1: Curr Pharm Des. 2005;11(20):2647-68. 

Focus on the three key enzymes hydrolysing endocannabinoids as new drug targets.

Vandevoorde S, Lambert DM.

Unite de Chimie Pharmaceutique et de Radiopharmacie, Universite catholique de
Louvain, Avenue E. Mounier, 73, UCL-CMFA 73-40, B-1200 Brussels, Belgium.

The family of endocannabinoids (i.e., the endogenous agonists of cannabinoid
receptors) contains several polyunsaturated fatty acid amides such as anandamide
(AEA) and oleamide but also esters such as 2-arachidonoylglycerol (2-AG). These
compounds are the subject of growing interest in pharmacology for their multiple
therapeutic potentials. Unfortunately, they are rapidly inactivated by enzymatic
hydrolysis, which prevents their effective medical use. Inhibitors of
endocannabinoid degradation seem to be necessary tools for the development of
endocannabinoid therapeutics. But hitting this target is inconceivable without
good knowledge of the enzymes. Fatty acid amide hydrolase (FAAH) is the oldest
and the best characterised enzyme involved in the degradation of
endocannabinoids. Cloning, distribution in the body and crystal structure of
FAAH have been described. A large number of FAAH inhibitors have also been
synthesised and tested. For a long time, FAAH was considered as the only key
enzyme hydrolysing endocannabinoids. But recent findings indicate that at least
two other enzymes have critical role in the endocannabinoids degradation.
Monoglyceride lipase participates in 2-AG degradation and some data indicate
that it is the primary mechanism for 2-AG inactivation in intact neurons.
N-palmitoylethanolamine-selective acid amidase (NPAA) is a second fatty acid
amide hydrolase more active with N-palmitoylethanolamine, an anti-inflammatory
substance. The purpose of this review is to collect and compare the catalytic
properties of these 3 key enzymes hydrolysing endocannabinoids.

PMID: 16101463 [PubMed - in process]