AM404
{{Short description|Active metabolite of paracetamol}}
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{{Infobox drug
| Verifiedfields = changed
| Watchedfields = changed
| verifiedrevid = 477236071
| IUPAC_name = (5Z,8Z,11Z,14Z)- N-(4-Hydroxyphenyl)icosa- 5,8,11,14-tetraenamide
| image = AM404_skel.svg
| width = 240
| image2 = AM-404.png
| width2 = 240
| tradename =
| legal_status =
| routes_of_administration =
| elimination_half-life =
| excretion =
| CAS_number_Ref =
| CAS_number = 183718-77-6
| CAS_supplemental =
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = XVJ94H0U21
| PubChem = 6604822
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 5037081
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 39878
| C = 26
| H = 37
| N = 1
| O = 2
| smiles = O=C(Nc1ccc(O)cc1)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C26H37NO2/c1-2-3-4-5-6-7-8-9-10-11-12-13-14-15-16-17-18-19-26(29)27-24-20-22-25(28)23-21-24/h6-7,9-10,12-13,15-16,20-23,28H,2-5,8,11,14,17-19H2,1H3,(H,27,29)/b7-6-,10-9-,13-12-,16-15-
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = IJBZOOZRAXHERC-DOFZRALJSA-N
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AM404, also known as N-arachidonoylphenolamine,{{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 }}{{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 | 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 }} is an active metabolite of paracetamol (acetaminophen), responsible for all or part of its analgesic action{{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 }} and anticonvulsant effects.{{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 }} Chemically, it is the amide formed from 4-aminophenol and arachidonic acid. AM404 is one of the AM cannabinoids discovered by Alexandros Makriyannis and his team.
Pharmacology
It is established that AM404 increases concentrations of the endogenous cannabinoid anandamide within the synaptic cleft, contributing to its analgesic activity. This has been well characterised as involving endocannabinoid transporter inhibition, but the precise transporter responsible is yet to be determined.
AM404 was originally reported to be an endogenous cannabinoid reuptake inhibitor, preventing the transport of anandamide and other related compounds back from the 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.{{cite journal |author2-link=Nada Abumrad | 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 }} 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.{{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 }} It is this mechanism which is inhibited by AM404.
AM404 is also a TRPV1 agonist{{cite journal |vauthors=Zygmunt PM, Chuang H, Movahed P, Julius D, Högestätt ED |date=May 2000 |title=The anandamide transport inhibitor AM404 activates vanilloid receptors |journal=European Journal of Pharmacology |volume=396 |issue=1 |pages=39–42 |doi=10.1016/s0014-2999(00)00207-7 |pmid=10822052}} and inhibitor of cyclooxygenase COX-1 and COX-2, thus attenuating prostaglandin synthesis. AM404 acts on the endocannabinoid, COX, and TRPV systems, all of which are present in pain and thermoregulatory pathways.{{cite journal | vauthors = Högestätt ED, Jönsson BA, Ermund A, Andersson DA, Björk H, Alexander JP, Cravatt BF, Basbaum AI, Zygmunt PM | 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 }} The anticonvulsant action of AM404 is mediated through CB1 receptors.
AM404 has also been reported to inhibit voltage-gated sodium channels in the peripheral nervous system, with much greater potency than its effects at previously proposed targets.{{cite journal | vauthors = Maatuf Y, Kushnir Y, Nemirovski A, Ghantous M, Iskimov A, Binshtok AM, Priel A | title = The analgesic paracetamol metabolite AM404 acts peripherally to directly inhibit sodium channels | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 122 | issue = 23 | pages = e2413811122 | date = June 2025 | pmid = 40465624 | doi = 10.1073/pnas.2413811122 }}
See also
- VDM-11 (2-methyl analogue)
References
{{Reflist}}
{{Cannabinoids}}
{{Analgesics}}
{{Cannabinoid receptor modulators}}
{{Prostanoid signaling modulators}}
{{Transient receptor potential channel modulators}}
Category:4-Hydroxyphenyl compounds
Category:Human drug metabolites