AM404
AM404, also known as N-arachidonoylphenolamine, is an active metabolite of paracetamol, responsible for all or part of its analgesic action and anticonvulsant effects. 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
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.It is also generated in vitro from 4-aminophenol by peripheral sensory neurons.
Pharmacodynamics
AM404 is a weak agonist of cannabinoid receptors CB1 and CB2, an inhibitor of endocannabinoid transporter, a potent activator of TRPV1, and a very potent inhibitor of Nav1.8 and 1.7. It weakly inhibits cyclooxygenases. The endocannbinoid system, TRPV1, and COX are involved in pain and thermoregulatory pathways. Nav1.8 and 1.7 are involved in peripheral pain perception.CB1 and CB2
AM404 is a weak agonist of cannabinoid receptors CB1 and CB2.Endocannabinoid concentration
It is established that AM404 increases concentrations of the endogenous cannabinoid anandamide within the synaptic cleft, contributing to its analgesic activity. This has been well characterised as involving endocannabinoid transporter inhibition, but the precise transporter responsible is yet to be determined.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 antidepressants prevent the reuptake of serotonin. Earlier work on the mechanism of AM404 suggested that the inhibition of fatty acid amide hydrolase by AM404 was responsible for all of its attributed reuptake properties, since intracellular FAAH hydrolysis of anandamide changes the intra/extracellular anandamide equilibrium. 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. It is this mechanism which is inhibited by AM404.
TRPV1
AM404 is also a TRPV1 agonist 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., rebutting a previous explanation involving CB1 receptors.