Fatty acid amide hydrolase or FAAH (EC3.5.1.99, oleamide hydrolase, anandamide amidohydrolase) is a member of the serine hydrolase family of enzymes. It was first shown to break down anandamide in 1993.[1] In humans, it is encoded by the geneFAAH.[2][3][4]
FAAH is an integral membrane hydrolase with a single N-terminal transmembrane domain. In vitro, FAAH has esterase and amidase activity.[5]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:
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.[11] Finally, because of their impaired ability to degrade anandamide, FAAH KOs also display supersensitivity to exogenous anandamide, a cannabinoid receptor (CB) agonist.[6]
Due to the ability of FAAH to regulate nociception, it is currently viewed as an attractive drug target for the treatment of pain.[12][13][14]
A mutation in FAAH was initially provisionally linked to drug abuse and dependence but this was not borne out in subsequent studies.[15]
Studies in cells and animals and genetic studies in humans have shown that inhibiting FAAH may be a useful strategy to treat anxiety disorders.[15][16][17]
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.[26] 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,[29] trials suspended as a precautionary measure following serious adverse event with BIA 10-2474[30]
SSR-411298 well tolerated in clinical trials but insufficient efficacy against depression, subsequently trialled against cancer pain as an adjunctive treatment.[35][36]
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.[33]
V-158866 (Vernalis) in clinical trials for neuropathic pain following spinal injury,[38] and spasticity associated with multiple sclerosis. Structure not revealed though Vernalis holds several patents in the area.[39][40]
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.[41]
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.[42][43]
Structures
The first crystal structure of FAAH was published in 2002 (PDB code 1MT5).[4] Structures of FAAH with drug-like ligands were first reported in 2008, and include non-covalent inhibitor complexes and covalent adducts.[44]
↑Saghatelian A, Trauger SA, Want EJ, Hawkins EG, Siuzdak G, Cravatt BF (November 2004). "Assignment of endogenous substrates to enzymes by global metabolite profiling". Biochemistry. 43 (45): 14332–9. doi:10.1021/bi0480335. PMID15533037.
↑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): 1506–9. 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): 9007–15. 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.
↑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.
↑Khanna IK, Alexander CW (August 2011). "Fatty acid amide hydrolase inhibitors--progress and potential". CNS & Neurological Disorders Drug Targets. 10 (5): 545–58. doi:10.2174/187152711796234989. PMID21631410.
↑Bisogno T, Maccarrone M (May 2013). "Latest advances in the discovery of fatty acid amide hydrolase inhibitors". Expert Opinion on Drug Discovery. 8 (5): 509–22. doi:10.1517/17460441.2013.780021. PMID23488865.
↑Pertwee RG (February 2014). "Elevating endocannabinoid levels: pharmacological strategies and potential therapeutic applications". The Proceedings of the Nutrition Society. 73 (1): 96–105. doi:10.1017/S0029665113003649. PMID24135210.
↑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): 1247–66. doi:10.1517/13543776.2015.1067683. PMID26413912.
↑ 33.033.1Ahn K, Johnson DS, Fitzgerald LR, Liimatta M, Arendse A, Stevenson T, Lund ET, Nugent RA, Nomanbhoy TK, Alexander JP, Cravatt BF (November 2007). "Novel mechanistic class of fatty acid amide hydrolase inhibitors with remarkable selectivity". Biochemistry. 46 (45): 13019–30. doi:10.1021/bi701378g. PMID17949010.
↑Fowler CJ (2015). "The Potential of Inhibitors of Endocannabinoid Metabolism for Drug Development: A Critical Review". Handbook of Experimental Pharmacology. Handbook of Experimental Pharmacology. 231: 95–128. doi:10.1007/978-3-319-20825-1_4. ISBN978-3-319-20824-4. PMID26408159.
↑Clinical trial number NCT00822744 for "An Eight-week Study of SSR411298 as Treatment for Major Depressive Disorder in Elderly Patients (FIDELIO)" at ClinicalTrials.gov
↑Clinical trial number NCT01748695 NCT01748695 for " A Safety, Tolerability and Efficacy Study of V158866 in Central Neuropathic Pain Following Spinal Cord Injury" at ClinicalTrials.gov
↑US granted 8450346, "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): 901–6. 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): 265–70. doi:10.1016/S0960-894X(98)00734-3. PMID10021942.