Fatty acid derivatives of phenethylamine and glycerol as endocannabinoids and endovanilloids

The endocannabinoid system (ECS) was discovered to be the biological target for the psychoactive components from hemp. It consists of two GPC receptors (CB1 and CB2), a few endocannabinoids, their degradative enzymes FAAH and MAGL and the connected signaling pathways. The ECS also shares some endogenous ligands with the TRPV1 ion channels of the endovanilloid system.

Several putative fatty acid metabolites of biogenic amines and glycerol were prepared and their activity was tested in vitro on components of the endocannabinoid and endovanilloid system. The arachidonic acid amides of 2-(3,4-dimethoxyphenyl)ethanamine and 3-hydroxy-4-methoxyphenyl-ethanamine, both derivatives of the natural alkaloid phenethylamine, showed very good replacement rates in both CB1 and CB2 binding assays, and the latter was an active agonist on the TRPV1 receptor.

The 2-acylglycerolesters of different C16 fatty acids were less active in the receptor assays but showed better values in the enzyme inhibition assays. These potential metabolites could take part in endocannabinoid signaling, contributing to the overall activity of biogenic amines and fatty acids.