Wikipedia:WikiProject Chemicals/Chembox validation/VerifiedDataSandbox and Aniracetam: Difference between pages

{{Short description|Medication}}

{{cs1 config|name-list-style=vanc}}

{{Infobox drug

| Verifiedfields = changed

| Watchedfields = changed

| verifiedrevid = 477164594

| IUPAC_name = 1-[(4-Methoxybenzoyl)]-2-pyrrolidinone

| image = Aniracetam.svg

| width = 200

| image2 = Aniracetam3d.png

| width2 = 175

<!--Clinical data-->| tradename = Ampamet, Memodrin, Pergamid

| Drugs.com = {{drugs.com|international|aniracetam}}

| pregnancy_category =

| legal_US_comment = Unapproved "New Drug" (as defined by 21 U.S. Code § 321(p)(1)). Use in [[dietary supplement]]s, [[food]], or [[medicine]] is unlawful; otherwise uncontrolled.

| legal_AU = S4

| legal_status =

| routes_of_administration = [[Oral administration|By mouth]]

<!--Pharmacokinetic data-->| bioavailability =

| metabolism =

| elimination_half-life = 0.5 hours<ref>{{cite journal | vauthors = Roncari G |title=Human Pharmacokinetics of Aniracetam |journal=Drug Investigation |date=June 1993 |volume=5 |issue=S1 |pages=68–72 |doi=10.1007/BF03258428|s2cid=96775295 }}</ref><ref name ="lee"/>

| excretion = <!--Identifiers-->

| IUPHAR_ligand = 4133

| CAS_number_Ref = {{cascite|changed|??}}

| CAS_number = 72432-10-1

| ATC_prefix = N06

| ATC_suffix = BX11

| PubChem = 2196

| DrugBank_Ref = {{drugbankcite|correct|drugbank}}

| DrugBank = DB04599

| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}

| ChemSpiderID = 2111

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

| UNII = 5L16LKN964

| KEGG_Ref = {{keggcite|correct|kegg}}

| KEGG = D01883

| ChEBI_Ref = {{ebicite|correct|EBI}}

| ChEBI = 47943

| ChEMBL_Ref = {{ebicite|correct|EBI}}

| ChEMBL = 36994

<!--Chemical data-->| C = 12

| H = 13

| N = 1

| O = 3

| smiles = O=C2N(C(=O)c1ccc(OC)cc1)CCC2

| StdInChI_Ref = {{stdinchicite|correct|chemspider}}

| StdInChI = 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

| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}

| StdInChIKey = ZXNRTKGTQJPIJK-UHFFFAOYSA-N

'''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]].<ref name="Neuro">{{cite journal | vauthors = Malykh AG, Sadaie MR | title = Piracetam and piracetam-like drugs: from basic science to novel clinical applications to CNS disorders | journal = Drugs | volume = 70 | issue = 3 | pages = 287–312 | date = February 2010 | pmid = 20166767 | doi = 10.2165/11319230-000000000-00000 | s2cid = 12176745 }}</ref><ref>{{cite journal | vauthors = Cohen PA, Avula B, Wang YH, Zakharevich I, Khan I | title = Five Unapproved Drugs Found in Cognitive Enhancement Supplements | journal = Neurology. Clinical Practice | volume = 11 | issue = 3 | pages = e303–e307 | date = June 2021 | pmid = 34484905 | pmc = 8382366 | doi = 10.1212/CPJ.0000000000000960 }}</ref> Despite the FDA's lack of approval, the drug is readily available over-the-counter in misbranded dietary supplements.<ref name="Neuro"/>

== Medical uses ==

Aniracetam has been used to treat [[dementia]] following [[stroke]] and in [[Alzheimer's disease]].<ref>{{cite journal | vauthors = Nakamura K | title = Aniracetam: its novel therapeutic potential in cerebral dysfunctional disorders based on recent pharmacological discoveries | journal = CNS Drug Reviews | volume = 8 | issue = 1 | pages = 70–89 | date = March 2002 | pmid = 12070527 | pmc = 6741661 | doi = 10.1111/j.1527-3458.2002.tb00216.x }}</ref> It has undergone a number of experiments in rodents; in a 1982 experiment on rats and mice it was found to have a variety of [[Psychoactive drug|psychoactive]] effects, improving learning and memory that was otherwise impaired experimentally.<ref>{{cite journal | vauthors = Cumin R, Bandle EF, Gamzu E, Haefely WE | title = Effects of the novel compound aniracetam (Ro 13-5057) upon impaired learning and memory in rodents | journal = Psychopharmacology | volume = 78 | issue = 2 | pages = 104–111 | date = October 1982 | pmid = 6817363 | doi = 10.1007/bf00432244 | s2cid = 21784298 }}</ref> It has been identified as a [[nootropic]] drug due to these memory effects.<ref>{{cite journal | vauthors = Isaacson JS, Nicoll RA | title = Aniracetam reduces glutamate receptor desensitization and slows the decay of fast excitatory synaptic currents in the hippocampus | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 88 | issue = 23 | pages = 10936–10940 | date = December 1991 | pmid = 1660156 | doi = 10.1073/pnas.88.23.10936 | doi-access = free | pmc = 53047 | bibcode = 1991PNAS...8810936I }}</ref> A 2001 study reported that in mice it has modest effects similar to an [[anxiolytic]].<ref>{{cite journal | vauthors = Nakamura K, Kurasawa M | title = Anxiolytic effects of aniracetam in three different mouse models of anxiety and the underlying mechanism | journal = European Journal of Pharmacology | volume = 420 | issue = 1 | pages = 33–43 | date = May 2001 | pmid = 11412837 | doi = 10.1016/s0014-2999(01)01005-6 }}</ref>

== Pharmacology ==

Aniracetam has been shown to positively modulate the [[AMPA receptor]].<ref>{{cite journal | vauthors = Ito I, Tanabe S, Kohda A, Sugiyama H | title = Allosteric potentiation of quisqualate receptors by a nootropic drug aniracetam | journal = The Journal of Physiology | volume = 424 | pages = 533–543 | date = May 1990 | pmid = 1975272 | pmc = 1189827 | doi = 10.1113/jphysiol.1990.sp018081 }}</ref>

When ingested orally aniracetam is quickly broken down via first pass hepatic metabolism. The primary metabolites of aniracetam are [[N-anisoyl-GABA|''N''-anisoyl-GABA]], (70–80%), [[2-Pyrrolidinone]] and [[p-Anisic acid|''p''-anisic acid]] (20–30%).<ref name ="lee">{{cite journal | vauthors = Lee CR, Benfield P | title = Aniracetam. An overview of its pharmacodynamic and pharmacokinetic properties, and a review of its therapeutic potential in senile cognitive disorders | journal = Drugs & Aging | volume = 4 | issue = 3 | pages = 257–273 | date = March 1994 | pmid = 8199398 | doi = 10.2165/00002512-199404030-00007 }}</ref><ref>{{cite book | vauthors = Action A | chapter = Clinical Trials and Studies | title=Schizophrenia: New Insights for the Healthcare Professional | chapter-url = https://books.google.com/books?id=zsSvvZfC8cgC&pg=PA152|date=22 July 2013 | publisher = ScholarlyEditions | isbn = 978-1-4816-6196-6 | pages = 152– }}</ref><ref name="TestaMayer2003">{{cite book | vauthors = Testa B, Mayer JM | chapter = The Hydrolysis of Amides | title = Hydrolysis in Drug and Prodrug Metabolism| chapter-url = https://books.google.com/books?id=U-PDqHikphYC&pg=PA109 |date=1 August 2003|publisher=John Wiley & Sons|isbn=978-3-906390-25-3|pages=109–}}</ref> 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.<ref name="ratsdepression"/> Further work in rats suggests that N-anisoyl-GABA may contribute more to increasing acetylcholine release than aniracetam itself.<ref>{{cite journal | vauthors = Shirane M, Nakamura K | title = 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 | journal = Neuropharmacology | volume = 39 | issue = 5 | pages = 866–872 | date = March 2000 | pmid = 10699452 | doi = 10.1016/s0028-3908(99)00271-3 | s2cid = 44976290 }}</ref> For instance, a study using the [[Behavioural despair test|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.<ref name="ratsdepression">{{cite journal | vauthors = Nakamura K, Tanaka Y | title = Antidepressant-like effects of aniracetam in aged rats and its mode of action | journal = Psychopharmacology | volume = 158 | issue = 2 | pages = 205–212 | date = November 2001 | pmid = 11702095 | doi = 10.1007/s002130100849 | s2cid = 26390117 }}</ref> The authors of the aforementioned study hypothesized that the metabolites work by increasing levels of dopamine and by stimulating the nicotinic acetylcholine receptors.<ref name="ratsdepression"/>

Plasma concentrations are generally in the 5–15 ''μ''g/L range for aniracetam and 5–15&nbsp;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.<ref name="Cai_2012">{{cite journal | vauthors = Cai S, Wang L | title = Determination of aniracetam's main metabolite, N-anisoyl-GABA, in human plasma by LC-MS/MS and its application to a pharmacokinetic study | journal = Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences | volume = 897 | pages = 50–54 | date = May 2012 | pmid = 22552003 | doi = 10.1016/j.jchromb.2012.04.007 }}</ref><ref>{{cite journal | vauthors = Zhang J, Liang J, Tian Y, Zhang Z, Chen Y | title = Sensitive and selective liquid chromatography-tandem mass spectrometry method for the quantification of aniracetam in human plasma | journal = Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences | volume = 858 | issue = 1–2 | pages = 129–134 | date = October 2007 | pmid = 17826366 | doi = 10.1016/j.jchromb.2007.08.010 }}</ref><ref>{{cite book | title = Disposition of Toxic Drugs and Chemicals in Man | edition = 10th | vauthors = Baselt RC | publisher = Biomedical Publications | location = Seal Beach, CA | date = 2014| isbn = 978-0-9626523-9-4 | pages = 142–143 }}</ref>

==Synthesis==

The drug was first made in the 1970s by [[Hoffmann-La Roche]].<ref>{{cite patent |country= EP |number= 44088 |status= application |title= p-Methoxy-benzoyl derivatives |pubdate= 9 February 1979 |gdate= |fdate= |pridate= 10 February 1978 |inventor= Kyburz E, Aschwanden W |assign1= Hoffmann-La Roche }}</ref><ref>{{cite patent |country= EP |number= 5143 |status= |title= 1-Benzoyl-2-pyrrolidinone derivative, processes for its preparation and medicaments containing it. |pubdate= 9 February 1979 |gdate= |fdate= |pridate = 10 February 1978 | inventor = Kyburz E, Aschwanden W |assign1= Hoffmann-La Roche }}</ref> Synthesis can be accomplished by reacting [[2-pyrrolidone]] with [[anisoyl chloride]] in the presence of [[triethylamine]].<ref name="Kleemann">{{cite book | vauthors = Kleemann A, Engels J, Kutscher B, Reichert D | title = Pharmaceutical substances: syntheses, patents, applications | date = 2001 | publisher = Thieme | location = Stuttgart | isbn = 978-3-13-558404-1 | edition = 4th }}</ref>

[[Image:Aniracetam synthesis 01.svg|480px]]

Alternatively, [[gamma-aminobutyric acid]] can react with anisoyl chloride. Ring closure can be accomplished in the presence of [[thionyl chloride]].<ref name="Kleemann"/>

[[Image:Aniracetam synthesis 02.svg|500px]]

== 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.<ref name="nz_medsafe">{{cite web |title=Classification Status of Racetams |url=https://medsafe.govt.nz/profs/class/Agendas/agen53Racetams.pdf |publisher=New Zealand Medicines and Medical Devices Safety Authority |access-date=5 February 2023}}</ref>

=== Australia ===

Aniracetam is a schedule 4 substance in Australia under the [[Standard for the Uniform Scheduling of Medicines and Poisons|Poisons Standard (February 2020)]].<ref name="Poisons Stanrard">[https://www.legislation.gov.au/Details/F2020C00148 Poisons Standard February 2020]. comlaw.gov.au</ref> 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."<ref name="Poisons Stanrard" />

== See also ==

* [[AMPA receptor positive allosteric modulator]]

== References ==

{{Reflist|32em}}

{{Ionotropic glutamate receptor modulators}}

{{Racetams}}

[[Category:AMPA receptor positive allosteric modulators]]

[[Category:Nootropics]]

[[Category:4-Methoxyphenyl compounds]]

[[Category:Racetams]]