FAAHknockout mice display highly elevated (>15-fold) levels ofN-acylethanolamines andN-acyltaurines in various tissues. Because of their significantly elevated anandamide levels,FAAH KOs have an analgesic phenotype, showing reduced pain sensation in thehot plate test, theformalin test, and thetail flick test.[16] Finally, because of their impaired ability to degrade anandamide,FAAH KOs also display supersensitivity toexogenous anandamide, a cannabinoid receptor (CB) agonist.[11] (Humans have two fatty-acid amide hydrolase genes, the other beingFAAH2, while rodents only haveFAAH. This is likely to complicate translations between human and rodent biology.)[17]
Due to the ability of FAAH to regulatenociception, it is currently viewed as an attractive drug target for the treatment of pain.[18][19][20]
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.[34] Many other pharmaceutical companies have previously taken other FAAH inhibitors into clinical trials without reporting such adverse events.
JNJ-42165279 in clinical trials against social anxiety and depression,[37] trials suspended as a precautionary measure following serious adverse event with BIA 10-2474[38]
Redafamdastat (JZP-150; PF-04457845) – "exquisitely selective" for FAAH over other serine hydrolases, but failed in clinical trials againstosteoarthritis[42]
SSR-411298 well tolerated in clinical trials but insufficient efficacy against depression, subsequently trialled against cancer pain as an adjunctive treatment.[43][44]
URB597 (KDS-4103,Kadmus Pharmaceuticals), is an irreversible inactivator with acarbamate-based mechanism, and appears in one report as a somewhat selective, though it also inactivates other serine hydrolases (e.g., carboxylesterases) in peripheral tissues.[41]
V-158866 (Vernalis) in clinical trials for neuropathic pain following spinal injury,[46] and spasticity associated with multiple sclerosis. Structure not revealed though Vernalis holds several patents in the area.[47][48]
Structural and conformational properties that contribute to enzyme inhibition and substrate binding imply an extended bound conformation, and a role for the presence, position, andstereochemistry of adeltacisdouble bond.[49]
The FAAH gene contains asingle nucleotide polymorphism (SNP) called rs324420. The variant allele, C385A, is associated with a higher sensitivity of FAAH toproteolytic degradation and a shorterhalf-life compared to the standard C variant. As a result, carriers of the A variant has increasedN-acylethanolamine (NAE) levels andanandamide (AEA) signaling at thecannabinoid receptors. The A variant may be responsible for lower levels of the FAAH protein seen in high-performing athletes, providing increased physical and mental fitness.[51] However, among elitePolish athletes, the A variant is under-represented regardless of metabolic characteristics of their sport disciplines; this seems to suggest an opposite role for the A variant.[52]
A 2017 study found a strong correlation between national percentage of very happy people (as measured by theWorld Values Survey) and the presence of the rs324420 C385A allele in citizens' genetic make-up.[53]
The C385A allele was initially provisionally linked to drug abuse and dependence but this was not borne out in subsequent studies. According to later studies, carriers of the A allele are more likely to try cannabis, but less likely to become dependent.[21]: § 5.6
FAAH-OUT is apseudogene downstream of theFAAH coding region. It expresses along non-coding RNA (lncRNA) that increases the expression of FAAH.[54] In 2019, a Scottish woman namedJo Cameron was found to have both a previously unreportedmicrodeletion mutation inFAAH-OUT and a rs324420 C385A mutation. The result is extreme disruption of FAAH function leading to elevated anandamide levels. She was immune to anxiety, unable to experience fear, and insensitive to pain. The frequent burns and cuts suffered due to her hypoalgesia healed quicker than average with little or no scarring.[55][56][57] Her son, who shares theFAAH-OUT deletion but has no C385A mutation, has a lesser degree of pain insensitivity.[55]
A 2023 study looks further into the functions ofFAAH-OUT using transcriptomic analyses of cell models, some created anew using CRISPR-Cas9, others obtained from the 2019 patient. The study confirms thatFAAH-OUT increases the expression of FAAH, both via its lncRNA product and through anintronic enhancer called FAAH-AMP. Loss ofFAAH-OUT also changes the expression of a wide network of genes beyond FAAH itself. For example, although the pain insensitivity is mostly due to loss of FAAH function (via increasedendocannabinoid levels and reducedACKR3 expression), lack of depression and anxiety is instead due to a non-canonicalWnt pathway upregulatingBDNF. The increased wound healing is due to both pathways: loss of FAAH function increasesN-acyltaurine levels; the non-canonical Wnt pathway is also beneficial to healing.[54]
The enzyme is typically assayed making use of a radiolabelled anandamidesubstrate, which generates free labelledethanolamine, although alternative LC-MS methods have also been described.[58][59]
The first crystal structure of FAAH was published in 2002 (PDB code 1MT5).[9] Structures of FAAH with drug-like ligands were first reported in 2008, and include non-covalent inhibitor complexes and covalent adducts.[60]
The slime moldDictyostelium discoideum produces a semispecific FAAH inhibitor. By controlling the levels of FAAH activity, they modulate endogenousN-acylethanolamine levels.[24]
In theEnzyme Commission numbering scheme, "fatty acid amide hydrolase" isEC3.5.1.99. The number applies to all enzymes that have the chemical activity; in humans it covers both the genesFAAH andFAAH2. The systematic name is "fatty acylamide amidohydrolase". Recorded synonyms include "oleamide hydrolase", "anandamide amidohydrolase".[61]
^"Human PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
^"Mouse PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
^"UniProt".www.uniprot.org. Retrieved18 July 2023.
^Deutsch DG, Chin SA (September 1993). "Enzymatic synthesis and degradation of anandamide, a cannabinoid receptor agonist".Biochemical Pharmacology.46 (5):791–796.doi:10.1016/0006-2952(93)90486-G.PMID8373432.
^Cravatt BF, Prospero-Garcia O, Siuzdak G, Gilula NB, Henriksen SJ, Boger DL, Lerner RA (June 1995). "Chemical characterization of a family of brain lipids that induce sleep".Science.268 (5216):1506–1509.Bibcode:1995Sci...268.1506C.doi:10.1126/science.7770779.PMID7770779.
^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):9007–9015.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):149–160.doi:10.1002/neu.20080.PMID15362158.
^Sałaga M, Sobczak M, Fichna J (February 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.52:173–179.doi:10.1016/j.ejps.2013.11.012.PMID24275607.
^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.111:668–678.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):828–858.doi:10.2174/156802610791164238.PMID20370710.
^Khanna IK, Alexander CW (August 2011). "Fatty acid amide hydrolase inhibitors--progress and potential".CNS & Neurological Disorders Drug Targets.10 (5):545–558.doi:10.2174/187152711796234989.PMID21631410.
^Lodola A, Castelli R, Mor M, Rivara S (2015). "Fatty acid amide hydrolase inhibitors: a patent review (2009-2014)".Expert Opinion on Therapeutic Patents.25 (11):1247–1266.doi:10.1517/13543776.2015.1067683.PMID26413912.S2CID41218277.
^abAhn K, Johnson DS, Fitzgerald LR, Liimatta M, Arendse A, Stevenson T, et al. (November 2007). "Novel mechanistic class of fatty acid amide hydrolase inhibitors with remarkable selectivity".Biochemistry.46 (45):13019–13030.doi:10.1021/bi701378g.PMID17949010.
^Fowler CJ (2015). "The Potential of Inhibitors of Endocannabinoid Metabolism for Drug Development: A Critical Review".Endocannabinoids. Handbook of Experimental Pharmacology. Vol. 231. pp. 95–128.doi:10.1007/978-3-319-20825-1_4.ISBN978-3-319-20824-4.PMID26408159.
^Clinical trial numberNCT00822744 for "An Eight-week Study of SSR411298 as Treatment for Major Depressive Disorder in Elderly Patients (FIDELIO)" atClinicalTrials.gov
^Clinical trial numberNCT01748695 for "A Safety, Tolerability and Efficacy Study of V158866 in Central Neuropathic Pain Following Spinal Cord Injury" atClinicalTrials.gov
^US granted 8450346, Roughly S, Walls S, Hart T, Parsons R, Brough P, Graham C, Macias A, "Azetidine derivatives as FAAH inhibitors", published 28 May 2013, assigned to Vernalis (R&D) Ltd.
^Roughley SD, Browne H, Macias AT, Benwell K, Brooks T, D'Alessandro J, et al. (January 2012). "Fatty acid amide hydrolase inhibitors. 3: tetra-substituted azetidine ureas with in vivo activity".Bioorganic & Medicinal Chemistry Letters.22 (2):901–906.doi:10.1016/j.bmcl.2011.12.032.PMID22209458.
^Boger DL, Sato H, Lerner AE, Austin BJ, Patterson JE, Patricelli MP, Cravatt BF (January 1999). "Trifluoromethyl ketone inhibitors of fatty acid amide hydrolase: a probe of structural and conformational features contributing to inhibition".Bioorganic & Medicinal Chemistry Letters.9 (2):265–270.doi:10.1016/S0960-894X(98)00734-3.PMID10021942.
^Wang Y, Jones P (2009). "A scintillation proximity assay for fatty acid amide hydrolase compatible with inhibitor screening".Ligand-Macromolecular Interactions in Drug Discovery. Methods in Molecular Biology. Vol. 572. pp. 247–59.doi:10.1007/978-1-60761-244-5_16.ISBN978-1-60761-243-8.PMID20694697.
