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 (what is this?)
AM404 , also known as N -arachidonoylaminophenol ,[1] is an active metabolite of paracetamol (acetaminophen), responsible for all or part of its analgesic action[2] and anticonvulsant effects.[3] Chemically, it is the amide formed from 4-aminophenol and arachidonic acid .
Pharmacology [ ]
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.[4] 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.[5] This mechanism 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.[6] AM404 activates vanilloid receptors causing vasodilation which is inhibited by the vanilloid receptor antagonist capsazepine.[7]
The anticonvulsant action is mediated through CB1 receptors .[3]
See also [ ]
VDM-11 (2-methyl analogue)
References [ ]
^ Rogosch T, Sinning C, Podlewski A, Watzer B, Schlosburg J, Lichtman AH, Cascio MG, Bisogno T, Di Marzo V, Nüsing R, Imming P (January 2012). "Novel bioactive metabolites of dipyrone (metamizol)" . Bioorg. Med. Chem . 20 (1): 101–7. 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". Eur. J. Pharmacol . 531 (1–3): 280–1. doi :10.1016/j.ejphar.2005.12.015 . PMID 16438952 .
^ a b Deshpande, Laxmikant S.; DeLorenzo, Robert J. (2011-01-05). "Acetaminophen inhibits status epilepticus in cultured hippocampal neurons" . NeuroReport . 22 (1): 15–18. doi :10.1097/WNR.0b013e3283413231 . ISSN 0959-4965 . PMC 3052417 . PMID 21037491 .
^ Glaser ST, Abumrad NA, Fatade F, Kaczocha M, Studholme KM, Deutsch DG (April 2003). "Evidence against the presence of an anandamide transporter" . Proc. Natl. Acad. Sci. U.S.A . 100 (7): 4269–74. Bibcode :2003PNAS..100.4269G . doi :10.1073/pnas.0730816100 . PMC 153082 . PMID 12655057 .
^ Fegley, D.; Kathuria, S.; Mercier, R.; Li, C.; Goutopoulos, A.; Makriyannis, A. ; Piomelli, D. (11 May 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 . 101 (23): 8756–8761. doi :10.1073/pnas.0400997101 . PMC 423268 . PMID 15138300 .
^ Högestätt ED, Jönsson BA, Ermund A, Andersson DA, Björk H, Alexander JP, Cravatt BF, Basbaum AI, Zygmunt PM (September 2005). "Conversion of acetaminophen to the bioactive N-acylphenolamine AM404 via fatty acid amide hydrolase-dependent arachidonic acid conjugation in the nervous system" (PDF) . J. Biol. Chem . 280 (36): 31405–12. doi :10.1074/jbc.M501489200 . PMID 15987694 . S2CID 10837155 .
^ Zygmunt, P. M.; Chuang, H.; Movahed, P.; Julius, D.; Högestätt, E. D. (2000-05-12). "The anandamide transport inhibitor AM404 activates vanilloid receptors". European Journal of Pharmacology . 396 (1): 39–42. doi :10.1016/s0014-2999(00)00207-7 . ISSN 0014-2999 . PMID 10822052 .
Cannabinoids
Phytocannabinoids
Cannabichromenes Cannabicyclols Cannabidiols Cannabielsoins Cannabigerols Cannabinols and cannabinodiols Cannabitriols Delta-8-tetrahydrocannabinols Delta-9-tetrahydrocannabinols
Delta-9-THC (THC)
THCH
THCP
THCV
Miscellaneous cannabinoids Active metabolites
Endocannabinoids
Arachidonoyl ethanolamide (AEA; anandamide)
2-Arachidonoylglycerol (2-AG)
2-Arachidonyl glyceryl ether (2-AGE; noladin ether)
2-Oleoylglycerol (2-OG)
N-Arachidonoyl dopamine (NADA)
N-Arachidonylglycine (NAGly)
N-Arachidonoyl serotonin (AA-5-HT)
Docosatetraenoylethanolamide (DEA)
Lysophosphatidylinositol (LPI)
Oleamide
Oleoylethanolamide (OEA)
Palmitoylethanolamide (PEA)
RVD-Hpα
Stearoylethanolamide (SEA)
O-Arachidonoyl ethanolamine (O-AEA; virodhamine)
Synthetic cannabinoid receptor agonists / neocannabinoids
Classical cannabinoids (dibenzopyrans) Non-classical cannabinoids Adamantoylindoles Benzimidazoles Benzoylindoles
AM-630
AM-679
AM-694
AM-1241
AM-2233
GW-405,833 (L-768,242)
Pravadoline
RCS-4
WIN 54,461
Cyclohexylphenols Eicosanoids
ACEA
ACPA
Methanandamide (AM-356)
O-1812
Hydrocarbons Indazole carboxamides Indazole-3- carboxamides Indole-3-carboxamides Indole-3-carboxylates Naphthoylindazoles Naphthoylindoles Naphthoylpyrroles Naphthylmethylindenes Naphthylmethylindoles Phenylacetylindoles Pyrazolecarboxamides Pyrrolobenzoxazines Quinolinyl esters Tetramethylcyclo- propanoylindazoles Tetramethylcyclo- propanoylindoles
A-796,260
A-834,735
FUB-144
UR-144
XLR-11
XLR-12
Tetramethylcyclo- propylindoles Others
Allosteric CBR ligands Endocannabinoid enhancers (inactivation inhibitors) Anticannabinoids (antagonists/inverse agonists/antibodies)
AM-251
AM-630
AM-6545
BML-190
Drinabant (AVE1625)
Hemopressin
Ibipinabant (SLV319)
JTE-907
LY-320,135
MK-9470
NESS-0327
O-1918
O-2050
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PF-514273
PipISB
PSB-SB-487
Rimonabant (SR141716)
Rosonabant (E-6776)
SR-144,528
Surinabant (SR147778)
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TM-38837
VCHSR
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# WHO-EM
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Clinical trials :
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Receptor (ligands )
CB1
Agonists (abridged; see here for more) : 2-AG
2-AGE (noladin ether)
11-Hydroxy-THC
α-Amyrin · β-Amyrin
AB-CHMINACA
AM-1220
AM-1221
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Anandamide
AZ-11713908
Cannabinol
CB-13
CP 47,497
CP 55,940
Dimethylheptylpyran
DEA
ECG
EGCG
Epicatechin
Gallocatechol (gallocatechin)
Honokiol
HU-210
JWH-007
JWH-015
JWH-018
JWH-073
Kavain
L-759,633
Levonantradol
Menabitan
Nabilone
Nabitan
NADA
O-1812
Oleamide
Pravadoline
Serinolamide A
THC (dronabinol)
UR-144
WIN 55,212-2
Yangonin
Antagonists: AM-251
AM-6545
Cannabidiol
Cannabigerol
Drinabant
Falcarinol (carotatoxin)
Hemopressin
Ibipinabant
LY-320,135
MK-9470
NESS-0327
O-2050
Otenabant
PF-514273
PipISB
Rimonabant
Rosonabant
Surinabant
Taranabant
THCV
TM-38837
VCHSR
Virodhamine
CB2
Agonists: 2-AG
2-AGE (noladin ether)
3,3'-Diindolylmethane
4-O-Methylhonokiol
α-Amyrin · β-Amyrin
A-796,260
A-834,735
A-836,339
AM-1221
AM-1235
AM-1241
AM-2232
Anandamide
AZ-11713908
Cannabinol
Caryophyllene
CB-13
CBS-0550
CP 55,940
GW-405,833 (L-768,242)
GW-842,166X
HU-308
JTE 7-31
JWH-007
JWH-015
JWH-018
JWH-133
L-759,633
L-759,656
Magnolol
MDA-19
Nabitan
NADA
Olorinab (APD-371)
PF-03550096
S-444,823
SER-601
Serinolamide A
UR-144
Tedalinab
THC (dronabinol)
THCV
Virodhamine
Antagonists: 4-O-Methylhonokiol
AM-630
BML-190
Cannabidiol
Honokiol
JTE-907
SR-144,528
WIN 54,461
WIN 56,098
NAGly (GPR18 )
Agonists: Abnormal cannabidiol
ACPA
AM251
Anandamide
Cannabidiol
NADGly
THC (dronabinol)
O-1602
GPR55
Agonists: 2-AGE (noladin ether)
Abnormal cannabidiol
AM-251
CP 55,940
Lysophosphatidylinositol
O-1602
Oleoylethanolamide
Palmitoylethanolamide
THC (dronabinol)
GPR119 Unsorted
Transporter (modulators )
eCBTs
Inhibitors:
AM-404
Arachidonoyl serotonin
Cannabidiol
Guineensine
LY-2183240
Paracetamol (acetaminophen)
URB-597
VDM-11
Enzyme (modulators )
FAAH MAGL
Inhibitors:
IDFP
JZL-184
JZL-195
MAFP
URB-602
ABHD6 ABHD12
Inhibitors: Betulinic acid
Maslinic acid
MAFP
Oleanolic acid
Orlistat (tetrahydrolipstatin)
Ursolic acid
Others
Precursors: Phosphatidylethanolamine
NAPE
Diacylglycerol
Others: (directly potentiates activity of 2-AG at CB1 receptor)
(FAAH-like anandamide transporter inhibitor)
See also
Receptor/signaling modulators
Cannabinoids (cannabinoids by structure)
TRPA
Activators
4-Hydroxynonenal
4-Oxo-2-nonenal
4,5-EET
12S-HpETE
15-Deoxy-Δ12,14 -prostaglandin J2
α-Sanshool (ginger , Sichuan and melegueta peppers )
Acrolein
Allicin (garlic )
Allyl isothiocyanate (mustard , radish , horseradish , wasabi )
AM404
ASP-7663
Bradykinin
Cannabichromene (cannabis )
Cannabidiol (cannabis )
Cannabigerol (cannabis )
Cinnamaldehyde (cinnamon )
CR gas (dibenzoxazepine; DBO)
CS gas (2-chlorobenzal malononitrile)
Cuminaldehyde (cumin )
Curcumin (turmeric )
(celery )
Diallyl disulfide
Dicentrine (Lindera spp.)
Formalin
Gingerols (ginger )
Hepoxilin A3
Hepoxilin B3
Hydrogen peroxide
Icilin
Isothiocyanate
JT-010
(celery , Angelica acutiloba )
Linalool (Sichuan pepper , thyme )
Methylglyoxal
Methyl salicylate (wintergreen )
N-Methylmaleimide
Nicotine (tobacco )
Oleocanthal (olive oil )
Paclitaxel (Pacific yew )
Paracetamol (acetaminophen)
PF-4840154
Phenacyl chloride
Polygodial (Dorrigo pepper )
Shogaols (ginger , Sichuan and melegueta peppers )
Tear gases
Tetrahydrocannabinol (cannabis )
Tetrahydrocannabiorcol
Thiopropanal S-oxide (onion )
Umbellulone (Umbellularia californica )
WIN 55,212-2
Blockers
TRPC
Activators
Adhyperforin (St John's wort )
Diacyl glycerol
GSK1702934A
Hyperforin (St John's wort )
Substance P
Blockers
DHEA-S
Flufenamic acid
GSK417651A
Meclofenamic acid
N-(p-Amylcinnamoyl)anthranilic acid
Niflumic acid
Pregnenolone sulfate
Progesterone
Tolfenamic acid
TRPM
Activators
ADP-ribose
Calcium (intracellular)
CIM-0216
Cold
Cooling Agent 10
Eucalyptol (eucalyptus )
Geraniol
Hydroxycitronellal
Icilin
Linalool
Menthol (mint )
Pregnenolone sulfate
(Ruta graveolens )
Steviol glycosides (e.g., stevioside ) (Stevia rebaudiana )
Sweet tastants (e.g., glucose , fructose , sucrose ; indirectly)
WS-12
Blockers
AMG-333
Capsazepine
Clotrimazole
Flufenamic acid
Meclofenamic acid
Mefenamic acid
N-(p-Amylcinnamoyl)anthranilic acid
Nicotine (tobacco )
Niflumic acid
Ononetin
PF-05105679
RQ-00203078
Ruthenium red
(Ruta graveolens )
Tolfenamic acid
TPPO
TRPM4-IN-5
TRPML
TRPP
Activators
Triptolide (Tripterygium wilfordii )
Blockers
TRPV
Activators
2-APB
5',6'-EET
9-HODE
9-oxoODE
12S-HETE
12S-HpETE
13-HODE
13-oxoODE
20-HETE
α-Sanshool (ginger , Sichuan and melegueta peppers )
Allicin (garlic )
AM404
Anandamide
(Andrographis paniculata )
Camphor (camphor laurel , rosemary , camphorweed , African blue basil , camphor basil )
Cannabidiol (cannabis )
Cannabidivarin (cannabis )
Capsaicin (chili pepper )
Carvacrol (oregano , thyme , pepperwort , wild bergamot , others)
DHEA
Diacyl glycerol
Dihydrocapsaicin (chili pepper )
Estradiol
Eugenol (basil , clove )
Evodiamine (Euodia ruticarpa )
Gingerols (ginger )
GSK1016790A
Heat
Hepoxilin A3
Hepoxilin B3
Homocapsaicin (chili pepper )
Homodihydrocapsaicin (chili pepper )
Incensole (incense )
Lysophosphatidic acid
Low pH (acidic conditions)
Menthol (mint )
N-Arachidonoyl dopamine
N-Oleoylethanolamide
Nonivamide (PAVA) (PAVA spray )
Nordihydrocapsaicin (chili pepper )
Paclitaxel (Pacific yew )
Paracetamol (acetaminophen)
Phenylacetylrinvanil
Phorbol esters (e.g., )
Piperine (black pepper , long pepper )
Polygodial (Dorrigo pepper )
Probenecid
Protons
RhTx
(Ruta graveolens )
Resiniferatoxin (RTX) (Euphorbia resinifera /pooissonii )
Shogaols (ginger , Sichuan and melegueta peppers )
Tetrahydrocannabivarin (cannabis )
Thymol (thyme , oregano )
Tinyatoxin (Euphorbia resinifera /pooissonii )
Tramadol
Vanillin (vanilla )
Zucapsaicin
Blockers
α-Spinasterol (Vernonia tweediana )
AMG-517
AMG-9810
Cannabigerol (cannabis )
Cannabigerolic acid (cannabis )
Cannabigerovarin (cannabis )
Cannabinol (cannabis )
Capsazepine
DHEA
DHEA-S
Flufenamic acid
GRC-6211
HC-067047
Lanthanum
Mavatrep
Meclofenamic acid
N-(p-Amylcinnamoyl)anthranilic acid
Niflumic acid
Pregnenolone sulfate
RN-9893
Ruthenium red
SB-366791
SB-705498
Tolfenamic acid
TRPV3-74a
See also: Receptor/signaling modulators • Ion channel modulators