized GLP toxicology (repeat-dose, reproductive, carcinogenicity) is not available in indexed literature specific to Selank. Status: Not established.

Human

Small clinical studies and experimental imaging sessions did not reveal major acute safety issues; nonetheless, systematic AE capture, long-term safety, and drug–drug interaction profiling are insufficient. Status: Unknown/Not established.PubMed

Data gaps: rigorous human PK, exposure verification, dose–response, and long-term outcomes.

Limitations & Controversies

• Evidence base concentrated in a limited number of research groups; independent, multicenter replication is limited.

• Mechanistic ambiguity persists—allosteric GABAergic interactions and neuroimmune gene modulation are plausible, but a primary molecular target is lacking.PMC

• PK uncertainty and lack of modern RCTs constrain translational conclusions.SCIRP

Future Directions

1. Define the PK: establish absolute bioavailability, t½, brain exposure, and metabolites for intranasal vs parenteral routes.

2. Target deconvolution: apply photoaffinity/chemoproteomics to identify membrane or allosteric protein targets and quantify binding (Kd) in native tissue.

3. Mechanism-informed RCTs: design randomized, placebo-controlled trials in anxiety-spectrum populations, integrating exposure verification and GABAergic biomarkers (e.g., MRS GABA, EEG endophenotypes).

4. Adjunctive strategies: test Selank with low-dose benzodiazepines or atypical antipsychotics using factorial designs to examine synergy and tolerability (guided by rodent data).PMC

5. Immune-brain cross-talk: explore whether peripheral immune modulation (derived from tuftsin lineage) contributes to central anxiolysis, using single-cell multi-omics in spleen/brain.

References

1. Volkova A, et al. Selank Administration Affects the Expression of Some Genes Involved in GABAergic Neurotransmission. Front Pharmacol. 2016;7:31. PMID: 26924987. (Early gene-expression shifts; allosteric GABAergic hypothesis.) PMC

2. Filatova E, et al. GABA, Selank, and Olanzapine Affect the Expression of GABAergic Genes in IMR-32 Cells.Front Pharmacol. 2017;8:89. PMID: 28293176. (No direct GABA-gene upregulation; modulation of GABA–GABA_A interaction.) PMC

3. Kasian A, et al. Peptide Selank Enhances the Effect of Diazepam in a Rat Model. Neural Plast.2017;2017:5091027. (Rodent UCMS; Selank alone and synergistic with diazepam.) PMC

4. Kozlovskaya MM, et al. Selank and Tuftsin-family Peptides in Regulation of Adaptive Behavior in Stress. Neurosci Behav Physiol. 2003;33(9):853–860. PMID: 14969422. (Early behavioral pharmacology.) PubMed

5. Kolomin T, et al. Expression of inflammation-related genes in mouse spleen under Selank and fragments. Neurosci Lett. 2011; (abstracted on ScienceDirect). (Immune-gene modulation.) ScienceDirect

6. Zozulia AA, et al. Efficacy and possible mechanisms of action of Selank in GAD/neurasthenia. Zh Nevrol Psikhiatr Im S S Korsakova. 2008;108(4):38–49. PMID: 18454096. (Small clinical comparison vs medazepam.) PubMed

7. Kolik LG, et al. Selank (tuftsin analog) protects against ethanol-induced memory impairment via BDNF regulation. Bull Exp Biol Med. 2019;167(6):760–764. PMID: 31625062. (Aging + ethanol; BDNF mechanism.) PubMed

8. Panikratova YR, et al. Functional connectomic approach to Selank and Semax effects (rs-fMRI). Bull Exp Biol Med. 2020;169(2):260–265. PMID: 32342318. (Acute FC changes in healthy volunteers.) PubMed

9. Vyunova TV, et al. Molecular aspects of Selank biological activity. Curr Drug Targets. 2018;19(6):700–711. PMID: 30255741. (Sequence confirmation; mechanistic overview.) PubMed

10. Tuftsin—Properties and Analogs (review). Curr Med Chem. 2017;24: (Siebert A.). PMID: 28745220. (Tuftsin analogs; Selank lineage context.) PubMed

Investigational amounts (illustrative):
• Rodent ethanol/aging model: 0.3 mg·kg⁻¹ day⁻¹ i.p. × 7 days prevented memory impairment and modulated BDNF. Investigational dose used in Kolik 2019. PubMed
• Rodent UCMS (anxiety): Selank alone and Selank + diazepam regimens per Kasian 2017 reduced anxiety in UCMS; dose/schedule per paper. Investigational doses used in Kasian 2017. PMC
• Human GAD/neurasthenia: Small clinical comparison vs medazepam; intranasal Selank regimens per protocol; similar anxiolysis on Hamilton/Zung/CGI scales. Investigational regimen used in Zozulia 2008.PubMed

⚠️ Disclaimer This peptide is intended strictly for laboratory research use. It is not FDA-approved or authorized for human use, consumption, or therapeutic application.