Wikipedia:WikiProject Chemicals/Chembox validation/VerifiedDataSandbox and AM404: Difference between pages

{{Short description|Active metabolite of paracetamol}}

{{missing information|history of discovery — who gave it this codename?|date=December 2022}}

{{Infobox drug

| Verifiedfields = changed

| Watchedfields = changed

| verifiedrevid = 477236071

| IUPAC_name = (5''Z'',8''Z'',11''Z'',14''Z'')- ''N''-(4-Hydroxyphenyl)icosa- 5,8,11,14-tetraenamide

| routes_of_administration =

| excretion =

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

| CAS_number = 183718-77-6

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

| UNII = XVJ94H0U21

| C=26 | H=37 | N=1 | O=2

'''AM404''', also known as '''''N''-arachidonoylphenolamine''',<ref name="Nakamura2022">{{cite journal | vauthors = Nakamura S, Nonaka T, Komatsu S, Yamada T, Yamamoto T | title = Oral acetaminophen-induced spinal 5-hydroxytriyptamine release produces analgesic effects in the rat formalin test | journal = Biomedicine & Pharmacotherapy | volume = 146 | pages = 112578 | date = February 2022 | pmid = 34959121 | doi = 10.1016/j.biopha.2021.112578 | s2cid = 245483361 | doi-access = free }}</ref><ref name="Rogosch2012">{{cite journal | vauthors = Rogosch T, Sinning C, Podlewski A, Watzer B, Schlosburg J, Lichtman AH, Cascio MG, Bisogno T, Di Marzo V, Nüsing R, Imming P | display-authors = 6 | title = Novel bioactive metabolites of dipyrone (metamizol) | journal = Bioorganic & Medicinal Chemistry | volume = 20 | issue = 1 | pages = 101–107 | date = January 2012 | pmid = 22172309 | pmc = 3248997 | doi = 10.1016/j.bmc.2011.11.028 }}</ref> is an [[active metabolite]] of [[paracetamol]] (acetaminophen), responsible for all or part of its [[analgesic]] action<ref name="pmid16438952">{{cite journal | vauthors = Ottani A, Leone S, Sandrini M, Ferrari A, Bertolini A | title = The analgesic activity of paracetamol is prevented by the blockade of cannabinoid CB1 receptors | journal = European Journal of Pharmacology | volume = 531 | issue = 1–3 | pages = 280–281 | date = February 2006 | pmid = 16438952 | doi = 10.1016/j.ejphar.2005.12.015 }}</ref> and [[anticonvulsant]] effects.<ref name=":0">{{cite journal | vauthors = Deshpande LS, DeLorenzo RJ | title = Acetaminophen inhibits status epilepticus in cultured hippocampal neurons | journal = NeuroReport | volume = 22 | issue = 1 | pages = 15–18 | date = January 2011 | pmid = 21037491 | pmc = 3052417 | doi = 10.1097/WNR.0b013e3283413231 }}</ref> Chemically, it is the [[amide]] formed from [[4-Aminophenol|4-aminophenol]] and [[arachidonic acid]].

== Pharmacology ==

It is established that AM404 increases concentrations of the endogenous cannabinoid [[anandamide]] within the [[synapse|synaptic cleft]], contributing to its analgesic activity.<ref name="pmid15987694" /> This has been well characterised as involving [[endocannabinoid transporter]] inhibition, but the precise transporter responsible is yet to be determined.<ref name="pmid15987694" /><ref name=":1" /><ref name="pmid12655057" />

AM404 was originally reported to be an [[endocannabinoid reuptake inhibitor|endogenous cannabinoid reuptake inhibitor]], preventing the transport of anandamide and other related compounds back from the [[synapse|synaptic cleft]], much in the same way that common [[selective serotonin reuptake inhibitor]] (SSRI) antidepressants prevent the reuptake of [[serotonin]]. Earlier work on the mechanism of AM404 suggested that the inhibition of [[fatty acid amide hydrolase]] (FAAH) by AM404 was responsible for all of its attributed reuptake properties, since intracellular FAAH hydrolysis of [[anandamide]] changes the intra/extracellular anandamide equilibrium.<ref name="pmid12655057">{{cite journal | vauthors = Glaser ST, Abumrad NA, Fatade F, Kaczocha M, Studholme KM, Deutsch DG | title = Evidence against the presence of an anandamide transporter | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 100 | issue = 7 | pages = 4269–4274 | date = April 2003 | pmid = 12655057 | pmc = 153082 | doi = 10.1073/pnas.0730816100 | doi-access = free | bibcode = 2003PNAS..100.4269G }}</ref> However, this is not the case, as newer research on FAAH [[knockout mice]] has found that brain cells internalize anandamide through a selective transport mechanism which is independent of FAAH activity.<ref name=":1">{{cite journal | vauthors = Fegley D, Kathuria S, Mercier R, Li C, Goutopoulos A, Makriyannis A, Piomelli D | title = Anandamide transport is independent of fatty-acid amide hydrolase activity and is blocked by the hydrolysis-resistant inhibitor AM1172 | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 101 | issue = 23 | pages = 8756–8761 | date = June 2004 | pmid = 15138300 | pmc = 423268 | doi = 10.1073/pnas.0400997101 | doi-access = free | authorlink6 = Alexandros Makriyannis }}</ref> It is this mechanism which is inhibited by AM404.

AM404 is also a [[TRPV1]] agonist and inhibitor of [[cyclooxygenase]] COX-1 and COX-2, thus attenuating [[prostaglandin]] synthesis. AM404 is thought to induce its analgesic action through its activity on the [[endocannabinoid system|endocannabinoid]], [[COX]], and [[TRPV]] systems, all of which are present in [[Nociception|pain]] and [[thermoregulation|thermoregulatory]] pathways.<ref name="pmid15987694">{{cite journal | vauthors = Högestätt ED, Jönsson BA, Ermund A, Andersson DA, Björk H, Alexander JP, Cravatt BF, Basbaum AI, Zygmunt PM | display-authors = 6 | title = Conversion of acetaminophen to the bioactive N-acylphenolamine AM404 via fatty acid amide hydrolase-dependent arachidonic acid conjugation in the nervous system | journal = The Journal of Biological Chemistry | volume = 280 | issue = 36 | pages = 31405–31412 | date = September 2005 | pmid = 15987694 | doi = 10.1074/jbc.M501489200 | s2cid = 10837155 | doi-access = free }}</ref> AM404 activates [[vanilloid receptor]]s causing [[vasodilation]] which is inhibited by the vanilloid receptor antagonist capsazepine.<ref>{{cite journal | vauthors = Zygmunt PM, Chuang H, Movahed P, Julius D, Högestätt ED | title = The anandamide transport inhibitor AM404 activates vanilloid receptors | journal = European Journal of Pharmacology | volume = 396 | issue = 1 | pages = 39–42 | date = May 2000 | pmid = 10822052 | doi = 10.1016/s0014-2999(00)00207-7 }}</ref>

The anticonvulsant action is mediated through [[Cannabinoid receptor type 1|CB1 receptors]].<ref name=":0" />

== See also ==

* [[VDM-11]] (2-methyl analogue)

== References ==

{{Reflist}}

{{Cannabinoids}}

{{Analgesics}}

{{Cannabinoid receptor modulators}}

{{Prostanoid signaling modulators}}

{{Transient receptor potential channel modulators}}

[[Category:Anilides]]

[[Category:Phenols]]

[[Category:AM cannabinoids]]

[[Category:Fatty acid amides]]

[[Category:Human drug metabolites]]

[[Category:Endocannabinoid reuptake inhibitors]]

[[Category:Arachidonyl compounds]]