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Fatty acid amide hydrolase

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Target not currently curated in GtoImmuPdb

Target id: 1400

Nomenclature: Fatty acid amide hydrolase

Abbreviated Name: FAAH

Family: Hydrolases & Lipases, N-Acylethanolamine turnover

Contents:

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 1 579 1p33 FAAH fatty acid amide hydrolase 6,23
Mouse 1 579 4 53.08 cM Faah fatty acid amide hydrolase 6
Rat 1 579 5q35 Faah fatty acid amide hydrolase
Previous and Unofficial Names Click here for help
FAAH1 | Oleamide hydrolase, anandamide hydrolase | anandamide amidohydrolase 1
Database Links Click here for help
Alphafold O00519 (Hs), O08914 (Mm), P97612 (Rn)
BRENDA 3.5.1.99
CATH/Gene3D 3.90.1300.10
ChEMBL Target CHEMBL2243 (Hs), CHEMBL3455 (Mm), CHEMBL3229 (Rn)
Ensembl Gene ENSG00000117480 (Hs), ENSMUSG00000034171 (Mm), ENSRNOG00000045949 (Rn)
Entrez Gene 2166 (Hs), 14073 (Mm), 100911581 (Rn)
Human Protein Atlas ENSG00000117480 (Hs)
KEGG Enzyme 3.5.1.99
KEGG Gene hsa:2166 (Hs), mmu:14073 (Mm), rno:100911581 (Rn)
OMIM 602935 (Hs)
Pharos O00519 (Hs)
UniProtKB O00519 (Hs), O08914 (Mm), P97612 (Rn)
Wikipedia FAAH (Hs)
Enzyme Reaction Click here for help
EC Number: 3.5.1.99 anandamide + H2O <=> arachidonic acid + ethanolamine
oleamide + H2O <=> oleic acid + NH3
Description Reaction Reference
The enzyme is responsible for the catabolism of neuromodulatory fatty acid amides, including anandamide and oleamide anandamide + H2O <=> arachidonic acid + ethanolamine
oleamide + H2O <=> oleic acid + NH3
Rank order of affinity (Human)
anandamide > oleamide > N-oleoylethanolamide > N-palmitoylethanolamine  [25]

Download all structure-activity data for this target as a CSV file go icon to follow link

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
dual sEH/FAAH inhibitor 11 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 7.4 pKi 15
⤷ pKi 7.4 (Ki 3.7x10-8 M) [15]
UCM1341 Small molecule or natural product Rn Inhibition 9.1 pIC50 21
⤷ pIC50 9.1 (IC50 8.5x10-10 M) [21]
JNJ40355003 Small molecule or natural product Primary target of this compound Hs Inhibition 8.9 pIC50 10
⤷ pIC50 8.9 (IC50 1.4x10-9 M) [10]
SA-57 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 8.7 pIC50 19
⤷ pIC50 8.7 (IC50 1.9x10-9 M) [19]
JZL195 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 8.7 pIC50 16
⤷ pIC50 8.7 (IC50 2x10-9 M) [16]
Description: in vitro assay
URB937 Small molecule or natural product Rn Inhibition 8.7 pIC50 18
⤷ pIC50 8.7 (IC50 2x10-9 M) [18]
PF-04457845 Small molecule or natural product Hs Inhibition 8.0 – 9.0 pIC50 9,22
⤷ pIC50 8.0 – 9.0 (IC50 1x10-8 – 1x10-9 M) [9,22]
Description: Inhibition of human FAAH in vitro.
SA-57 Small molecule or natural product Click here for species-specific activity table Mm Inhibition 8.5 pIC50 19
⤷ pIC50 8.5 (IC50 3.2x10-9 M) [19]
ASP8477 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 8.4 pIC50 24
⤷ pIC50 8.4 (IC50 3.99x10-9 M) [24]
compound 19y [Kiss et al., 2011] Small molecule or natural product Rn Inhibition 8.2 pIC50 14
⤷ pIC50 8.2 (IC50 6x10-9 M) [14]
Description: Measured in rat brain homogenate.
dual sEH/FAAH inhibitor 11 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 8.1 pIC50 8
⤷ pIC50 8.1 (IC50 8x10-9 M) [8]
(S)-ARN2508 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 8.0 pIC50 17
⤷ pIC50 8.0 (IC50 9.4x10-9 M) [17]
(R)-ARN2508 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 8.0 pIC50 17
⤷ pIC50 8.0 (IC50 9.9x10-9 M) [17]
CAY10499 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 7.8 pIC50 7
⤷ pIC50 7.8 (IC50 1.4x10-8 M) [7]
JNJ1661010 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Hs Inhibition 7.8 pIC50 11
⤷ pIC50 7.8 (IC50 1.58x10-8 M) [11]
JNJ40355003 Small molecule or natural product Rn Inhibition 7.5 pIC50 10
⤷ pIC50 7.5 (IC50 3.3x10-8 M) [10]
example 13 [WO2009109743] Small molecule or natural product Hs Inhibition 7.4 pIC50 20
⤷ pIC50 7.4 (IC50 3.8x10-8 M) [20]
OL135 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 7.4 pIC50 25
⤷ pIC50 7.4 (IC50 3.98x10-8 M) [25]
PF750 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 6.3 – 8.2 pIC50 1,15
⤷ pIC50 8.2 (IC50 6.4x10-9 M) [15]
Description: Following a 5 min preincubation with inhibitor.
pIC50 6.3 – 7.8 (IC50 5.01x10-7 – 1.58x10-8 M) [1]
BIA 10-2474 Small molecule or natural product Hs Inhibition 7.2 – 7.3 pIC50 22
⤷ pIC50 7.2 – 7.3 (IC50 7x10-8 – 5x10-8 M) [22]
Description: Inhibition of human FAAH expressed in HEK293T cells.
BIA 10-2639 Small molecule or natural product Hs Inhibition 7.2 – 7.3 pIC50 22
⤷ pIC50 7.2 – 7.3 (IC50 7x10-8 – 5x10-8 M) [22]
Description: In situ inhibition in HEK3293T cells expressing human FAAH.
JNJ-42165279 Small molecule or natural product Primary target of this compound Hs Inhibition 7.1 pIC50 12
⤷ pIC50 7.1 (IC50 7.5x10-8 M) [12]
MM-433593 Small molecule or natural product Immunopharmacology Ligand Hs Inhibition 7.0 pIC50
⤷ pIC50 7.0 (IC50 1x10-7 M)
BIA 10-2474 Small molecule or natural product Rn Inhibition ~6.7 pIC50 13
⤷ pIC50 ~6.7 (IC50 ~2x10-7 M) [13]
Description: This value is an extrapolated estimate from % inhibition data provided in Table 1 of the referenced patent.
URB597 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 6.3 – 7.0 pIC50 25
⤷ pIC50 6.3 – 7.0 (IC50 5.01x10-7 – 1x10-7 M) [25]
PF3845 Small molecule or natural product Ligand has a PDB structure Hs Inhibition 6.6 pIC50 2
⤷ pIC50 6.6 (IC50 2.51x10-7 M) [2]
dual sEH/FAAH inhibitor 11 Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Rn Inhibition 6.5 pIC50 15
⤷ pIC50 6.5 (IC50 3x10-7 M) [15]
Description: Following a 60 min preincubation with inhibitor.
JNJ-42165279 Small molecule or natural product Rn Inhibition 6.5 pIC50 12
⤷ pIC50 6.5 (IC50 3.2x10-7 M) [12]
dual sEH/FAAH inhibitor 11 Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Mm Inhibition 5.8 pIC50 15
⤷ pIC50 5.8 (IC50 1.4x10-6 M) [15]
View species-specific inhibitor tables
Physiological Functions Click here for help
FAAH regulates anandamide signaling in vivo, setting an endogenous cannabinoid tone that modulates pain perception.
Species:  Mouse
Tissue: 
References:  5
Physiological Consequences of Altering Gene Expression Click here for help
FAAH-null mice manifest an impaired ability to degrade anandamide, leading to elevated brain anandamide levels and show reduced pain sensation. Treating these animals with a CB1 receptor antagonist (SR141716A) can reverse these effects.
Species:  Mouse
Tissue:  Brain and in vivo.
Technique:  Gene knockout
References:  5
Clinically-Relevant Mutations and Pathophysiology Click here for help
Disease:  Polysubstance abuse, susceptibility to; PSAB
OMIM: 606581
Click column headers to sort
Type Species Amino acid change Nucleotide change Description Reference
Missense Human Pro129Thr C>A This missense mutation has been associated with a propensity to drug abuse or alcoholism and pain insensitivity. 3-4
Biologically Significant Variants Click here for help
Type:  Missense mutation
Species:  Human
Description:  FAAH polymorphism associated with some substance use disorders and pain tolerance.
Amino acid change:  Pro129Thr
Nucleotide change:  C>A
Global MAF (%):  26
SNP accession:  rs324420, VAR_013563
Validation:  1000 Genomes
References:  3-4
General Comments
FAAH is the molecular target of the investigational drug BIA 10-274, which caused serious, and in one case fatal, effects in volunteers in a Phase I clinical trial in France in January 2016.

References

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1. Ahn K, Johnson DS, Fitzgerald LR, Liimatta M, Arendse A, Stevenson T, Lund ET, Nugent RA, Nomanbhoy TK, Alexander JP et al.. (2007) Novel mechanistic class of fatty acid amide hydrolase inhibitors with remarkable selectivity. Biochemistry, 46 (45): 13019-30. [PMID:17949010]

2. Ahn K, Johnson DS, Mileni M, Beidler D, Long JZ, McKinney MK, Weerapana E, Sadagopan N, Liimatta M, Smith SE et al.. (2009) Discovery and characterization of a highly selective FAAH inhibitor that reduces inflammatory pain. Chem Biol, 16 (4): 411-20. [PMID:19389627]

3. Bühler KM, Huertas E, Echeverry-Alzate V, Giné E, Moltó E, Montoliu L, López-Moreno JA. (2014) Risky alcohol consumption in young people is associated with the fatty acid amide hydrolase gene polymorphism C385A and affective rating of drug pictures. Mol Genet Genomics, 289 (3): 279-89. [PMID:24407958]

4. Cajanus K, Holmström EJ, Wessman M, Anttila V, Kaunisto MA, Kalso E. (2016) Effect of endocannabinoid degradation on pain: role of FAAH polymorphisms in experimental and postoperative pain in women treated for breast cancer. Pain, 157 (2): 361-9. [PMID:26808012]

5. Cravatt BF, Demarest K, Patricelli MP, Bracey MH, Giang DK, Martin BR, Lichtman AH. (2001) Supersensitivity to anandamide and enhanced endogenous cannabinoid signaling in mice lacking fatty acid amide hydrolase. Proc Natl Acad Sci USA, 98 (16): 9371-6. [PMID:11470906]

6. Giang DK, Cravatt BF. (1997) Molecular characterization of human and mouse fatty acid amide hydrolases. Proc Natl Acad Sci USA, 94 (6): 2238-42. [PMID:9122178]

7. Granchi C, Rizzolio F, Bordoni V, Caligiuri I, Manera C, Macchia M, Minutolo F, Martinelli A, Giordano A, Tuccinardi T. (2016) 4-Aryliden-2-methyloxazol-5(4H)-one as a new scaffold for selective reversible MAGL inhibitors. J Enzyme Inhib Med Chem, 31 (1): 137-46. [PMID:25669350]

8. Hammock B, Kodani S. (2017) Inhibitors for soluble epoxide hydrolase (seh) and fatty acid amide hydrolase (faah). Patent number: WO2017160861A1. Assignee: The Regents Of The University Of California. Priority date: 15/03/2016. Publication date: 21/09/2017.

9. Johnson DS, Stiff C, Lazerwith SE, Kesten SR, Fay LK, Morris M, Beidler D, Liimatta MB, Smith SE, Dudley DT et al.. (2011) Discovery of PF-04457845: A Highly Potent, Orally Bioavailable, and Selective Urea FAAH Inhibitor. ACS Med Chem Lett, 2 (2): 91-96. [PMID:21666860]

10. Keith JM, Apodaca R, Tichenor M, Xiao W, Jones W, Pierce J, Seierstad M, Palmer J, Webb M, Karbarz M et al.. (2012) Aryl Piperazinyl Ureas as Inhibitors of Fatty Acid Amide Hydrolase (FAAH) in Rat, Dog, and Primate. ACS Med Chem Lett, 3 (10): 823-7. [PMID:24900385]

11. Keith JM, Apodaca R, Xiao W, Seierstad M, Pattabiraman K, Wu J, Webb M, Karbarz MJ, Brown S, Wilson S et al.. (2008) Thiadiazolopiperazinyl ureas as inhibitors of fatty acid amide hydrolase. Bioorg Med Chem Lett, 18 (17): 4838-43. [PMID:18693015]

12. Keith JM, Liu J. (2011) Modulators of fatty acid amide hydrolase. Patent number: WO2011139951 A1. Assignee: Janssen Pharmaceutica Nv. Priority date: 03/05/2010. Publication date: 10/11/2011.

13. Kiss LE et al.. (2010) Pharmaceutical compounds. Patent number: WO2010074588 A2. Assignee: BIAL- PORTELA & Cª, S.A. Priority date: 24/12/2008. Publication date: 01/07/2010.

14. Kiss LE, Ferreira HS, Beliaev A, Torrao L, Bonafacio MJ Learmonth DA. (2011) Design, synthesis, and structure–activity relationships of 1,3,4-oxadiazol-2(3H)-ones as novel FAAH inhibitors. Medchemcomm, 2: 889-894.

15. Kodani SD, Wan D, Wagner KM, Hwang SH, Morisseau C, Hammock BD. (2018) Design and Potency of Dual Soluble Epoxide Hydrolase/Fatty Acid Amide Hydrolase Inhibitors. ACS Omega, 3 (10): 14076-14086. DOI: 10.1021/acsomega.8b01625 [PMID:30411058]

16. Long JZ, Nomura DK, Vann RE, Walentiny DM, Booker L, Jin X, Burston JJ, Sim-Selley LJ, Lichtman AH, Wiley JL et al.. (2009) Dual blockade of FAAH and MAGL identifies behavioral processes regulated by endocannabinoid crosstalk in vivo. Proc Natl Acad Sci USA, 106 (48): 20270-5. [PMID:19918051]

17. Migliore M, Habrant D, Sasso O, Albani C, Bertozzi SM, Armirotti A, Piomelli D, Scarpelli R. (2016) Potent multitarget FAAH-COX inhibitors: Design and structure-activity relationship studies. Eur J Med Chem, 109: 216-37. [PMID:26774927]

18. Moreno-Sanz G, Duranti A, Melzig L, Fiorelli C, Ruda GF, Colombano G, Mestichelli P, Sanchini S, Tontini A, Mor M et al.. (2013) Synthesis and structure-activity relationship studies of O-biphenyl-3-yl carbamates as peripherally restricted fatty acid amide hydrolase inhibitors. J Med Chem, 56 (14): 5917-30. [PMID:23822179]

19. Niphakis MJ, Johnson DS, Ballard TE, Stiff C, Cravatt BF. (2012) O-hydroxyacetamide carbamates as a highly potent and selective class of endocannabinoid hydrolase inhibitors. ACS Chem Neurosci, 3 (5): 418-26. [PMID:22860211]

20. Roughley S, Walls S, Hart T, Parsons R, Brough P, Graham C, Macias A. (2009) Azetidine derivatives. Patent number: WO2009109743 A1. Assignee: Vernalis (R&D) Ltd.. Priority date: 04/03/2008. Publication date: 11/09/2009.

21. Spadoni G, Bedini A, Furiassi L, Mari M, Mor M, Scalvini L, Lodola A, Ghidini A, Lucini V, Dugnani S et al.. (2018) Identification of Bivalent Ligands with Melatonin Receptor Agonist and Fatty Acid Amide Hydrolase (FAAH) Inhibitory Activity That Exhibit Ocular Hypotensive Effect in the Rabbit. J Med Chem, 61 (17): 7902-7916. [PMID:30126274]

22. van Esbroeck ACM, Janssen APA, Cognetta 3rd AB, Ogasawara D, Shpak G, van der Kroeg M, Kantae V, Baggelaar MP, de Vrij FMS, Deng H et al.. (2017) Activity-based protein profiling reveals off-target proteins of the FAAH inhibitor BIA 10-2474. Science, 356 (6342): 1084-1087. [PMID:28596366]

23. Wan M, Cravatt BF, Ring HZ, Zhang X, Francke U. (1998) Conserved chromosomal location and genomic structure of human and mouse fatty-acid amide hydrolase genes and evaluation of clasper as a candidate neurological mutation. Genomics, 54 (3): 408-14. [PMID:9878243]

24. Watabiki T, Tsuji N, Kiso T, Ozawa T, Narazaki F, Kakimoto S. (2017) In vitro and in vivo pharmacological characterization of ASP8477: A novel highly selective fatty acid amide hydrolase inhibitor. Eur J Pharmacol, 815: 42-48. [PMID:29017758]

25. Wei BQ, Mikkelsen TS, McKinney MK, Lander ES, Cravatt BF. (2006) A second fatty acid amide hydrolase with variable distribution among placental mammals. J Biol Chem, 281 (48): 36569-78. [PMID:17015445]

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