Biology:Fatty-acid amide hydrolase 1

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Short description: Mammalian protein found in Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

Fatty-acid amide hydrolase 1 or FAAH-1[1](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 (AEA), an N-acylethanolamine (NAE) in 1993.[2] In humans, it is encoded by the gene FAAH.[3][4][5] FAAH also regulate the contents of NAE's in Dictyostelium discoideum, as they modulate their NAE levels in vivo through the use of a semispecific FAAH inhibitor.[6]

The FAAH protein, involved in the metabolism of endocannabinoids, is encoded by the FAAH gene, which also contains the SNP rs324420 (C385A allele), associated with a higher sensitivity of FAAH to proteolytic degradation and a shorter half-life, as compared to the C variant, as the A variant displays normal catalytic properties, but an enhanced sensitivity to the proteolytic degradation, and shorter half-life, leading to increased N-acylethanolamine (NAE) and anandamide (AEA) signaling at the CB1 receptor etc., and which accounts for the protein’s lower amounts seen in high-level performance athletes (i.e., elite athletes), that present an extraordinary interindividual variability of physical, but also mental traits, which greatly influence their sports accomplishments and their career longevity. However, the role of the C385A variant in athletic performance is not consensual, as other evidence suggesting, that the A polymorphism allele genotype is underrepresented in the Polish elite athletes, regardless of metabolic characteristics of their sport disciplines, where it seems to affect the elite athletic performance negatively.[7][8]

Function

FAAH is an integral membrane hydrolase with a single N-terminal transmembrane domain. In vitro, FAAH has esterase and amidase activity.[9] 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:

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.[15] Finally, because of their impaired ability to degrade anandamide, FAAH KOs also display supersensitivity to exogenous anandamide, a cannabinoid receptor (CB) agonist.[10]

Due to the ability of FAAH to regulate nociception, it is currently viewed as an attractive drug target for the treatment of pain.[16][17][18]

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.[19][20][21]

A 2017 study found a strong correlation between national percentage of very happy people (as measured by the World Values Survey) and the presence of the A allele in the FAAH gene variant rs324420 in citizens' genetic make-up.[22]

A mutation in FAAH was initially provisionally linked to drug abuse and dependence but this was not borne out in subsequent studies.[23]

Studies in cells and animals and genetic studies in humans have shown that inhibiting FAAH may be a useful strategy to treat anxiety disorders,[23][24][25] as inhibition produce analgesic, anxiolytic, neuroprotective, and anti-inflammatory effects by elevated N-acylethanolamines (NAE's) and their activation of cannabinoid receptors.[6]

Inhibitors and inactivators

Activation of the cannabinoid receptor CB1 or CB2 in different tissues, including skin, inhibit FAAH, and thereby increases endocannabinoid levels.[26]

Based on the hydrolytic mechanism of fatty acid amide hydrolase, a large number of irreversible and reversible inhibitors of this enzyme have been developed.[27][28][29][30][31][32][33][34]

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.[35] Many other pharmaceutical companies have previously taken other FAAH inhibitors into clinical trials without reporting such adverse events.
  • BMS-469908[36]
  • CAY-10402
  • JNJ-245
  • JNJ-1661010[37]
  • JNJ-28833155
  • JNJ-40413269
  • JNJ-42119779
  • JNJ-42165279 in clinical trials against social anxiety and depression,[38] trials suspended as a precautionary measure following serious adverse event with BIA 10-2474[39]
  • LY-2183240[40]
  • Cannabidiol[41]
  • MK-3168
  • MK-4409
  • MM-433593
  • OL-92
  • OL-135
  • PF-622
  • PF-750[42]
  • PF-3845
  • PF-04457845 "exquisitely selective" for FAAH over other serine hydrolases, but failed in clinical trials against osteoarthritis[43]
  • 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.[44][45]
  • 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.[42]
  • URB694
  • URB937
  • VER-156084 (Vernalis)[46]
  • V-158866 (Vernalis) in clinical trials for neuropathic pain following spinal injury,[47] and spasticity associated with multiple sclerosis. Structure not revealed though Vernalis holds several patents in the area.[48][49]


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.[50]

Enhancements of FAAH and its activity

Insulin medication and intraoperative doses of insulin increase the production and activity of fatty acid amide hydrolase, which, beside of other N-acylethanolamines (NAE's), degrade the endocannabinoid NAE 20:4 (AEA: C22H37NO2; 20:4, ω-6),[51] also suggest that insulin may play a key role in the obesity-linked dysregulation of the adipose ECS at the gene level,[52] is possible why the European Medicines Agency (EMA), in 2023 are investigating several reports from European countries about suicidal thoughts and thoughts of self-harm in patients who have been treated with Novo Nordisk's popular medicines for obesity and diabetes, revealed by the Denmark newspaper Belingske,[53] an outcome also seen in the CB1 receptor blocker rimonabant, an anorectic antiobesity drug that was first approved in Europe in 2006, but several years later was withdrawn worldwide due to serious psychiatric side effects,[54][55][56] and happening at the same time as BT reveal that EMA also has raised a safety alert for Wegovy, and the companies diabetes medication Ozempic, based on a study that suggests that the active substance in the two preparations, can increase the risk of thyroid cancer in patients with type 2 diabetes.[57]

The phytocannabinoid Δ9-tetrahydrocannabinol, that can mimic endocannabinoid activation at CB1 and CB2 receptors in different tissues, thereby inhibit FAAH,[26] is found to induce apoptosis in different cancer cells by increased de novo synthesized ceramide levels in a CB2 dependent manner, and moreover, cannabinoid administration selectively increased apoptosis in pancreatic tumor cells, but not in normal tissue.[58][59]

And by its cannabinoid receptor activation, the influence of cannabis on insulin observed in an human study, is in line with the established role of the endocannabinoid system (ECS) in regulating glucose metabolism and, at large, energy balance, an homeostatic function that is carried out via interactions between ECS and multiple central and peripheral pathways (e.g., brain, pancreas, liver). And through autocrine, paracrine, and endocrine mechanisms, endocannabinoids modulate pancreatic β-cells function, proliferation, and survival, as well as insulin production, secretion, and resistance, through CB1 and CB2 receptors also widely expressed in islets of Langerhans, but the direction and magnitude of the relationship between cannabinoids and insulin is not linear, and may depend of duration and frequency of exposure, as chronic cannabis use (daily consumption) reduces the risk of obesity, insulin resistance, and diabetes mellitus (DM), where acute cannabis administration in cannabis users also blunt the insulin spike secondary to a brownie intake, and the found activation of cannabinoid receptors expressed by pancreatic β-cells, can stimulate insulin secretion and, therefore, may be beneficial in treating impaired glucose tolerance and diabetes mellitus,[60][61] as the lower odds of DM among marijuana users is found significant,[62] as well as former and, to a greater extent, chronic (daily) cannabis use, is consistently associated with smaller waist circumference, lower BMI, and lower risks of overweight, obesity, and central obesity in patients with chronic hepatitis C virus (HCV) infection,[63] where obesity is found with various diseases and conditions, particularly cardiovascular diseases, type 2 diabetes, obstructive sleep apnea, certain types of cancer, and osteoarthritis.

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.[64][65]

Structures

The first crystal structure of FAAH was published in 2002 (PDB code 1MT5).[5] Structures of FAAH with drug-like ligands were first reported in 2008, and include non-covalent inhibitor complexes and covalent adducts.[66]

See also

References

  1. ↑ "UniProt". https://www.uniprot.org/uniprotkb/O00519/entry#names_and_taxonomy. 
  2. ↑ "Enzymatic synthesis and degradation of anandamide, a cannabinoid receptor agonist". Biochemical Pharmacology 46 (5): 791–796. September 1993. doi:10.1016/0006-2952(93)90486-G. PMID 8373432. 
  3. ↑ "Molecular characterization of an enzyme that degrades neuromodulatory fatty-acid amides". Nature 384 (6604): 83–87. November 1996. doi:10.1038/384083a0. PMID 8900284. Bibcode: 1996Natur.384...83C. 
  4. ↑ "Molecular characterization of human and mouse fatty acid amide hydrolases". Proceedings of the National Academy of Sciences of the United States of America 94 (6): 2238–2242. March 1997. doi:10.1073/pnas.94.6.2238. PMID 9122178. Bibcode: 1997PNAS...94.2238G. 
  5. ↑ 5.0 5.1 PDB: 1MT5​; "Structural adaptations in a membrane enzyme that terminates endocannabinoid signaling". Science 298 (5599): 1793–1796. November 2002. doi:10.1126/science.1076535. PMID 12459591. Bibcode: 2002Sci...298.1793B. 
  6. ↑ 6.0 6.1 "Identification of N-acylethanolamines in Dictyostelium discoideum and confirmation of their hydrolysis by fatty acid amide hydrolase". Journal of Lipid Research 54 (2): 457–466. February 2013. doi:10.1194/jlr.M032219. PMID 23187822. 
  7. ↑ "Association of FAAH rs324420 (C385A) Polymorphism with High-Level Performance in Volleyball Players". Genes 14 (6): 1164. May 2023. doi:10.3390/genes14061164. PMID 37372343. 
  8. ↑ "Genetic variants associated with physical and mental characteristics of the elite athletes in the Polish population". Scandinavian Journal of Medicine & Science in Sports 27 (8): 788–800. August 2017. doi:10.1111/sms.12687. PMID 27140937. 
  9. ↑ "Fatty acid amide hydrolase competitively degrades bioactive amides and esters through a nonconventional catalytic mechanism". Biochemistry 38 (43): 14125–14130. October 1999. doi:10.1021/bi991876p. PMID 10571985. 
  10. ↑ 10.0 10.1 "Supersensitivity to anandamide and enhanced endogenous cannabinoid signaling in mice lacking fatty acid amide hydrolase". Proceedings of the National Academy of Sciences of the United States of America 98 (16): 9371–9376. July 2001. doi:10.1073/pnas.161191698. PMID 11470906. Bibcode: 2001PNAS...98.9371C. 
  11. ↑ "The fatty acid amide hydrolase (FAAH)". Chemistry and Physics of Lipids 108 (1–2): 107–121. November 2000. doi:10.1016/S0009-3084(00)00190-0. PMID 11106785. 
  12. ↑ "Assignment of endogenous substrates to enzymes by global metabolite profiling". Biochemistry 43 (45): 14332–14339. November 2004. doi:10.1021/bi0480335. PMID 15533037. 
  13. ↑ "Chemical characterization of a family of brain lipids that induce sleep". Science 268 (5216): 1506–1509. June 1995. doi:10.1126/science.7770779. PMID 7770779. Bibcode: 1995Sci...268.1506C. 
  14. ↑ "A FAAH-regulated class of N-acyl taurines that activates TRP ion channels". Biochemistry 45 (30): 9007–9015. August 2006. doi:10.1021/bi0608008. PMID 16866345. 
  15. ↑ "The endogenous cannabinoid system and its role in nociceptive behavior". Journal of Neurobiology 61 (1): 149–160. October 2004. doi:10.1002/neu.20080. PMID 15362158. 
  16. ↑ "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. February 2014. doi:10.1016/j.ejps.2013.11.012. PMID 24275607. 
  17. ↑ "The endocannabinoid system as a potential therapeutic target for pain modulation". Balkan Medical Journal 31 (2): 115–120. June 2014. doi:10.5152/balkanmedj.2014.13103. PMID 25207181. 
  18. ↑ "Full Fatty Acid Amide Hydrolase Inhibition Combined with Partial Monoacylglycerol Lipase Inhibition: Augmented and Sustained Antinociceptive Effects with Reduced Cannabimimetic Side Effects in Mice". The Journal of Pharmacology and Experimental Therapeutics 354 (2): 111–120. August 2015. doi:10.1124/jpet.115.222851. PMID 25998048. 
  19. ↑ "Microdeletion in a FAAH pseudogene identified in a patient with high anandamide concentrations and pain insensitivity". British Journal of Anaesthesia 123 (2): e249–e253. August 2019. doi:10.1016/j.bja.2019.02.019. PMID 30929760. 
    • "Woman with novel gene mutation lives almost pain-free". ScienceDaily (Press release). March 27, 2019.
  20. ↑ "At 71, She's Never Felt Pain or Anxiety. Now Scientists Know Why.". The New York Times. 28 March 2019. https://www.nytimes.com/2019/03/28/health/woman-pain-anxiety.html. 
  21. ↑ "Scientists find genetic mutation that makes woman feel no pain". The Guardian. 28 March 2019. https://www.theguardian.com/science/2019/mar/28/scientists-find-genetic-mutation-that-makes-woman-feel-no-pain. 
  22. ↑ "A Genetic Component to National Differences in Happiness" (in en). Journal of Happiness Studies 18 (2): 321–340. 2017-04-01. doi:10.1007/s10902-015-9712-y. ISSN 1573-7780. 
  23. ↑ 23.0 23.1 "Inhibition of FAAH and activation of PPAR: new approaches to the treatment of cognitive dysfunction and drug addiction". Pharmacology & Therapeutics 138 (1): 84–102. April 2013. doi:10.1016/j.pharmthera.2013.01.003. PMID 23333350. 
  24. ↑ "Amygdala FAAH and anandamide: mediating protection and recovery from stress". Trends in Pharmacological Sciences 34 (11): 637–644. November 2013. doi:10.1016/j.tips.2013.08.008. PMID 24325918. 
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  26. ↑ 26.0 26.1 "N-Palmitoyl Serinol Stimulates Ceramide Production through a CB1-Dependent Mechanism in In Vitro Model of Skin Inflammation". International Journal of Molecular Sciences 22 (15): 8302. August 2021. doi:10.3390/ijms22158302. PMID 34361066. 
  27. ↑ "Pharmacotherapeutic modulation of the endocannabinoid signalling system in psychiatric disorders: drug-discovery strategies". International Review of Psychiatry 21 (2): 122–133. April 2009. doi:10.1080/09540260902782778. PMID 19367506. 
  28. ↑ "Fatty acid amide hydrolase as a potential therapeutic target for the treatment of pain and CNS disorders". Expert Opinion on Drug Discovery 4 (7): 763–784. July 2009. doi:10.1517/17460440903018857. PMID 20544003. 
  29. ↑ "FAAH and MAGL inhibitors: therapeutic opportunities from regulating endocannabinoid levels". Current Opinion in Investigational Drugs 11 (1): 51–62. January 2010. PMID 20047159. 
  30. ↑ "Discovery and development of endocannabinoid-hydrolyzing enzyme inhibitors". Current Topics in Medicinal Chemistry 10 (8): 828–858. 2010. doi:10.2174/156802610791164238. PMID 20370710. 
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  32. ↑ "Latest advances in the discovery of fatty acid amide hydrolase inhibitors". Expert Opinion on Drug Discovery 8 (5): 509–522. May 2013. doi:10.1517/17460441.2013.780021. PMID 23488865. 
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  34. ↑ "Fatty acid amide hydrolase inhibitors: a patent review (2009-2014)". Expert Opinion on Therapeutic Patents 25 (11): 1247–1266. 2015. doi:10.1517/13543776.2015.1067683. PMID 26413912. 
  35. ↑ "More Details Emerge on Fateful French Drug Trial" (online). Science (January 16). 2016. doi:10.1126/science.aae0247. https://www.science.org/content/article/more-details-emerge-fateful-french-drug-trial. Retrieved 16 January 2016. 
  36. ↑ "Chemical probes of endocannabinoid metabolism". Pharmacological Reviews 65 (2): 849–871. April 2013. doi:10.1124/pr.112.006387. PMID 23512546. 
  37. ↑ "Discovery and molecular basis of potent noncovalent inhibitors of fatty acid amide hydrolase (FAAH)". Proceedings of the National Academy of Sciences of the United States of America 108 (18): 7379–7384. May 2011. doi:10.1073/pnas.1016167108. PMID 21502526. Bibcode: 2011PNAS..108.7379M. 
  38. ↑ "Preclinical Characterization of the FAAH Inhibitor JNJ-42165279". ACS Medicinal Chemistry Letters 6 (12): 1204–1208. December 2015. doi:10.1021/acsmedchemlett.5b00353. PMID 26713105. 
  39. ↑ "Janssen Research & Development, LLC Voluntarily Suspends Dosing in Phase 2 Clinical Trials of Experimental Treatment for Mood Disorders". Janssen.com. 17 January 2016. http://www.janssen.com/janssen-research-development-llc-voluntarily-suspends-dosing-phase-2-clinical-trials-experimental. 
  40. ↑ "Identification of a high-affinity binding site involved in the transport of endocannabinoids". Proceedings of the National Academy of Sciences of the United States of America 102 (49): 17852–17857. December 2005. doi:10.1073/pnas.0507470102. PMID 16314570. 
  41. ↑ "Multiple mechanisms involved in the large-spectrum therapeutic potential of cannabidiol in psychiatric disorders". Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences 367 (1607): 3364–3378. December 2012. doi:10.1098/rstb.2011.0389. PMID 23108553. 
  42. ↑ 42.0 42.1 "Novel mechanistic class of fatty acid amide hydrolase inhibitors with remarkable selectivity". Biochemistry 46 (45): 13019–13030. November 2007. doi:10.1021/bi701378g. PMID 17949010. 
  43. ↑ "The Potential of Inhibitors of Endocannabinoid Metabolism for Drug Development: A Critical Review". Endocannabinoids. Handbook of Experimental Pharmacology. 231. 2015. pp. 95–128. doi:10.1007/978-3-319-20825-1_4. ISBN 978-3-319-20824-4. 
  44. ↑ Clinical trial number NCT00822744 for "An Eight-week Study of SSR411298 as Treatment for Major Depressive Disorder in Elderly Patients (FIDELIO)" at ClinicalTrials.gov
  45. ↑ "Clinical trials for SSR411298.". EU Clinical Trials Register. https://www.clinicaltrialsregister.eu/ctr-search/search?query=SSR411298. 
  46. ↑ "Fatty acid amide hydrolase inhibitors. Surprising selectivity of chiral azetidine ureas". Bioorganic & Medicinal Chemistry Letters 19 (15): 4241–4244. August 2009. doi:10.1016/j.bmcl.2009.05.097. PMID 19515560. 
  47. ↑ Clinical trial number NCT01748695 for "A Safety, Tolerability and Efficacy Study of V158866 in Central Neuropathic Pain Following Spinal Cord Injury" at ClinicalTrials.gov
  48. ↑ Roughly S, Walls S, Hart T, Parsons R, Brough P, Graham C, Macias A, "Azetidine derivatives as FAAH inhibitors", US patent granted 8450346, published 28 May 2013, assigned to Vernalis (R&D) Ltd.
  49. ↑ "Fatty acid amide hydrolase inhibitors. 3: tetra-substituted azetidine ureas with in vivo activity". Bioorganic & Medicinal Chemistry Letters 22 (2): 901–906. January 2012. doi:10.1016/j.bmcl.2011.12.032. PMID 22209458. 
  50. ↑ "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. January 1999. doi:10.1016/S0960-894X(98)00734-3. PMID 10021942. 
  51. ↑ "Effect of anaesthesia and cardiopulmonary bypass on blood endocannabinoid concentrations during cardiac surgery". British Journal of Anaesthesia 105 (2): 139–144. 2010. doi:10.1093/bja/aeq117. PMID 20525978. https://www.bjanaesthesia.org/article/S0007-0912(17)33532-8/fulltext. 
  52. ↑ "Insulin differentially modulates the peripheral endocannabinoid system in human subcutaneous abdominal adipose tissue from lean and obese individuals". Journal of Endocrinological Investigation 30 (8): RC17–RC21. September 2007. doi:10.1007/BF03347440. PMID 17923791. 
  53. ↑ "Ny bekymring om populære Novo Nordisk-lægemidler – undersøger om de kan give selvmordstanker" (in da). 2023-06-23. https://www.berlingske.dk/content/item/1735511. 
  54. ↑ Courtney W (2008). (in en) Marijuana Symposium Mendocino Sept 11 '08, https://www.youtube.com/watch?v=GQMgQUo-1ng, retrieved 2023-07-15 
  55. ↑ "The endocannabinoid system, eating behavior and energy homeostasis: the end or a new beginning?". Pharmacology, Biochemistry, and Behavior 95 (4): 375–382. June 2010. doi:10.1016/j.pbb.2010.03.012. PMID 20347862. 
  56. ↑ "[Therapeutical use of the cannabinoids in psychiatry]". Revista Brasileira de Psiquiatria 32 (Suppl 1): S56–S66. May 2010. PMID 20512271. 
  57. ↑ "Novo Nordisk-slankemiddel undersøges for at øge kræftrisiko" (in da). 2023-06-21. https://www.bt.dk/content/item/1700794. 
  58. ↑ "Cannabinoids induce apoptosis of pancreatic tumor cells via endoplasmic reticulum stress-related genes". Cancer Research 66 (13): 6748–6755. July 2006. doi:10.1158/0008-5472.CAN-06-0169. PMID 16818650. 
  59. ↑ "The stress-regulated protein p8 mediates cannabinoid-induced apoptosis of tumor cells". Cancer Cell 9 (4): 301–312. April 2006. doi:10.1016/j.ccr.2006.03.005. PMID 16616335. 
  60. ↑ "Effects of oral, smoked, and vaporized cannabis on endocrine pathways related to appetite and metabolism: a randomized, double-blind, placebo-controlled, human laboratory study". Translational Psychiatry 10 (1): 71. February 2020. doi:10.1038/s41398-020-0756-3. PMID 32075958. 
  61. ↑ "Δ9-Tetrahydrocannabivarin (THCV): a commentary on potential therapeutic benefit for the management of obesity and diabetes". Journal of Cannabis Research 2 (1): 6. January 2020. doi:10.1186/s42238-020-0016-7. PMID 33526143. 
  62. ↑ "Decreased prevalence of diabetes in marijuana users: cross-sectional data from the National Health and Nutrition Examination Survey (NHANES) III". BMJ Open 2 (1): e000494. 2012-01-01. doi:10.1136/bmjopen-2011-000494. PMID 22368296. 
  63. ↑ "Cannabis use as a factor of lower corpulence in hepatitis C-infected patients: results from the ANRS CO22 Hepather cohort". Journal of Cannabis Research 4 (1): 31. June 2022. doi:10.1186/s42238-022-00138-9. PMID 35690798. 
  64. ↑ "A scintillation proximity assay for fatty acid amide hydrolase compatible with inhibitor screening". Ligand-Macromolecular Interactions in Drug Discovery. Methods in Molecular Biology. 572. 2009. pp. 247–59. doi:10.1007/978-1-60761-244-5_16. ISBN 978-1-60761-243-8. 
  65. ↑ "Quantitative LC-MS/MS analysis of arachidonoyl amino acids in mouse brain with treatment of FAAH inhibitor". Analytical Biochemistry 432 (2): 74–81. January 2013. doi:10.1016/j.ab.2012.09.031. PMID 23044255. 
  66. ↑ PDB: 2VYA​; "Structure-guided inhibitor design for human FAAH by interspecies active site conversion". Proceedings of the National Academy of Sciences of the United States of America 105 (35): 12820–12824. September 2008. doi:10.1073/pnas.0806121105. PMID 18753625. Bibcode: 2008PNAS..10512820M. 

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