Fatty acid amide hydrolase or FAAH (oleamide hydrolase, anandamide amidohydrolase) is a member of the serine hydrolase family of enzymes. FAAH is an integral membrane hydrolase with a single N-terminal transmembrane domain. In vitro, FAAH has esterase and amidase activity. In vivo, FAAH is the principal catabolic enzyme for a class of bioactive lipids called the fatty acid amides (FAAs).

Introduction of FAAH

Fatty acid amide hydrolase (FAAH) is a crucial enzyme distributed on the membrane with high expression in the cerebellum and cortex in the brain, responsible for the termination of endocannabinoid anandamide signaling in vivo. The endocannabinoid system is an important network for regulating neuroendocrine immunity, and it has been proved by many studies that endogenous cannabis system can influence the function of emotion and cognition via regulating central nervous system. Endocannabinoids are a kind of endogenous lipid ligands that activate the cannabinoid G-protein coupled receptors CB1 and CB2. Two endocannabinoids have been identified in mammals, namely N-arachidonoyl ethanolamine (anandamide, AEA) and 2-arachidonoylglycerol (2-AG), and the biological activity of these signaling lipids are inactivated by FAAH enzymatic hydrolysis. FAAH also concurs to the deactivating hydrolysis of other neuromodulatory amides, such as oleoylethanolamide and palmitoylethanolamide. FAAH belongs to a large group of enzymes termed the amidase signature family. There are more than 100 members of this enzyme family and FAAH was the first characterized mammalian member, characterized by a highly conserved region that is rich in serine, glycine, and alanine residues comprising approximately 130 amino acid residues. Different from most other amidase signature enzymes, FAAH is an integral membrane protein with a single predicted NH2-terminal transmembrane domain.

FAAH Inhibitors

Genetic or pharmacological inactivation of FAAH produces analgesic, anti-inflammatory, anxiolytic, and antidepressant phenotypes and other CNS and peripheral diseases without bringing the adverse side effects of direct cannabinoid receptor agonists, indicating that FAAH may be a potential therapeutic target. The search for effective FAAH inhibitors has thus become a key focus in present drug discovery. In the past few years, great efforts have been made to develop new FAAH inhibitors to complete the arsenal of tools for modulating FAAH activity. Inhibitors belong to two large classes characterized by excellent potency and selectivity: reversible (e.g., trifluoromethyl ketones α-ketoheterocycles) and irreversible (e.g., fluorophosphonates, carbamates, ureas) action. According to the chemical structure, FAAH inhibitors can be divided into substrate-derived inhibitors, electrophilic ketone inhibitors, carbamate inhibitors, urea inhibitors, boronic acid inhibitors and other FAAH inhibitors. Covalent, irreversible inhibitors generally have strong potency, following greater risk of off-target effects as well. Currently, non-covalent and reversible or covalent but partially reversible inhibitors with high potency and selectivity are being developed. These may reduce the risks of off-target effects and side effects owing to enzyme inhibition. Therefore, reversible drugs have advantages in drug development. Reversible inhibitors (such as OL-135) have been demonstrated to perform well in vitro potency and selectivity for FAAH relative to other serine hydrolases in mammalian proteomes, but induce only transient elevations in anandamide in vivo. The submaximal efficacy of reversible FAAH inhibitors probably attributes to their rapid metabolism, as well as the fact that near-complete (more than 85%) blockade of FAAH activity is required to maintain elevated anandamide levels in vivo. Inhibition of FAAH leading to elevated levels of several N-acyl ethanolamine substrates is another conundrum with developing reversible inhibitors, which can reduce the efficiency and potency of the inhibitor by mass-action competition with the substrates.


1. Alessio Lodola , Riccardo Castelli , Marco Mor, Silvia Rivara. Fatty acid amide hydrolase inhibitors: a patent review (2009-2014). Expert Opinion on Therapeutic Patents. 2015,25(11):1247-1266.

2. Kay Ahn, Douglas S. Johnson , Benjamin F. Cravatt. Fatty acid amide hydrolase as a potential therapeutic target for the treatment of pain and CNS disorders. Expert Opin Drug Discov. 2009,4(7):763-784.

3. Shintaro Ogawa, Hiroshi Kunugi. Inhibitors of Fatty Acid Amide Hydrolase and Monoacylglycerol Lipase: New Targets for Future Antidepressants. Current Neuropharmacology. 2015, 13(6):760-775.

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