Fatty acid amide hydrolase
Fatty acid amide hydrolase or FAAH (EC 3.5.1.99, oleamide hydrolase, anandamide amidohydrolase) is a member of the serine hydrolase family of enzymes. It was first shown to break down anandamide in 1993. In humans, it is encoded by the gene FAAH.

# Function
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). Members of the FAAs include:
- Anandamide (N-arachidonoylethanolamine), an endocannabinoid
- 2-arachidonoylglycerol (2-AG), an endocannabinoid.
- Other N-acylethanolamines, such as N-oleoylethanolamine and N-palmitoylethanolamine
- The sleep-inducing lipid oleamide
- The N-acyltaurines, which are agonists of the transient receptor potential (TRP) family of calcium channels.
FAAH knockout mice display highly elevated (>15-fold) levels of N-acylethanolamines and N-acyltaurines in various tissues. Because of their significantly elevated anandamide levels, FAAH KOs have an analgesic phenotype, showing reduced pain sensation in the hot plate test, the formalin test, and the tail flick test. Finally, because of their impaired ability to degrade anandamide, FAAH KOs also display supersensitivity to exogenous anandamide, a cannabinoid receptor (CB) agonist.
Due to the ability of FAAH to regulate nociception, it is currently viewed as an attractive drug target for the treatment of pain.
A mutation in FAAH was initially provisionally linked to drug abuse and dependence but this was not borne out in subsequent studies.
Studies in cells and animals and genetic studies in humans have shown that inhibiting FAAH may be a useful strategy to treat anxiety disorders.

# Inhibitors and inactivators
Based on the hydrolytic mechanism of fatty acid amide hydrolase, a large number of irreversible and reversible inhibitors of this enzyme have been developed.
Some of the more significant compounds are listed below;
- AM374, palmitylsulfonyl fluoride, one of the first FAAH inhibitors developed for in vitro use, but too reactive for research in vivo
- ARN2508, derivative of flurbiprofen, dual FAAH / COX inhibitor
- BIA 10-2474 (Bial-Portela & Ca. SA, Portugal) has been linked to severe adverse events affecting 5 patients in a drug trial in Rennes, France, and at least one death, in January 2016.  Many other pharmaceutical companies have previously taken other FAAH inhibitors into clinical trials without reporting such adverse events.
- BMS-469908
- CAY-10402
- JNJ-245
- JNJ-1661010
- JNJ-28833155
- JNJ-40413269
- JNJ-42119779
- JNJ-42165279 in clinical trials against social anxiety and depression, trials suspended as a precautionary measure following serious adverse event with BIA 10-2474
- LY-2183240 
- Cannabidiol
- MK-3168
- MK-4409
- MM-433593
- OL-92
- OL-135
- PF-622
- PF-750 
- PF-3845
- PF-04457845 "exquisitely selective" for FAAH over other serine hydrolases, but failed in clinical trials against osteoarthritis
- PF-04862853
- RN-450
- SA-47
- SA-73
- SSR-411298 well tolerated in clinical trials but insufficient efficacy against depression, subsequently trialled against cancer pain as an adjunctive treatment.
- ST-4068, reversible inhibitor of FAAH
- TK-25
- URB524
- URB597 (KDS-4103, Kadmus Pharmaceuticals), is an irreversible inactivator with a carbamate-based mechanism, and appears in one report as a somewhat selective, though it also inactivates other serine hydrolases (e.g., carboxylesterases) in peripheral tissues.
- URB694
- URB937
- VER-156084 (Vernalis)
- V-158866 (Vernalis) in clinical trials for neuropathic pain following spinal injury, and spasticity associated with multiple sclerosis. Structure not revealed though Vernalis holds several patents in the area.

## Inhibition and binding
Structural and conformational properties that contribute to enzyme inhibition and substrate binding imply an extended bound conformation, and a role for the presence, position, and stereochemistry of a delta cis double bond.

# Assays
The enzyme is typically assayed making use of a radiolabelled anandamide substrate, which generates free labelled ethanolamine, although alternative LC-MS methods have also been described.

# Structures
The first crystal structure of FAAH was published in 2002 (PDB code 1MT5).  Structures of FAAH with drug-like ligands were first reported in 2008, and include non-covalent inhibitor complexes and covalent adducts.