AM404
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| Formula | C26H37NO2 |
| Molar mass | 395.587 g·mol−1 |
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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.
Pharmacokinetics
[edit]AM404 is found in the brains of animals and cerebrospinal fluid of humans taking paracetamol. It is produced from 4-aminophenol by the action of FAAH.[5][6]
It is also generated in vitro from 4-aminophenol by peripheral sensory neurons.[7]
Pharmacodynamics
[edit]AM404 is a weak agonist of cannabinoid receptors CB1 and CB2, an inhibitor of endocannabinoid transporter, a potent activator of TRPV1,[5] and a very potent inhibitor of Nav1.8 and 1.7.[7] It weakly inhibits cyclooxygenases (COX).[8] The endocannbinoid system, TRPV1, COX are involved in pain and thermoregulatory pathways.[8] Nav1.8 and 1.7 are involved in peripheral pain perception.[7]
CB1 and CB2
[edit]AM404 is a weak agonist of cannabinoid receptors CB1 and CB2.[5]
Endocannabinoid concentration
[edit]It is established that AM404 increases concentrations of the endogenous cannabinoid anandamide within the synaptic cleft, contributing to its analgesic activity.[8] This has been well characterised as involving endocannabinoid transporter inhibition, but the precise transporter responsible is yet to be determined.[8][9][10]
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.[10] 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.[9] It is this mechanism which is inhibited by AM404.
TRPV1
[edit]AM404 is also a TRPV1 agonist[11] and inhibitor of cyclooxygenase COX-1 and COX-2, thus attenuating prostaglandin synthesis.
The anticonvulsant action of AM404 is mediated through TRPV1, according to Suemaru et al. (2018),[12] rebutting a previous explanation involving CB1 receptors.[4]
Sodium channels
[edit]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. Specifically, it inhibits Nav1.8 and 1.7 channels at nanomolar concentrations in vitro.[7] AM404 injected into the hind paw of rats increase the pain threshold for the treated paw, but not the untreated paw, confirming the peripheral nature of this effect. It also lowers pain responses in a few other in vivo models when injected directly into the affected area. Other tested metabolites of paracetamol do not block pain-sensing sodium channels in vitro.[13]
See also
[edit]- VDM-11 (2-methyl analogue)
References
[edit]- ^ 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.
- ^ 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.
- ^ 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.
- ^ a b 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.
- ^ a b c Ghanem CI, Pérez MJ, Manautou JE, Mottino AD (July 2016). "Acetaminophen from liver to brain: New insights into drug pharmacological action and toxicity". Pharmacological Research. 109: 119–31. doi:10.1016/j.phrs.2016.02.020. PMC 4912877. PMID 26921661.
- ^ Sharma CV, Long JH, Shah S, Rahman J, Perrett D, Ayoub SS, et al. (2017). "First evidence of the conversion of paracetamol to AM404 in human cerebrospinal fluid". J Pain Res. 10: 2703–2709. doi:10.2147/JPR.S143500. PMC 5716395. PMID 29238213.
- ^ a b c d Maatuf Y, Kushnir Y, Nemirovski A, Ghantous M, Iskimov A, Binshtok AM, et al. (June 2025). "The analgesic paracetamol metabolite AM404 acts peripherally to directly inhibit sodium channels". Proceedings of the National Academy of Sciences of the United States of America. 122 (23): e2413811122. doi:10.1073/pnas.2413811122. PMID 40465624.
- ^ a b c d 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.
- ^ a b Fegley D, Kathuria S, Mercier R, Li C, Goutopoulos A, Makriyannis A, et al. (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.
- ^ a b 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.
- ^ 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.
- ^ Suemaru K, Yoshikawa M, Aso H, Watanabe M (September 2018). "TRPV1 mediates the anticonvulsant effects of acetaminophen in mice". Epilepsy Research. 145: 153–159. doi:10.1016/j.eplepsyres.2018.06.016. PMID 30007240. S2CID 51652230.
- ^ "Does Paracetamol Block Peripheral Pain?". Conexiant. 11 June 2025.