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Daniele Amadio"The endocannabinoid system and its molecular modulation: natural and synthetic inhibitors of FAAH"

Abstract :

Endocannabinoids are a class of endogenous lipid mediators with neuro- and immuno-modulatory functions.
Several enzymes for the biosynthesis and degradation of the endocannabinoids have been discovered and characterized, forming the so called "endocannabinoid system" (ECS). Due to the involvement of the ECS in several human diseases (including neurodegenerative disease) it has emerged as a very promising therapeutic target, stimulating both companies and academic research.
The biological activity of endocannabinoids like anandamide (AEA) and 2-arachidonoylglycerol (2-AG) is subjected in vivo to a "metabolic control", exerted mainly by catabolic enzymes.
AEA is inactivated by fatty acid amide hydrolase (FAAH), that is inhibited competitively by hydroxyanandamides (HAEAs) generated from AEA by lipoxygenase activity. Our study extend the characterization of these endogenous compounds towards the main enzymes involved in the AEA metabolism (NAPE-PLD, AMT, FAAH) and in the 2-AG metabolism (DAG, 2-AGMT, MAG), also including the cannabinoid receptors (CBR1 and CBR2). In addition, we synthesized methyl and acetyl derivatives of 15-HAEA in order to check their ability to modulate FAAH and the other ECS elements. In fact, methylation and acetylation are common biochemical reactions in the cellular environment, and these reactions might represent in vivo a mechanism for the regulation of the inhibitory activity of HAEAs. The advantage of these natural substances, unlike the most powerful synthetic compounds, is that HAEAs are reversible rather than irreversible inhibitors of FAAH, and they seem to be suitable tools for flexible modulation of the endocannabinoid system in vivo.
The ECS modulation achieved through the regulation of FAAH activity represents a fascinating field also for the pharmaceutical industry. In collaboration with the company Sigma-Tau we develop a new series of enol carbamates, which appear to reversibly inhibit FAAH. Here we report the synthesis, the analytical and the biochemical characterization of these new bioactive compounds towards the ECS enzymes.
Overall, it can be proposed that cells may know how to modulate the endocannabinoid signaling through FAAH inhibition, and they do it using molecules much simpler than those synthesized in our laboratories.

Selected publications

Enol carbamates as inhibitors of fatty acid amide hydrolase (FAAH) endowed with high selectivity for FAAH over the other targets of the endocannabinoid system. Gattinoni S, De Simone C, Dallavalle S, Fezza F, Nannei R, Amadio D et al.
ChemMedChem. 2010 Mar 1;5(3):357-60.

Methylation and acetylation of 15-hydroxyanandamide modulate its interaction with the endocannabinoid system. Amadio D, Fezza F, Catanzaro G, Incani O, van Zadelhoff G, Finazzi Agrò A, Maccarrone M. Biochimie. 2010 Apr;92(4):378-87. Epub 2010 Jan 21.

Characterization of the endocannabinoid system in human neuronal cells and proteomic analysis of anandamide-induced apoptosis.Pasquariello N, Catanzaro G, Marzano V, Amadio D, Barcaroli D, Oddi S, Federici G, Urbani A, Finazzi Agrò A, Maccarrone M.J Biol Chem. 2009 Oct 23;284(43):29413-26. Epub 2009 Aug 18.

Michèlle Allard