AM404

AM404

Identifiers
IUPAC name (5Z,8Z,11Z,14Z)- N-(4-Hydroxyphenyl)icosa- 5,8,11,14-tetraenamide
CAS Number	183718-77-6^N 198022-70-7
PubChem CID	6604822
ChemSpider	5037081^Y
UNII	XVJ94H0U21
ChEMBL	ChEMBL39878^Y
CompTox Dashboard (EPA)	DTXSID60424985
Chemical and physical data
Formula	C26H37NO2
Molar mass	395.587 g·mol^−1
3D model (JSmol)	Interactive image
SMILES O=C(Nc1ccc(O)cc1)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC
InChI InChI=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-^Y Key:IJBZOOZRAXHERC-DOFZRALJSA-N^Y
^NY (what is this?)  (verify)

AM404, also known as N-arachidonoylphenolamine,^[1][2] is an active metabolite of paracetamol (acetaminophen), responsible for all or part of its analgesic action^[3] and anticonvulsant effects.^[4] 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.^[5] This has been well characterised as involving endocannabinoid transporter inhibition, but the precise transporter responsible is yet to be determined.^[5][6][7]

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.^[7] 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.^[6] 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, COX, and TRPV systems, all of which are present in pain and thermoregulatory pathways.^[5] AM404 activates vanilloid receptors causing vasodilation which is inhibited by the vanilloid receptor antagonist capsazepine.^[8]

The anticonvulsant action is mediated through CB1 receptors.^[4]

See also

• VDM-11 (2-methyl analogue)

References

1. Nakamura S, Nonaka T, Komatsu S, Yamada T, Yamamoto T (February 2022). "Oral acetaminophen-induced spinal 5-hydroxytriyptamine release produces analgesic effects in the rat formalin test". Biomedicine & Pharmacotherapy. 146: 112578. doi:10.1016/j.biopha.2021.112578. PMID 34959121. S2CID 245483361.
2. Rogosch T, Sinning C, Podlewski A, Watzer B, Schlosburg J, Lichtman AH, et al. (January 2012). "Novel bioactive metabolites of dipyrone (metamizol)". Bioorganic & Medicinal Chemistry. 20 (1): 101–107. doi:10.1016/j.bmc.2011.11.028. PMC 3248997. PMID 22172309.
3. Ottani A, Leone S, Sandrini M, Ferrari A, Bertolini A (February 2006). "The analgesic activity of paracetamol is prevented by the blockade of cannabinoid CB1 receptors". European Journal of Pharmacology. 531 (1–3): 280–281. doi:10.1016/j.ejphar.2005.12.015. PMID 16438952.
4. Deshpande LS, DeLorenzo RJ (January 2011). "Acetaminophen inhibits status epilepticus in cultured hippocampal neurons". NeuroReport. 22 (1): 15–18. doi:10.1097/WNR.0b013e3283413231. PMC 3052417. PMID 21037491.
5. Högestätt ED, Jönsson BA, Ermund A, Andersson DA, Björk H, Alexander JP, et al. (September 2005). "Conversion of acetaminophen to the bioactive N-acylphenolamine AM404 via fatty acid amide hydrolase-dependent arachidonic acid conjugation in the nervous system". The Journal of Biological Chemistry. 280 (36): 31405–31412. doi:10.1074/jbc.M501489200. PMID 15987694. S2CID 10837155.
6. Fegley D, Kathuria S, Mercier R, Li C, Goutopoulos A, Makriyannis A, Piomelli D (June 2004). "Anandamide transport is independent of fatty-acid amide hydrolase activity and is blocked by the hydrolysis-resistant inhibitor AM1172". Proceedings of the National Academy of Sciences of the United States of America. 101 (23): 8756–8761. doi:10.1073/pnas.0400997101. PMC 423268. PMID 15138300.
7. Glaser ST, Abumrad NA, Fatade F, Kaczocha M, Studholme KM, Deutsch DG (April 2003). "Evidence against the presence of an anandamide transporter". Proceedings of the National Academy of Sciences of the United States of America. 100 (7): 4269–4274. Bibcode:2003PNAS..100.4269G. doi:10.1073/pnas.0730816100. PMC 153082. PMID 12655057.
8. Zygmunt PM, Chuang H, Movahed P, Julius D, Högestätt ED (May 2000). "The anandamide transport inhibitor AM404 activates vanilloid receptors". European Journal of Pharmacology. 396 (1): 39–42. doi:10.1016/s0014-2999(00)00207-7. PMID 10822052.