FAAHknockout 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 Scottish woman with a previously unreported genetic mutation (dubbed FAAH-OUT) in her FAAH gene with resultant elevated anandamide levels was reported in 2019 to be immune to anxiety, unable to experience fear and insensitive to pain. The frequent burns and cuts she suffered due to her hypoalgesia healed quicker than average.
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.
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.
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
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.
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 deltacisdouble bond.
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.
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.
^Saghatelian A, McKinney MK, Bandell M, Patapoutian A, Cravatt BF (August 2006). "A FAAH-regulated class of N-acyl taurines that activates TRP ion channels". Biochemistry. 45 (30): 9007–15. doi:10.1021/bi0608008. PMID16866345.
^Cravatt BF, Lichtman AH (October 2004). "The endogenous cannabinoid system and its role in nociceptive behavior". Journal of Neurobiology. 61 (1): 149–60. doi:10.1002/neu.20080. PMID15362158.
^Sałaga M, Sobczak M, Fichna J (2014). "Inhibition of fatty acid amide hydrolase (FAAH) as a novel therapeutic strategy in the treatment of pain and inflammatory diseases in the gastrointestinal tract". European Journal of Pharmaceutical Sciences. 52: 173–9. doi:10.1016/j.ejps.2013.11.012. PMID24275607.
^Habib AM, Okorokov AL, Hill MN, Bras JT, Lee M, Li S, Gossage SJ, van Drimmelen M, Morena M (March 2019). "Microdeletion in a pseudogene identified in a patient with high anandamide concentrations and pain insensitivity". British Journal of Anaesthesia. doi:10.1016/j.bja.2019.02.019. Lay summary.
^Berardi A, Schelling G, Campolongo P (September 2016). "The endocannabinoid system and Post Traumatic Stress Disorder (PTSD): From preclinical findings to innovative therapeutic approaches in clinical settings". Pharmacological Research. 111: 668–78. doi:10.1016/j.phrs.2016.07.024. PMID27456243.
^Petrosino S, Di Marzo V (January 2010). "FAAH and MAGL inhibitors: therapeutic opportunities from regulating endocannabinoid levels". Current Opinion in Investigational Drugs. 11 (1): 51–62. PMID20047159.
^Minkkilä A, Saario S, Nevalainen T (2010). "Discovery and development of endocannabinoid-hydrolyzing enzyme inhibitors". Current Topics in Medicinal Chemistry. 10 (8): 828–58. doi:10.2174/156802610791164238. PMID20370710.