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| Formula | C26H37NO2 |
| Molar mass | 395.587 g·mol−1 |
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AM404, also known asN-arachidonoylphenolamine,[1][2] is anactive metabolite ofparacetamol (acetaminophen), responsible for all or part of itsanalgesic action[3] andanticonvulsant effects.[4] Chemically, it is theamide formed from4-aminophenol andarachidonic acid. AM404 is one of theAM cannabinoids discovered byAlexandros Makriyannis and his team.
It is established that AM404 increases concentrations of the endogenous cannabinoidanandamide within thesynaptic cleft, contributing to its analgesic activity.[5] This has been well characterised as involvingendocannabinoid transporter inhibition, but the precise transporter responsible is yet to be determined.[5][6][7]
AM404 was originally reported to be anendogenous cannabinoid reuptake inhibitor, preventing the transport of anandamide and other related compounds back from thesynaptic cleft, much in the same way that commonselective serotonin reuptake inhibitor (SSRI) antidepressants prevent the reuptake ofserotonin. Earlier work on the mechanism of AM404 suggested that the inhibition offatty acid amide hydrolase (FAAH) by AM404 was responsible for all of its attributed reuptake properties, since intracellular FAAH hydrolysis ofanandamide changes the intra/extracellular anandamide equilibrium.[7] However, this is not the case, as newer research on FAAHknockout 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 aTRPV1 agonist and inhibitor ofcyclooxygenase COX-1 and COX-2, thus attenuatingprostaglandin synthesis. AM404 is thought to induce its analgesic action through its activity on theendocannabinoid,COX, andTRPV systems, all of which are present inpain andthermoregulatory pathways.[5] AM404 activatesvanilloid receptors causingvasodilation which is inhibited by the vanilloid receptor antagonist capsazepine.[8]
The anticonvulsant action is mediated throughCB1 receptors.[4]
