HEP (2005) 168:147–185
©cSpringer-Verlag 2005
The Biosynthesis, Fate and Pharmacological Properties
of Endocannabinoids
V. D i Ma rzo^1 ()·L.DePetrocellis^2 ·T.Bisogno^1
(^1) Endocannabinoid Research Group, Istituto di Chimica Biomolecolare,
Via Campi Flegrei 34, Comprensorio Olivetti, Fabbricato 70, 80078 Pozzuoli (Napoli), Italy
[email protected]
(^2) Endocannabinoid Research Group, Istituto di Cibernetica, Consiglio Nazionale
delle Ricerche, Via Campi Flegrei 34, Comprensorio Olivetti, Fabbricato 70, 80078 Italy
1Introduction.................................... 148
2 Biosynthesis and Release of Endocannabinoids................. 149
2.1 BiosynthesisofAEAandOtherN-Acylethanolamines ............. 150
2.2 Biosynthesisof2-Arachidonoylglycerol ..................... 152
2.3 BiosynthesisofOtherPutativeEndocannabinoids................ 153
2.4 InhibitorsofEndocannabinoidBiosynthesis................... 155
2.5 EndocannabinoidRelease............................. 156
3 Endocannabinoid Metabolic Fate......................... 156
3.1 CellularUptake .................................. 156
3.2 EnzymaticHydrolysis............................... 158
3.2.1AnandamideHydrolysis.............................. 158
3.2.22-ArachidonoylglycerolHydrolysis........................ 159
3.3 OtherMetabolicReactions ............................ 160
3.3.1Re-esterification.................................. 160
3.3.2OxidationandMethylation ............................ 160
3.4 InhibitorsofEndocannabinoidInactivation................... 161
4 Pharmacology of Endocannabinoids....................... 164
4.1 Endocannabinoid Molecular Targets: Beyond CB 1 and CB 2 Receptors..... 164
4.2 Endocannabinoid Pharmacological Actions: Some Major Differences
fromTHC ..................................... 167
5 New Drugs from the Endocannabinoid System ................. 169
5.1 RegulationofEndocannabinoidLevelsUnderPathologicalConditions .... 169
5.2 Potential Therapeutic Use of Inhibitors of Endocannabinoid Metabolic Fate. 171
6ConcludingRemarks............................... 172
References ........................................ 173
AbstractThe finding of endogenous ligands for cannabinoid receptors, the en-
docannabinoids, opened a new era in cannabinoid research. It meant that the
biological role of cannabinoid signalling could be finally studied by investigating
not only the pharmacological actions subsequent to stimulation of cannabinoid
receptors by their agonists, but also how the activity of these receptors was reg-
ulated under physiological and pathological conditions by varying levels of the