Fatty acid amide hydrolase

Target id: 1400

Nomenclature: Fatty acid amide hydrolase

Abbreviated Name: FAAH

Family: Hydrolases, N-Acylethanolamine turnover

Annotation status:  image of an orange circle Annotated and awaiting review. Please contact us if you can help with reviewing.  » Email us

   GtoImmuPdb view: OFF:     Currently no data for Fatty acid amide hydrolase in GtoImmuPdb

Gene and Protein Information
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 1 579 1p34-p35 FAAH fatty acid amide hydrolase 6,16
Mouse 1 579 4 D1 Faah fatty acid amide hydrolase 6
Rat 1 579 5q36 Faah fatty acid amide hydrolase
Previous and Unofficial Names
FAAH1
Oleamide hydrolase, anandamide hydrolase
anandamide amidohydrolase 1
Database Links
BRENDA
Ensembl Gene
Entrez Gene
GenitoUrinary Development Molecular Anatomy Project
KEGG Enzyme
KEGG Gene
OMIM
UniProtKB
Wikipedia
Enzyme Reaction
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  [17]

Download all structure-activity data for this target as a CSV file

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
JNJ40355003 Hs Inhibition 8.9 pIC50 8
pIC50 8.9 (IC50 1.4x10-9 M) [8]
JZL195 Hs Inhibition 8.7 pIC50 13
pIC50 8.7 (IC50 2x10-9 M) [13]
Description: in vitro assay
compound 19y [Kiss et al., 2011] Rn Inhibition 8.2 pIC50 12
pIC50 8.2 (IC50 6x10-9 M) [12]
Description: Measured in rat brain homogenate.
PF-04457845 Hs Inhibition 8.1 pIC50 7
pIC50 8.1 (IC50 7.2x10-9 M) [7]
(S)-ARN2508 Hs Inhibition 8.0 pIC50 14
pIC50 8.0 (IC50 9.4x10-9 M) [14]
(R)-ARN2508 Hs Inhibition 8.0 pIC50 14
pIC50 8.0 (IC50 9.9x10-9 M) [14]
JNJ1661010 Hs Inhibition 7.8 pIC50 9
pIC50 7.8 (IC50 1.58x10-8 M) [9]
JNJ40355003 Rn Inhibition 7.5 pIC50 8
pIC50 7.5 (IC50 3.3x10-8 M) [8]
example 13 [WO2009109743] Hs Inhibition 7.4 pIC50 15
pIC50 7.4 (IC50 3.8x10-8 M) [15]
OL135 Hs Inhibition 7.4 pIC50 17
pIC50 7.4 (IC50 3.98x10-8 M) [17]
JNJ-42165279 Hs Inhibition 7.1 pIC50 10
pIC50 7.1 (IC50 7.5x10-8 M) [10]
PF750 Hs Inhibition 6.3 – 7.8 pIC50 1
pIC50 6.3 – 7.8 (IC50 5.01x10-7 – 1.58x10-8 M) [1]
BIA 10-2474 Rn Inhibition ~6.7 pIC50 11
pIC50 ~6.7 (IC50 ~2x10-7 M) [11]
Description: This value is an extrapolated estimate from % inhibition data provided in Table 1 of the referenced patent.
URB597 Hs Inhibition 6.3 – 7.0 pIC50 17
pIC50 6.3 – 7.0 (IC50 5.01x10-7 – 1x10-7 M) [17]
PF3845 Hs Inhibition 6.6 pIC50 2
pIC50 6.6 (IC50 2.51x10-7 M) [2]
JNJ-42165279 Rn Inhibition 6.5 pIC50 10
pIC50 6.5 (IC50 3.2x10-7 M) [10]
View species-specific inhibitor tables
Physiological Functions
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
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
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
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: 
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. Biochemistry46 (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. Genomics289 (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. Pain157 (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. U.S.A.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. U.S.A.94 (6): 2238-42. [PMID:9122178]

7. 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 Lett2 (2): 91-96. [PMID:21666860]

8. 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 Lett3 (10): 823-7. [PMID:24900385]

9. 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]

10. 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.

11. 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.

12. 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.

13. 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. U.S.A.106 (48): 20270-5. [PMID:19918051]

14. Migliore M, Habrant D, Sasso O, Albani C, Bertozzi SM, Armirotti A, Piomelli D, Scarpelli R. (2015) Potent multitarget FAAH-COX inhibitors: Design and structure-activity relationship studies. Eur J Med Chem109: 216-237 [Epub ahead of print]. [PMID:26774927]

15. 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.

16. 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. Genomics54 (3): 408-14. [PMID:9878243]

17. 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]

How to cite this page

Hydrolases: Fatty acid amide hydrolase. Last modified on 28/02/2017. Accessed on 26/05/2017. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=1400.