Aniracetam

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Aniracetam
Aniracetam.svg
Aniracetam3d.png
Clinical data
Trade names Ampamet, Memodrin, Pergamid
AHFS/Drugs.com International Drug Names
Routes of
administration 		By mouth
ATC code
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.
Pharmacokinetic data
Elimination half-life 0.5 hours [1] [2]
Identifiers
  • 1-[(4-Methoxybenzoyl)]-2-pyrrolidinone
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.108.230 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C12H13NO3
Molar mass 219.240 g·mol−1
3D model (JSmol)
  • O=C2N(C(=O)c1ccc(OC)cc1)CCC2
  • InChI=1S/C12H13NO3/c1-16-10-6-4-9(5-7-10)12(15)13-8-2-3-11(13)14/h4-7H,2-3,8H2,1H3 Yes check.svgY
  • Key:ZXNRTKGTQJPIJK-UHFFFAOYSA-N Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Aniracetam (brand names Draganon, Sarpul, Ampamet, Memodrin, Referan), also known as N-anisoyl-2-pyrrolidinone, is a racetam which is sold in Europe as a prescription drug. It is not approved by the Food and Drug Administration for use in the United States as a prescription medication or dietary supplement. [3] [4] Despite the FDA's lack of approval, the drug is readily available over-the-counter in misbranded dietary supplements. [3]

Contents

Medical uses

Aniracetam has been used to treat dementia following stroke and in Alzheimer's disease. [5] Results from human clinical trials were published in 1991 (one multi-center placebo-controlled study and a follow-up) and in 2011 (one open-label study). [6]

It has undergone a larger number of experiments in rodents; in a 1982 experiment on rats and mice it was found to have a variety of psychoactive effects, improving learning and memory that was otherwise impaired experimentally. [7] It has been identified as a nootropic drug due to these memory effects. [8] A 2001 study reported that in mice it has modest effects similar to an anxiolytic. [9]

Pharmacology

Aniracetam has been shown to positively modulate the AMPA receptor. [10]

When ingested orally aniracetam is quickly broken down via first pass hepatic metabolism. The primary metabolites of aniracetam are N-anisoyl-GABA, (70–80%), 2-Pyrrolidinone and p-anisic acid (20–30%). [2] [11] [12] There is some preliminary research suggesting that N-anisoyl-GABA and to a lesser degree p-ansic acid may contribute to the stimulatory effects of aniracetam in rats. [13] Further work in rats suggests that N-anisoyl-GABA may contribute more to increasing acetylcholine release than aniracetam itself. [14] For instance, a study using the forced swim test in rats found that the two metabolites 2-pyrrolidinone and N-anisoyl-GABA alone yielded similar anti-depressant effects as aniracetam itself. [13] The authors of the aforementioned study hypothesized that the metabolites work by increasing levels of dopamine and by stimulating the nicotinic acetylcholine receptors. [13]

Plasma concentrations are generally in the 5–15 μg/L range for aniracetam and 5–15 mg/L range for N-anisoyl-GABA, a pharmacologically active metabolite, during the first few hours after oral administration of the drug. These two plasma species may be measured by liquid chromatography-mass spectrometry. [15] [16] [17]

Synthesis

The drug was first made in the 1970s by Hoffmann-La Roche. [18] [19] Synthesis can be accomplished by reacting 2-pyrrolidone with anisoyl chloride in the presence of triethylamine. [20]

Aniracetam synthesis 01.svg

Alternatively, gamma-aminobutyric acid can react with anisoyl chloride. Ring closure can be accomplished in the presence of thionyl chloride. [20]

Aniracetam synthesis 02.svg

Legality

Europe

Aniracetam is available by prescription in Greece (brand names Memodrin and Referan) and Italy (brand name Ampamet), where it is indicated for mental function disorders. [21]

Australia

Aniracetam is a schedule 4 substance in Australia under the Poisons Standard (February 2020). [22] A schedule 4 substance is classified as "Prescription Only Medicine, or Prescription Animal Remedy – Substances, the use or supply of which should be by or on the order of persons permitted by state or territory legislation to prescribe and should be available from a pharmacist on prescription." [22]

See also

References

  1. ↑ Roncari G (June 1993). "Human Pharmacokinetics of Aniracetam". Drug Investigation. 5 (S1): 68–72. doi:10.1007/BF03258428. S2CID   96775295.
  2. 1 2 Lee CR, Benfield P (March 1994). "Aniracetam. An overview of its pharmacodynamic and pharmacokinetic properties, and a review of its therapeutic potential in senile cognitive disorders". Drugs & Aging. 4 (3): 257–273. doi:10.2165/00002512-199404030-00007. PMID   8199398.
  3. 1 2 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. S2CID   12176745.
  4. ↑ Cohen PA, Avula B, Wang YH, Zakharevich I, Khan I (June 2021). "Five Unapproved Drugs Found in Cognitive Enhancement Supplements". Neurology. Clinical Practice. 11 (3): e303 –e307. doi:10.1212/CPJ.0000000000000960. PMC   8382366 . PMID   34484905.
  5. ↑ Nakamura K (March 2002). "Aniracetam: its novel therapeutic potential in cerebral dysfunctional disorders based on recent pharmacological discoveries". CNS Drug Reviews. 8 (1): 70–89. doi:10.1111/j.1527-3458.2002.tb00216.x. PMC   6741661 . PMID   12070527.
  6. ↑ Love R (2024). "Aniracetam: An Evidence-Based Model for Preventing the Accumulation of Amyloid-β Plaques in Alzheimer's Disease". Journal of Alzheimer's Disease. 98 (4): 1235–1241. doi:10.3233/JAD-231247. PMC   11091568 . PMID   38552113.– Part used: references section.
  7. ↑ Cumin R, Bandle EF, Gamzu E, Haefely WE (October 1982). "Effects of the novel compound aniracetam (Ro 13-5057) upon impaired learning and memory in rodents". Psychopharmacology. 78 (2): 104–111. doi:10.1007/bf00432244. PMID   6817363. S2CID   21784298.
  8. ↑ Isaacson JS, Nicoll RA (December 1991). "Aniracetam reduces glutamate receptor desensitization and slows the decay of fast excitatory synaptic currents in the hippocampus". Proceedings of the National Academy of Sciences of the United States of America. 88 (23): 10936–10940. Bibcode:1991PNAS...8810936I. doi: 10.1073/pnas.88.23.10936 . PMC   53047 . PMID   1660156.
  9. ↑ Nakamura K, Kurasawa M (May 2001). "Anxiolytic effects of aniracetam in three different mouse models of anxiety and the underlying mechanism". European Journal of Pharmacology. 420 (1): 33–43. doi:10.1016/s0014-2999(01)01005-6. PMID   11412837.
  10. ↑ Ito I, Tanabe S, Kohda A, Sugiyama H (May 1990). "Allosteric potentiation of quisqualate receptors by a nootropic drug aniracetam". The Journal of Physiology. 424: 533–543. doi:10.1113/jphysiol.1990.sp018081. PMC   1189827 . PMID   1975272.
  11. ↑ Action A (22 July 2013). "Clinical Trials and Studies". Schizophrenia: New Insights for the Healthcare Professional. ScholarlyEditions. pp. 152–. ISBN   978-1-4816-6196-6.
  12. ↑ Testa B, Mayer JM (1 August 2003). "The Hydrolysis of Amides". Hydrolysis in Drug and Prodrug Metabolism. John Wiley & Sons. pp. 109–. ISBN   978-3-906390-25-3.
  13. 1 2 3 Nakamura K, Tanaka Y (November 2001). "Antidepressant-like effects of aniracetam in aged rats and its mode of action". Psychopharmacology. 158 (2): 205–212. doi:10.1007/s002130100849. PMID   11702095. S2CID   26390117.
  14. ↑ Shirane M, Nakamura K (March 2000). "Group II metabotropic glutamate receptors are a common target of N-anisoyl-GABA and 1S,3R-ACPD in enhancing ACh release in the prefrontal cortex of freely moving SHRSP". Neuropharmacology. 39 (5): 866–872. doi:10.1016/s0028-3908(99)00271-3. PMID   10699452. S2CID   44976290.
  15. ↑ Cai S, Wang L (May 2012). "Determination of aniracetam's main metabolite, N-anisoyl-GABA, in human plasma by LC-MS/MS and its application to a pharmacokinetic study". Journal of Chromatography B. 897: 50–54. doi:10.1016/j.jchromb.2012.04.007. PMID   22552003.
  16. ↑ Zhang J, Liang J, Tian Y, Zhang Z, Chen Y (October 2007). "Sensitive and selective liquid chromatography-tandem mass spectrometry method for the quantification of aniracetam in human plasma". Journal of Chromatography B. 858 (1–2): 129–134. doi:10.1016/j.jchromb.2007.08.010. PMID   17826366.
  17. ↑ Baselt RC (2014). Disposition of Toxic Drugs and Chemicals in Man (10th ed.). Seal Beach, CA: Biomedical Publications. pp. 142–143. ISBN   978-0-9626523-9-4.
  18. ↑ EPapplication 44088,Kyburz E, Aschwanden W,"p-Methoxy-benzoyl derivatives",published 9 February 1979, assigned to Hoffmann-La Roche
  19. ↑ EP 5143,Kyburz E, Aschwanden W,"1-Benzoyl-2-pyrrolidinone derivative, processes for its preparation and medicaments containing it.",published 9 February 1979, assigned to Hoffmann-La Roche
  20. 1 2 Kleemann A, Engels J, Kutscher B, Reichert D (2001). Pharmaceutical substances: syntheses, patents, applications (4th ed.). Stuttgart: Thieme. ISBN   978-3-13-558404-1.
  21. ↑ "Classification Status of Racetams" (PDF). New Zealand Medicines and Medical Devices Safety Authority. Retrieved 5 February 2023.
  22. 1 2 Poisons Standard February 2020. comlaw.gov.au
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