This article is missing information about history of discovery — who gave it this codename?. Please expand the article to include this information. Further details may exist on the talk page. (December 2022)
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.
^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. PMID16438952.
^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. PMID10822052.