semax

{{Drugbox

| drug_name =

| image = Semax.svg

| width = 250px

| tradename = Semax

| legal_US = Not FDA approved; unscheduled

| CAS_number_Ref = {{cascite|correct|CAS}}

| CAS_number = 80714-61-0

| CAS_supplemental =
4037-01-8

| UNII_Ref = {{fdacite|correct|FDA}}

| UNII = I5FAL2585H

| ATC_prefix = N06BX

| PubChem = 122178

| synonyms = L-Methionyl-L-α-glutamylhistidyl-L-phenylalanyl-L-prolylglycyl-L-proline, (Pro⁸,Gly⁹,Pro¹⁰)ACTH-(4-10)

| IUPAC_name = (2S)-1-[2-{[(2S)-1-[(2S)-2-{[2-{[(2S)-2-{[(2S)-2-amino-4-methylsulfanylbutanoyl]amino}-4-carboxybutanoyl]amino}-3-(1H-imidazol-5-yl)propanoyl]amino}-3-phenylpropanoyl]pyrrolidine-2-carbonyl]amino}acetyl]pyrrolidine-2-carboxylic acid

| C=37 | H=51 | N=9 | O=10 | S=1

| SMILES = O=C(N[C@@H](CCC(O)=O)C(N[C@@H](CC1=CNC=N1)C(N[C@@H](CC2=CC=CC=C2)C(N3[C@@H](CCC3)C(NCC(N4[C@@H](CCC4)C(O)=O)=O)=O)=O)=O)=O)[C@H](CCSC)N

| ChemSpiderID = 108969

| StdInChI = 1S/C37H51N9O10S/c1-57-16-13-24(38)32(50)42-25(11-12-31(48)49)33(51)43-26(18-23-19-39-21-41-23)34(52)44-27(17-22-7-3-2-4-8-22)36(54)46-15-5-9-28(46)35(53)40-20-30(47)45-14-6-10-29(45)37(55)56/h2-4,7-8,19,21,24-29H,5-6,9-18,20,38H2,1H3,(H,39,41)(H,40,53)(H,42,50)(H,43,51)(H,44,52)(H,48,49)(H,55,56)/t24-,25-,26?,27-,28-,29-/m0/s1

| StdInChIKey = AFEHBIGDWIGTEH-CXFOGXNKSA-N

}}

Semax is a medication which is used in Russia and Eastern Europe for the treatment of a broad range of conditions like brain trauma but predominantly for its claimed nootropic, neuroprotective, and neurorestorative effects.{{cite journal | vauthors = Voronina TA | title=Cognitive Impairment and Nootropic Drugs: Mechanism of Action and Spectrum of Effects | journal=Neurochemical Journal | volume=17 | issue=2 | date=2023 | issn=1819-7124 | doi=10.1134/S1819712423020198 | pages=180–188| doi-access=free }}

The mechanism of action of Semax is unknown. It might interact with certain melanocortin receptors or inhibit enkephalinase enzymes. Chemically, Semax is a peptide and a synthetic analogue of a fragment of adrenocorticotropic hormone (ACTH).

Semax was first described by 1991. Although used as a prescription drug in Russia and Eastern Europe, Semax has not been evaluated, approved for use, or marketed in most other countries.{{cite web | title=Home | website=AdisInsight | url=https://adisinsight.springer.com/ | access-date=3 September 2024}} The drug is widely sold by online vendors and used as a purported nootropic (cognitive enhancer).{{cite journal | vauthors = Jędrejko K, Catlin O, Stewart T, Anderson A, Muszyńska B, Catlin DH | title = Unauthorized ingredients in "nootropic" dietary supplements: A review of the history, pharmacology, prevalence, international regulations, and potential as doping agents | journal = Drug Testing and Analysis | volume = 15 | issue = 8 | pages = 803–839 | date = August 2023 | pmid = 37357012 | doi = 10.1002/dta.3529 | publisher = Wiley | url = https://ruj.uj.edu.pl/xmlui/handle/item/313008 }}

Medical uses

File:Semax 1% from Russia.jpg.]]

Semax has undergone extensive study in Russia and is on the Russian List of Vital & Essential Drugs approved by the Russian Federation government on December 7, 2011.{{cite web | url=http://apps.who.int/medicinedocs/en/d/Js19766ru/ | archive-url=https://web.archive.org/web/20150202044326/http://apps.who.int/medicinedocs/en/d/Js19766ru/ | url-status=dead | archive-date=February 2, 2015 | title=ПЕРЕЧЕНЬ. жизненно необходимых и важнейших лекарственных препаратов на 2012 год. (Vital and Essential Drugs List, 2012) - Russian Federation | publisher=World Health Organization | date=2012}} Medical uses for Semax include treatment of stroke, transient ischemic attack, memory and cognitive disorders, peptic ulcers, optic nerve disease, and to boost the immune system.{{cite web | url = http://old.img.ras.ru/semax1-e.htm | title = Semax | publisher = Institute of Molecular Genetics, Russian Academy of Sciences}}{{cite journal | vauthors = Kurysheva NI, Shpak AA, Ioĭleva EE, Galanter LI, Nagornova ND, Shubina NI, Shlyshalova NN | title = [Semax in the treatment of glaucomatous optic neuropathy in patients with normalized ophthalmic tone] | journal = Vestnik Oftalmologii | volume = 117 | issue = 4 | pages = 5–8 | year = 2001 | pmid = 11569188 }}{{cite journal | vauthors = Ivanikov IO, Brekhova ME, Samonina GE, Myasoedov NF, Ashmarin IP | title = Therapy of peptic ulcer with semax peptide | journal = Bulletin of Experimental Biology and Medicine | volume = 134 | issue = 1 | pages = 73–74 | date = July 2002 | pmid = 12459874 | doi = 10.1023/A:1020621124776 | s2cid = 23447014 }}{{cite journal | vauthors = Korneev EA, Kazakova TB |title=Current approaches to the analysis of the effects of stress on metabolic processes in cells of the nervous and immune systems |journal=Med. Immunology |year=1999 |volume=1 |issue=1–2 |pages=17–22}}

=Clinical trials=

In a 1996 study, 250 to 1000{{nbsp}}μg Semax improved attention and short-term memory in 11{{nbsp}}healthy subjects performing 8{{nbsp}}hour work shifts, though the effects were most pronounced when subjects were fatigued (after the shift was over) and the effects lasted going into the next day.{{cite journal | vauthors = Kaplan AY, Kochetova AG, Nezavibathko VN, Rjasina TV, Ashmarin IP | title = Synthetic acth analogue semax displays nootropic-like activity in humans. | journal = Neuroscience Research Communications | date = September 1996 | volume = 19 | issue = 2 | pages = 115–123 | doi = 10.1002/(SICI)1520-6769(199609)19:2<115::AID-NRC171>3.0.CO;2-B }} In a follow-up memory test administered the morning after Semax administration, the treatment group made more correct responses (71%) than the control group (41%).

A 2018 study involving 110{{nbsp}}patients recovering from ischemic stroke reported increases in brain-derived neurotrophic factor (BDNF) (correlated with early rehabilitation) in patients administered Semax.{{cite journal | vauthors = Gusev EI, Martynov MY, Kostenko EV, Petrova LV, Bobyreva SN | title = Éffektivnost' semaksa pri lechenii bol'nykh na raznykh stadiiakh ishemicheskogo insul'ta | trans-title = The efficacy of semax in the treatment of patients at different stages of ischemic stroke | journal = Zhurnal Nevrologii I Psikhiatrii imeni S.S. Korsakova | volume = 118 | issue = 3. Vyp. 2 | pages = 61–68 | date = 2018 | pmid = 29798983 | doi = 10.17116/jnevro20181183261-68 | doi-access = free }}

In another 2018 study involving 24{{nbsp}}healthy participants, Semax was shown to increase fMRI default mode network activity relative to placebo.{{cite journal | vauthors = Lebedeva IS, Panikratova YR, Sokolov OY, Kupriyanov DA, Rumshiskaya AD, Kost NV, Myasoedov NF | title = Effects of Semax on the Default Mode Network of the Brain | journal = Bulletin of Experimental Biology and Medicine | volume = 165 | issue = 5 | pages = 653–656 | date = September 2018 | pmid = 30225715 | doi = 10.1007/s10517-018-4234-3 | s2cid = 254292493 }}

As of November 2023, there are no published clinical trials involving Semax outside of Russia and post-Soviet states.{{Cite web |title=Semax - Search Results - PubMed |url=https://pubmed.ncbi.nlm.nih.gov/?term=Semax&filter=pubt.clinicaltrial&filter=pubt.meta-analysis&filter=pubt.randomizedcontrolledtrial |access-date=2023-11-12 |website=PubMed |language=en}}

Pharmacology

=Pharmacodynamics=

In animals, Semax rapidly elevates the levels and expression of brain-derived neurotrophic factor (BDNF) and its signaling receptor tropomyosin receptor kinase B (TrkB) in the hippocampus,{{cite journal | vauthors = Dolotov OV, Karpenko EA, Inozemtseva LS, Seredenina TS, Levitskaya NG, Rozyczka J, Dubynina EV, Novosadova EV, Andreeva LA, Alfeeva LY, Kamensky AA, Grivennikov IA, Myasoedov NF, Engele J | title = Semax, an analog of ACTH(4-10) with cognitive effects, regulates BDNF and trkB expression in the rat hippocampus | journal = Brain Research | volume = 1117 | issue = 1 | pages = 54–60 | date = October 2006 | pmid = 16996037 | doi = 10.1016/j.brainres.2006.07.108 | s2cid = 27592503 }} and rapidly activates serotonergic and dopaminergic brain systems.{{cite journal | vauthors = Eremin KO, Kudrin VS, Grivennikov IA, Miasoedov NF, Rayevsky KS | title = Effects of Semax on dopaminergic and serotoninergic systems of the brain | journal = Doklady Biological Sciences | volume = 394 | issue = 1–6 | pages = 1–3 | year = 2004 | pmid = 15088389 | doi = 10.1023/b:dobs.0000017114.24474.40 | s2cid = 12955434 }}{{cite journal | vauthors = Eremin KO, Kudrin VS, Saransaari P, Oja SS, Grivennikov IA, Myasoedov NF, Rayevsky KS | title = Semax, an ACTH(4-10) analogue with nootropic properties, activates dopaminergic and serotoninergic brain systems in rodents | journal = Neurochemical Research | volume = 30 | issue = 12 | pages = 1493–1500 | date = December 2005 | pmid = 16362768 | doi = 10.1007/s11064-005-8826-8 | s2cid = 38202287 }} Accordingly, it has been found to produce antidepressant-like and anxiolytic-like effects,{{cite journal | vauthors = Vilenskiĭ DA, Levitskaia NG, Andreeva LA, Alfeeva LI, Kamenskiĭ AA, Miasoedov NF | title = [Effects of chronic Semax administration on exploratory activity and emotional reaction in white rats] | language = ru | journal = Rossiiskii Fiziologicheskii Zhurnal imeni I.M. Sechenova | volume = 93 | issue = 6 | pages = 661–669 | date = June 2007 | pmid = 17850024 }}{{cite journal | vauthors = Yatsenko KA, Glazova NY, Inozemtseva LS, Andreeva LA, Kamensky AA, Grivennikov IA, Levitskaya NG, Dolotov OV, Myasoedov NF | title = Heptapeptide semax attenuates the effects of chronic unpredictable stress in rats | journal = Doklady Biological Sciences | volume = 453 | pages = 353–357 | date = November 2013 | pmid = 24385169 | doi = 10.1134/S0012496613060161 | s2cid = 9699654 }} attenuate the behavioral effects of exposure to chronic stress, and potentiate the locomotor activity produced by D-amphetamine.{{cite journal | vauthors = Volodina MA, Sebentsova EA, Glazova NY, Levitskaya NG, Andreeva LA, Manchenko DM, Kamensky AA, Myasoedov NF | title = Semax attenuates the influence of neonatal maternal deprivation on the behavior of adolescent white rats | journal = Bulletin of Experimental Biology and Medicine | volume = 152 | issue = 5 | pages = 560–563 | date = March 2012 | pmid = 22803132 | doi = 10.1007/s10517-012-1574-2 | s2cid = 1419653 }} As such, it has been suggested that Semax may be effective in the treatment of depression.{{cite journal | vauthors = Pae CU | title = Therapeutic possibility of "Semax" for depression | journal = CNS Spectrums | volume = 13 | issue = 1 | pages = 20–21 | date = January 2008 | pmid = 18204410 | doi = 10.1017/S1092852900016102 | doi-access = free }}

Though the exact mechanism of action of Semax is unclear, there is evidence that it may act through melanocortin receptors. Specifically, there is a report of Semax competitively antagonizing the action of the melanocortin receptor full agonist α-melanocyte-stimulating hormone (α-MSH) at the MC₄ and MC₅ receptors in both in vitro and in vivo experimental conditions, indicating that it may act as an antagonist or partial agonist of these receptors.{{cite journal | vauthors = Bertolini A | title = Drug-induced activation of the nervous control of inflammation: a novel possibility for the treatment of hypoxic damage | journal = European Journal of Pharmacology | volume = 679 | issue = 1–3 | pages = 1–8 | date = March 2012 | pmid = 22293371 | doi = 10.1016/j.ejphar.2012.01.004 }} Semax did not antagonize α-MSH at the MC₃ receptor, though this receptor could still be a target of the drug. As for the MC₁ and MC₂ receptors, they were not assayed. In addition to actions at receptors, Semax, as well as a related peptide drug, Selank, have been found to inhibit enzymes involved in the degradation of enkephalins and other endogenous regulatory peptides (IC₅₀ = 10{{nbsp}}μM), though the clinical significance of this property is uncertain.{{cite journal | vauthors = Kost NV, Sokolov OI, Gabaeva MV, Grivennikov IA, Andreeva LA, Miasoedov NF, Zozulia AA | title = Semax and selank inhibit the enkephalin-degrading enzymes from human serum | language = ru | journal = Bioorganicheskaia Khimiia | volume = 27 | issue = 3 | pages = 180–183 | year = 2001 | pmid = 11443939 | doi = 10.1023/A:1011373002885 | s2cid = 26029820 }}

=Pharmacokinetics=

As a peptide, Semax has poor oral bioavailability and hence is administered parenterally as a nasal spray or subcutaneous injection.

Chemistry

Semax is a heptapeptide and synthetic analogue of a fragment of adrenocorticotropic hormone (ACTH), ACTH (4-10), of the following amino acid sequence: Met-Glu-His-Phe-Pro-Gly-Pro ({{tt|MEHFPGP}} in single-letter form).{{cite journal | vauthors = Deigin VI, Poluektova EA, Beniashvili AG, Kozin SA, Poluektov YM | title = Development of Peptide Biopharmaceuticals in Russia | journal = Pharmaceutics | volume = 14 | issue = 4 | page = 716 | date = March 2022 | pmid = 35456550 | pmc = 9030433 | doi = 10.3390/pharmaceutics14040716 | doi-access = free }}

History

Semax was first described in the scientific literature by 1991.{{cite journal | vauthors = Potaman VN, Alfeeva LY, Kamensky AA, Levitzkaya NG, Nezavibatko VN | title = N-terminal degradation of ACTH(4-10) and its synthetic analog semax by the rat blood enzymes | journal = Biochemical and Biophysical Research Communications | volume = 176 | issue = 2 | pages = 741–746 | date = April 1991 | pmid = 1851003 | doi = 10.1016/S0006-291X(05)80247-5 }}

Society and culture

=Etymology=

Semax is composed of seven amino acid residues: Met-Glu-His-Phe-Pro-Gly-Pro (MEHFPGP), which is reflected in the name - from an abbreviation of "seven amino acids"—in Russian: СЕМь АминоКиСлот—СЕМАКС.

=Marketing=

Semax was developed, produced, and marketed by Peptogen in the Russian Federation with participation of the Institute of Molecular Genetics of the Russian Academy of Sciences.https://ignitepeptides.com/product/smax-10mg/ 6