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Active metabolite of paracetamol
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AM404
(5Z ,8Z ,11Z ,14Z )- N -(4-Hydroxyphenyl)icosa- 5,8,11,14-tetraenamide
CAS Number
PubChem
CID
ChemSpider
UNII
ChEMBL
CompTox Dashboard (
EPA )
Formula C 26 H 37 N O 2
Molar mass 395.587 g·mol−1 3D model (
JSmol )
O=C(Nc1ccc(O)cc1)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC
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
N Y
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(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 .
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
References
^ 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 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 , 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 .
^
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 .
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