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Semax

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Not to be confused with semaxanib.
Semax
Clinical data
Trade namesSemax
Other namesL-Methionyl-L-α-glutamylhistidyl-L-phenylalanyl-L-prolylglycyl-L-proline, (Pro8,Gly9,Pro10)ACTH-(4-10)
ATC code
Legal status
Legal status
  • US: Not FDA approved; unscheduled
Identifiers
  • (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
CAS Number
PubChem CID
ChemSpider
UNII
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC37H51N9O10S
Molar mass813.93 g·mol−1
3D model (JSmol)
  • 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
  • InChI=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
  • Key: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.[1]

The mechanism of action of Semax is unknown.[2][3] It might interact with certain melanocortin receptors or inhibit enkephalinase enzymes.[2][3] Chemically, Semax is a peptide and a synthetic analogue of a fragment of adrenocorticotropic hormone (ACTH).[4][5]

Semax was first described by 1991.[5] 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.[6][7] The drug is widely sold by online vendors and used as a purported nootropic (cognitive enhancer).[1][8]

Medical uses

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Semax 1% from Russia.

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.[9] 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.[10][11][12][13]

Clinical trials

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In a 1996 study, 250 to 1000 μg Semax improved attention and short-term memory in 11 healthy subjects performing 8 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.[14] 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%).[14]

A 2018 study involving 110 patients recovering from ischemic stroke reported increases in brain-derived neurotrophic factor (BDNF) (correlated with early rehabilitation) in patients administered Semax.[15]

In another 2018 study involving 24 healthy participants, Semax was shown to increase fMRI default mode network activity relative to placebo.[16]

As of November 2023, there are no published clinical trials involving Semax outside of Russia and post-Soviet states.[7]

Pharmacology

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Pharmacodynamics

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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,[17] and rapidly activates serotonergic and dopaminergic brain systems.[18][19] Accordingly, it has been found to produce antidepressant-like and anxiolytic-like effects,[20][21] attenuate the behavioral effects of exposure to chronic stress,[20][21] and potentiate the locomotor activity produced by D-amphetamine.[19][22] As such, it has been suggested that Semax may be effective in the treatment of depression.[23]

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.[2] Semax did not antagonize α-MSH at the MC3 receptor, though this receptor could still be a target of the drug.[2] As for the MC1 and MC2 receptors, they were not assayed.[2] 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 μM), though the clinical significance of this property is uncertain.[3]

Pharmacokinetics

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

Chemistry

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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 (MEHFPGP in single-letter form).[4]

History

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Semax was first described in the scientific literature by 1991.[5]

Society and culture

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Etymology

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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

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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.[citation needed]

References

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  1. ^ a b Voronina TA (2023). "Cognitive Impairment and Nootropic Drugs: Mechanism of Action and Spectrum of Effects". Neurochemical Journal. 17 (2): 180–188. doi:10.1134/S1819712423020198. ISSN 1819-7124.
  2. ^ a b c d e Bertolini A (March 2012). "Drug-induced activation of the nervous control of inflammation: a novel possibility for the treatment of hypoxic damage". European Journal of Pharmacology. 679 (1–3): 1–8. doi:10.1016/j.ejphar.2012.01.004. PMID 22293371.
  3. ^ a b c Kost NV, Sokolov OI, Gabaeva MV, Grivennikov IA, Andreeva LA, Miasoedov NF, et al. (2001). "Semax and selank inhibit the enkephalin-degrading enzymes from human serum". Bioorganicheskaia Khimiia (in Russian). 27 (3): 180–183. doi:10.1023/A:1011373002885. PMID 11443939. S2CID 26029820.
  4. ^ a b Deigin VI, Poluektova EA, Beniashvili AG, Kozin SA, Poluektov YM (March 2022). "Development of Peptide Biopharmaceuticals in Russia". Pharmaceutics. 14 (4): 716. doi:10.3390/pharmaceutics14040716. PMC 9030433. PMID 35456550.
  5. ^ a b c Potaman VN, Alfeeva LY, Kamensky AA, Levitzkaya NG, Nezavibatko VN (April 1991). "N-terminal degradation of ACTH(4-10) and its synthetic analog semax by the rat blood enzymes". Biochemical and Biophysical Research Communications. 176 (2): 741–746. doi:10.1016/S0006-291X(05)80247-5. PMID 1851003.
  6. ^ "Home". AdisInsight. Retrieved 3 September 2024.
  7. ^ a b "Semax - Search Results - PubMed". PubMed. Retrieved 2023-11-12.
  8. ^ Jędrejko K, Catlin O, Stewart T, Anderson A, Muszyńska B, Catlin DH (August 2023). "Unauthorized ingredients in "nootropic" dietary supplements: A review of the history, pharmacology, prevalence, international regulations, and potential as doping agents". Drug Testing and Analysis. 15 (8). Wiley: 803–839. doi:10.1002/dta.3529. PMID 37357012.
  9. ^ "ПЕРЕЧЕНЬ. жизненно необходимых и важнейших лекарственных препаратов на 2012 год. (Vital and Essential Drugs List, 2012) - Russian Federation". World Health Organization. 2012. Archived from the original on February 2, 2015.
  10. ^ "Semax". Institute of Molecular Genetics, Russian Academy of Sciences.
  11. ^ Kurysheva NI, Shpak AA, Ioĭleva EE, Galanter LI, Nagornova ND, Shubina NI, et al. (2001). "[Semax in the treatment of glaucomatous optic neuropathy in patients with normalized ophthalmic tone]". Vestnik Oftalmologii. 117 (4): 5–8. PMID 11569188.
  12. ^ Ivanikov IO, Brekhova ME, Samonina GE, Myasoedov NF, Ashmarin IP (July 2002). "Therapy of peptic ulcer with semax peptide". Bulletin of Experimental Biology and Medicine. 134 (1): 73–74. doi:10.1023/A:1020621124776. PMID 12459874. S2CID 23447014.
  13. ^ Korneev EA, Kazakova TB (1999). "Current approaches to the analysis of the effects of stress on metabolic processes in cells of the nervous and immune systems". Med. Immunology. 1 (1–2): 17���22.
  14. ^ a b Kaplan AY, Kochetova AG, Nezavibathko VN, Rjasina TV, Ashmarin IP (September 1996). "Synthetic acth analogue semax displays nootropic-like activity in humans". Neuroscience Research Communications. 19 (2): 115–123. doi:10.1002/(SICI)1520-6769(199609)19:2<115::AID-NRC171>3.0.CO;2-B.
  15. ^ Gusev EI, Martynov MY, Kostenko EV, Petrova LV, Bobyreva SN (2018). "Éffektivnost' semaksa pri lechenii bol'nykh na raznykh stadiiakh ishemicheskogo insul'ta" [The efficacy of semax in the treatment of patients at different stages of ischemic stroke]. Zhurnal Nevrologii I Psikhiatrii Imeni S.S. Korsakova. 118 (3. Vyp. 2): 61–68. doi:10.17116/jnevro20181183261-68. PMID 29798983.
  16. ^ Lebedeva IS, Panikratova YR, Sokolov OY, Kupriyanov DA, Rumshiskaya AD, Kost NV, et al. (September 2018). "Effects of Semax on the Default Mode Network of the Brain". Bulletin of Experimental Biology and Medicine. 165 (5): 653–656. doi:10.1007/s10517-018-4234-3. PMID 30225715. S2CID 254292493.
  17. ^ Dolotov OV, Karpenko EA, Inozemtseva LS, Seredenina TS, Levitskaya NG, Rozyczka J, et al. (October 2006). "Semax, an analog of ACTH(4-10) with cognitive effects, regulates BDNF and trkB expression in the rat hippocampus". Brain Research. 1117 (1): 54–60. doi:10.1016/j.brainres.2006.07.108. PMID 16996037. S2CID 27592503.
  18. ^ Eremin KO, Kudrin VS, Grivennikov IA, Miasoedov NF, Rayevsky KS (2004). "Effects of Semax on dopaminergic and serotoninergic systems of the brain". Doklady Biological Sciences. 394 (1–6): 1–3. doi:10.1023/b:dobs.0000017114.24474.40. PMID 15088389. S2CID 12955434.
  19. ^ a b Eremin KO, Kudrin VS, Saransaari P, Oja SS, Grivennikov IA, Myasoedov NF, et al. (December 2005). "Semax, an ACTH(4-10) analogue with nootropic properties, activates dopaminergic and serotoninergic brain systems in rodents". Neurochemical Research. 30 (12): 1493–1500. doi:10.1007/s11064-005-8826-8. PMID 16362768. S2CID 38202287.
  20. ^ a b Vilenskiĭ DA, Levitskaia NG, Andreeva LA, Alfeeva LI, Kamenskiĭ AA, Miasoedov NF (June 2007). "[Effects of chronic Semax administration on exploratory activity and emotional reaction in white rats]". Rossiiskii Fiziologicheskii Zhurnal Imeni I.M. Sechenova (in Russian). 93 (6): 661–669. PMID 17850024.
  21. ^ a b Yatsenko KA, Glazova NY, Inozemtseva LS, Andreeva LA, Kamensky AA, Grivennikov IA, et al. (November 2013). "Heptapeptide semax attenuates the effects of chronic unpredictable stress in rats". Doklady Biological Sciences. 453: 353–357. doi:10.1134/S0012496613060161. PMID 24385169. S2CID 9699654.
  22. ^ Volodina MA, Sebentsova EA, Glazova NY, Levitskaya NG, Andreeva LA, Manchenko DM, et al. (March 2012). "Semax attenuates the influence of neonatal maternal deprivation on the behavior of adolescent white rats". Bulletin of Experimental Biology and Medicine. 152 (5): 560–563. doi:10.1007/s10517-012-1574-2. PMID 22803132. S2CID 1419653.
  23. ^ Pae CU (January 2008). "Therapeutic possibility of "Semax" for depression". CNS Spectrums. 13 (1): 20–21. doi:10.1017/S1092852900016102. PMID 18204410.
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