Cannabinoids

The Biosynthesis, Fate and Pharmacological Properties of Endocannabinoids 149

Fig. 1.Established and newly proposed endocannabinoids. Chemical structures of the five endogenous
cannabinoid ligands identified so far

Hanus et al. 2001; Huang et al. 2002; Porter et al. 2002); (2) more possible targets
for AEA and some synthetic cannabimimetic compounds (Breivogel et al. 2001);
and (3) the biosynthetic enzymes for 2-AG and AEA (Bisogno et al. 2003; Okamoto
et al. 2004). Clearly, the history of the endocannabinoid system is far from set, but
nevertheless the following sections shall attempt at providing the reader with a
picture as updated and as complete as possible of the multi-faceted biochemical
and pharmacological aspects of the endocannabinoids (Fig. 1).

2

Biosynthesis and Release of Endocannabinoids

The biosynthetic and metabolic pathways of the two best-studied endocannabi-
noids, AEA and 2-AG, have several features in common. Both compounds are
produced from the enzymatic hydrolysis of precursors derived from the remod-
elling of membrane phospholipids; both appear to be released and then taken up
by cells via diffusion through the plasma membrane, possibly facilitated by a mem-
brane carrier protein; and both are inactivated mostly via intracellular enzymatic
hydrolysis. Yet, although overlaps are theoretically possible between the biosyn-
thetic pathways of the two endocannabinoids, fundamentally different enzymes
areinvolvedintheformationofAEAand2-AG.Thisexplainswhy,asisbecoming
increasingly clear, the two compounds can be produced independently from each
other and why their levels can undergo differential and even opposing changes with
different physiological and pathological stimuli. For this reason, the biochemical