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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.
AM404 is found in the brains of animals andcerebrospinal fluid of humans taking paracetamol. It is produced from4-aminophenol by the action of FAAH.[5][6]
It is also generatedin vitro from 4-aminophenol by peripheral sensory neurons.[7]
AM404 is a weak agonist of cannabinoid receptorsCB1 andCB2, an inhibitor ofendocannabinoid transporter, a potent activator ofTRPV1,[5] and a very potent inhibitor ofNav1.8 and1.7.[7] It weakly inhibitscyclooxygenases (COX).[8] The endocannbinoid system, TRPV1, and COX are involved inpain andthermoregulatory pathways.[8] Nav1.8 and 1.7 are involved in peripheral pain perception.[7]
AM404 is a weak agonist of cannabinoid receptors CB1 and CB2.[5]
It is established that AM404 increases concentrations of the endogenous cannabinoidanandamide within thesynaptic cleft, contributing to its analgesic activity.[8] This has been well characterised as involvingendocannabinoid transporter inhibition, but the precise transporter responsible is yet to be determined.[8][9][10]
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.[10] 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.[9] It is this mechanism which is inhibited by AM404.
AM404 is also aTRPV1 agonist[11] and inhibitor ofcyclooxygenase COX-1 and COX-2, thus attenuatingprostaglandin synthesis.
The anticonvulsant action of AM404 is mediated through TRPV1, according to Suemaruet al. (2018),[12] rebutting a previous explanation involvingCB1 receptors.[4]
AM404 has also been reported to inhibitvoltage-gated sodium channels in theperipheral nervous system, with much greaterpotency than its effects at previously proposed targets. Specifically, it inhibitsNav1.8 and1.7 channels at nanomolar concentrationsin 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 otherin vivo models when injected directly into the affected area. Other tested metabolites of paracetamol do not block pain-sensing sodium channelsin vitro.[13]
