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Phenylpiracetam

(Redirected from Carphedon)

Phenylpiracetam, also known as fonturacetam (INNTooltip International nonproprietary name) and sold under the brand names Phenotropil or Fenotropil and Carphedon, is a phenyl-substituted analog of the drug piracetam.[2] It was developed in 1983 as a medication for Soviet cosmonauts to treat the prolonged stresses of working in space. Phenylpiracetam was created at the Russian Academy of Sciences Institute of Biomedical Problems in an effort led by psychopharmacologist Valentina Ivanovna Akhapkina (Валентина Ивановна Ахапкина).[3][4] In Russia it is now available as a prescription drug. Research on animals has indicated that phenylpiracetam may have anti-amnesic, antidepressant, anticonvulsant, anxiolytic, and memory enhancement effects.[2][5]

Phenylpiracetam
Clinical data
Trade namesPhenotropil, Fenotropil, Carphedon
Other namesFonturacetam; Phenotropil; Fenotropil; 4-Phenylpiracetam
Pregnancy
category
  • Unknown
Routes of
administration		Oral (tablets)
Drug classAtypical dopamine reuptake inhibitor[1]
ATC code
  • None
Legal status
Legal status
  • AU: S4 (Prescription only)
  • US: Unapproved "New Drug" (as defined by 21 U.S. Code § 321(p)(1)). Use in dietary supplements, food, or medicine is unlawful; otherwise uncontrolled.
  • RU: Rx-only
Pharmacokinetic data
Bioavailability~100%
MetabolismNone
Onset of action20-40 minutes
Elimination half-life3–5 hours
ExcretionUrine (~40%), bile and perspiration (~60%)
Identifiers
  • (R,S)-2-(2-oxo-4-phenylpyrrolidin-1-yl)acetamide
CAS Number
PubChem CID
ChemSpider
UNII
CompTox Dashboard (EPA)
ECHA InfoCard100.214.874 Edit this at Wikidata
Chemical and physical data
FormulaC12H14N2O2
Molar mass218.256 g·mol−1
3D model (JSmol)
ChiralityRacemic mixture
Boiling point486.4 °C (907.5 °F)
  • C1=CC=CC=C1C2CN(C(C2)=O)CC(=O)N
  • InChI=1S/C12H14N2O2/c13-11(15)8-14-7-10(6-12(14)16)9-4-2-1-3-5-9/h1-5,10H,6-8H2,(H2,13,15) ☒N
  • Key:LYONXVJRBWWGQO-UHFFFAOYSA-N ☒N
 ☒NcheckY (what is this?)  (verify)

Clinical use of phenylpiracetam has shown to be more potent than piracetam and is used for a wider-range of indications.[2]

Phenylpiracetam is typically prescribed as a general stimulant or to increase tolerance to extreme temperatures and stress.[6]

A few small clinical studies have shown possible links between prescription of phenylpiracetam and improvement in a number of encephalopathic conditions, including lesions of cerebral blood pathways, traumatic brain injury and certain types of glioma.[7]

Phenylpiracetam has been researched for the treatment of Parkinson's disease.[8]

Clinical trials were conducted at the Serbsky State Scientific Center for Social and Forensic Psychiatry. The Serbsky Center, Moscow Institute of Psychiatry, and Russian Center of Vegetative Pathology are reported to have confirmed the effectiveness of Phenylpiracetam (Phenotropil) describing the following effects: improvement of regional blood flow in ischemic regions of the brain, reduction of depressive and anxiety disorders, increase the resistance of brain tissue to hypoxia and toxic effects, improving concentration and mental activity, a psycho-activating effect, increase in the threshold of pain sensitivity, improvement in the quality of sleep, and an anticonvulsant action,[9] though with the side effect of an anorexic effect in extended use.[10][11]

In 2014, phenylpiracetam's (R)-enantiomer, MRZ-9547, was found to act as a selective dopamine reuptake inhibitor.[1][12]

Animal model research

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Phenylpiracetam has been shown to reverse the depressant effects of the benzodiazepine diazepam, increases operant behavior, inhibits post-rotational nystagmus, prevents retrograde amnesia, and has anticonvulsant properties in animal models.[2][13][14][15]

In Wistar rats with gravitational cerebral ischemia, phenylpiracetam reduced the extent of neuralgic deficiency manifestations, retained the locomotor, research, and memory functions, increased the survival rate, and lead to the favoring of local cerebral flow restoration upon the occlusion of carotid arteries to a greater extent than did piracetam.[16]

Operant behavior

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In tests against a control, Sprague-Dawley rats given free access to less-preferred rat chow and trained to operate a lever repeatedly to obtain preferred rat chow performed additional work when given methylphenidate, dextroamphetamine, and phenylpiracetam. Rats administered 100 mg/kg phenylpiracetam performed, on average, 375% more work than rats given placebo, and consumed little non-preferred rat chow. In comparison, rats administered 1mg/kg d-amphetamine or 10 mg/kg methylphenidate performed, on average, 150% and 170% more work respectively, and consumed half as much non-preferred rat chow.

Present data show that (R)-phenylpiracetam increases motivation, i.e., the work load, which animals are willing to perform to obtain more rewarding food. At the same time consumption of freely available normal food does not increase. Generally this indicates that (R)-phenylpiracetam increase motivation [...] The effect of (R)-phenylpiracetam is much stronger than that of methylphenidate and amphetamine.[17]

Pharmacology

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Phenylpiracetam binds to α4β2 nicotinic acetylcholine receptors in the mouse brain cortex with IC50 = 5.86 μM.[13][18]

Experiments performed on Sprague-Dawley rats in a European patent for using Phenylpiracetam to treat sleep disorders showed an increase in extracellular dopamine levels after administration. The patent asserts discovery of phenylpiracetam's action as a dopamine reuptake inhibitor[17] as its basis.[19]

The peculiarity of this invention compared to former treatment approaches for treating sleep disorders is the so far unknown therapeutic efficacy of (R)-phenylpiracetam, which is presumably based at least in part on the newly identified activity of (R)-phenylpiracetam as the dopamine re-uptake inhibitor

Both enantiomers of phenylpiracetam have been described in peer-reviewed research as dopamine transporter (DAT) inhibitors in rodents, confirming the patent claim.[20][21] Their action at the noradrenaline transporter vary: the R enantiomer acts as a noradrenaline reuptake inhibitor (thus, an NDRI) with 11-fold lower affinity to NET than to DAT, while the S enantiomer has no such effect.[21]

Chemistry

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Phenylpiracetam, also known as 4-phenylpiracetam, is a racetam and a derivative of piracetam.[2][14] In contrast to piracetam and most other racetams however, phenylpiracetam also contains β-phenylethylamine within its chemical structure and hence can be conceptualized as a substituted phenethylamine.[22]

Phenylpiracetam is a racemic mixture of (R)- and (S)-enantiomers.[22][1][12] The (R)-enantiomer of phenylpiracetam, (R)-phenylpiracetam, is also known as MRZ-9547.[1][12]

Derivatives

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RGPU-95 (p-chlorophenylpiracetam) is a derivative of phenylpiracetam described as having 5- to 10-fold greater potency.[23][24]

Methylphenylpiracetam, including all four of its stereoisomers, is a positive allosteric modulator of the sigma σ1 receptor.[25]

Phenylpiracetam hydrazide is a hydrazide derivative of phenylpiracetam described as having anticonvulsant effects.[26]

History

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Phenylpiracetam was first described in the scientific literature by 1983.[14]

Pilot-cosmonaut Aleksandr Serebrov described being issued and using phenylpiracetam, as well as it being included in the Soyuz spacecraft's standard emergency medical kit, during his 197-days working in space aboard the Mir space station. He reported "the drug acts as the equalizer of the whole organism, "tidying it up", completely excluding impulsiveness and irritability inevitable in the stressful conditions of space flight."[3]

Society and culture

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Availability

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Phenotropil 100 mg from Russia

While not prescribed as a pharmaceutical in the West, in Russia it is available as a prescription medicine under names Phenotropil, Actitropil, Nanotropil.

Phenylpiracetam is not scheduled by the United States Drug Enforcement Administration.[27]

Athlete doping

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Phenylpiracetam has stimulant-like effects in animals and may be used as a doping agent in sport.[28] As a result, it is on the list of stimulants banned for in-competition use by the World Anti-Doping Agency (WADA).[29][28] This list is applicable in all Olympic sports.[29][17]

See also

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References

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  1. ^ a b c d Veinberg G, Vavers E, Orlova N, Kuznecovs J, Domracheva I, Vorona M, Zvejniece L, Dambrova M (2015). "Stereochemistry of phenylpiracetam and its methyl derivative: improvement of the pharmacological profile". Chemistry of Heterocyclic Compounds. 51 (7): 601–606. doi:10.1007/s10593-015-1747-9. ISSN 0009-3122. Phenylpiracetam was originally designed as a nootropic drug for the sustenance and improvement of the physical condition and cognition abilities of Soviet space crews.2 Later, especially during the last decade, phenylpiracetam was introduced into general clinical practice in Russia and in some Eastern European countries. The possible target receptors and mechanisms for the acute activity of this drug remained unclear, until very recently it was found that (R)-phenylpiracetam (5) (MRZ-9547) is a selective dopamine transporter inhibitor that moderately stimulates striatal dopamine release.19
  2. ^ a b c d e Malykh AG, Sadaie MR (February 2010). "Piracetam and piracetam-like drugs: from basic science to novel clinical applications to CNS disorders". Drugs. 70 (3): 287–312. doi:10.2165/11319230-000000000-00000. PMID 20166767.
  3. ^ a b "Фенотропил: закономерное лидерство" [Phenotropil: natural leadership]. Medi.ru (in Russian). Archived from the original on August 6, 2017. Retrieved July 24, 2023.
  4. ^ Akhapkina VI, Akhapkin RV (2013). "[Identification and evaluation of the neuroleptic activity of phenotropil]". Zh Nevrol Psikhiatr Im S S Korsakova (in Russian). 113 (7): 42–46. PMID 23994920.
  5. ^ Zvejniece L, Svalbe B, Veinberg G, Grinberga S, Vorona M, Kalvinsh I, Dambrova M (November 2011). "Investigation into stereoselective pharmacological activity of phenotropil". Basic & Clinical Pharmacology & Toxicology. 109 (5): 407–412. doi:10.1111/j.1742-7843.2011.00742.x. PMID 21689376.
  6. ^ Kim S, Park JH, Myung SW, Lho DS (November 1999). "Determination of carphedon in human urine by solid-phase microextraction using capillary gas chromatography with nitrogen-phosphorus detection". The Analyst. 124 (11): 1559–1562. Bibcode:1999Ana...124.1559K. doi:10.1039/a906027h. PMID 10746314.
  7. ^ Savchenko AI, Zakharova NS, Stepanov IN (2005). "[The phenotropil treatment of the consequences of brain organic lesions]". Zhurnal Nevrologii I Psikhiatrii imeni S.S. Korsakova. 105 (12): 22–26. PMID 16447562.
  8. ^ WO application 2014005721, Russ H, Dekundy A, Danysz W, "Use of (r)-phenylpiracetam for the treatment of parkinson's disease", published 2014-01-09, assigned to Merz Pharma GmbH & Co. KGaA 
  9. ^ Lybzikova GN, Iaglova Zh, Kharlamova Iu (2008). "[The efficacy of phenotropil in the complex treatment of epilepsy]". Zh Nevrol Psikhiatr Im S S Korsakova (in Russian). 108 (2): 69–70. PMID 18646385. {{cite journal}}: Vancouver style error: name in name 2 (help)
  10. ^ Kalinskiĭ PP, Nazarov VV (2007). "[Use of phenotropil in the treatment of asthenic syndrome and autonomic disturbances in the acute period of mild cranial brain trauma]". Zh Nevrol Psikhiatr Im S S Korsakova (in Russian). 107 (2): 61–63. PMID 18689001.
  11. ^ Gustov AA, Smirnov AA, Korshunova Iu, Andrianova EI (2006). "[Phenotropil in the treatment of vascular encephalopathy]". Zh Nevrol Psikhiatr Im S S Korsakova (in Russian). 106 (3): 52–53. PMID 16608112. {{cite journal}}: Vancouver style error: name in name 3 (help)
  12. ^ a b c Sommer S, Danysz W, Russ H, Valastro B, Flik G, Hauber W (December 2014). "The dopamine reuptake inhibitor MRZ-9547 increases progressive ratio responding in rats". The International Journal of Neuropsychopharmacology. 17 (12): 2045–2056. doi:10.1017/S1461145714000996. PMID 24964269. Here, we tested the effects of MRZ-9547 [...], and its l-enantiomer MRZ-9546 on effort-related decision making in rats. The racemic form of these compounds referred to as phenotropil has been shown to stimulate motor activity in rats (Zvejniece et al., 2011) and enhance physical capacity and cognition in humans (Malykh and Sadaie, 2010). [...] MRZ-9547 turned out to be a DAT inhibitor as shown by displacement of binding of [125I] RTI-55 (IC50 = 4.82 ± 0.05 μM, n=3) to human recombinant DAT expressed in CHO-K1 cells and inhibition of DA uptake (IC50 = 14.5 ± 1.6 μM, n=2) in functional assays in the same cells. It inhibited norepinephrine transporter (NET) with an IC50 of 182 μM (one experiment in duplicate). The potencies for the l-enantiomer MRZ-9546 were as follows: DAT binding (Ki = 34.8 ± 14.8 μM, n=3), DAT function (IC50 = 65.5 ± 8.3 μM, n=2) and NET function (IC50 = 667 μM, one experiment performed in duplicate).
  13. ^ a b Firstova YY, Abaimov DA, Kapitsa IG, Voronina TA, Kovalev GI (2011). "The effects of scopolamine and the nootropic drug phenotropil on rat brain neurotransmitter receptors during testing of the conditioned passive avoidance task". Neurochemical Journal. 28 (2): 130–141. doi:10.1134/S1819712411020048. S2CID 5845024.
  14. ^ a b c Bobkov Iu, Morozov IS, Glozman OM, Nerobkova LN, Zhmurenko LA (April 1983). "[Pharmacological characteristics of a new phenyl analog of piracetam--4-phenylpiracetam]". Biull Eksp Biol Med (in Russian). 95 (4): 50–53. doi:10.1007/BF00838859. PMID 6403074.
  15. ^ Antonova, M. I.; Prokopov, A. A.; Akhapkina, V. I.; Berlyand, A. S. (2003). "Experimental Pharmacokinetics of Phenotropyl in Rats". Pharmaceutical Chemistry Journal. 37 (11). Springer Science and Business Media LLC: 571–572. doi:10.1023/b:phac.0000016064.51030.6f. ISSN 0091-150X.
  16. ^ Tiurenkov IN, Bagmetov MN, Epishina VV (2007). "[Comparative evaluation of the neuroprotective activity of phenotropil and piracetam in laboratory animals with experimental cerebral ischemia]". Eksperimental'naia i Klinicheskaia Farmakologiia. 70 (2): 24–29. PMID 17523446.
  17. ^ a b c EP application 20140000021, "Use of (r)-phenylpiracetam for the treatment of sleep disorders", published 2015-07-08, assigned to Merz Pharma GmbH and Co KGaA 
  18. ^ Zhao X, Kuryatov A, Lindstrom JM, Yeh JZ, Narahashi T (April 2001). "Nootropic drug modulation of neuronal nicotinic acetylcholine receptors in rat cortical neurons". Mol Pharmacol. 59 (4): 674–683. doi:10.1124/mol.59.4.674. PMID 11259610.
  19. ^ Kovalev, G. I., Akhapkina, V. I., Abaimov, D. A., & Firstova, Y. Y. (2007). Phenotropil as receptor modulator of synaptic neurotransmission. Nervnye Bolezni, 4, 22–26. https://scholar.google.com/scholar?cluster=617408379890668058
  20. ^ Zvejniece L, Zvejniece B, Videja M, Stelfa G, Vavers E, Grinberga S, et al. (October 2020). "Neuroprotective and anti-inflammatory activity of DAT inhibitor R-phenylpiracetam in experimental models of inflammation in male mice". Inflammopharmacology. 28 (5): 1283–1292. doi:10.1007/s10787-020-00705-7. PMID 32279140. S2CID 215731963.
  21. ^ a b Zvejniece L, Svalbe B, Vavers E, Makrecka-Kuka M, Makarova E, Liepins V, et al. (September 2017). "S-phenylpiracetam, a selective DAT inhibitor, reduces body weight gain without influencing locomotor activity". Pharmacology, Biochemistry, and Behavior. 160: 21–29. doi:10.1016/j.pbb.2017.07.009. PMID 28743458. S2CID 13658335.
  22. ^ a b "Fonturacetam". PubChem. Retrieved 27 September 2024.
  23. ^ "102. п-Хлорфенилпирацетам (RGPU-95, p-Cl-Phenylpiracetam)" [102. p-Chlorophenylpiracetam (RGPU-95, p-Cl-Phenylpiracetam)]. АИПСИН (in Russian). Retrieved 26 September 2024. p-Chlorophenylpiracetam is a synthetic substance that is a derivative of phenylpiracetam, a nootropic drug widely used for recreational purposes. The compound, along with other analogues, was developed to obtain more powerful analogues of phenylpiracetam for the treatment of anxiety disorders. The effect of p-chlorophenylpiracetam on the human body has not been thoroughly studied. Experiments on laboratory animals have shown that the substance has the properties of an anxiolytic, antidepressant, nootropic, and in its activity, p-chlorophenylpiracetam is 5-10 times more active than phenipiracetam, therefore, the recommended doses of the substance are about 10-60 mg. Based on the few data on specialized forums, the substance begins to act 10-15 minutes after oral administration, maximum effects are achieved after 1-3 hours, the duration of action is more than 6 hours. The prevalence of the compound is currently not great due to the presence of more studied analogs on the market. Nevertheless, p-chlorophenylpiracetam has a high social danger due to its properties and the effects it has on the body. Monitoring of the spread continues.
  24. ^ Tiurenkov IN, Bagmetova VV, Shishkina AV, Berestovitskaia VM, Vasil'eva OS, Ostrogliadov ES (November 2010). "[Gender differences in action Fenotropil and its structural analog--compound RGPU-95 on anxiety-depressive behavior animals]". Eksp Klin Farmakol (in Russian). 73 (11): 10–14. PMID 21254591.
  25. ^ Vavers E, Zvejniece L, Maurice T, Dambrova M (2019). "Allosteric Modulators of Sigma-1 Receptor: A Review". Front Pharmacol. 10: 223. doi:10.3389/fphar.2019.00223. PMC 6433746. PMID 30941035.
  26. ^ Wang, Pei-Ling; Chan, Yi-Xuan; Chang, Che-Chien (2023). "New synthesis of β-aryl-GABA drugs". Tetrahedron. 146. Elsevier BV: 133648. doi:10.1016/j.tet.2023.133648. ISSN 0040-4020.
  27. ^ "List of Controlled Substances" (PDF). Division Control Division. Drug Enforcement Administration, U.S. Department of Justice. 8 February 2016. Archived from the original (PDF) on 17 April 2016. Retrieved 16 September 2013.
  28. ^ a b Docherty JR (June 2008). "Pharmacology of stimulants prohibited by the World Anti-Doping Agency (WADA)". Br J Pharmacol. 154 (3): 606–622. doi:10.1038/bjp.2008.124. PMC 2439527. PMID 18500382.
  29. ^ a b "Prohibited List" (PDF). World Anti-Doping Agency (WADA). January 2017. p. 6.
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