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Synthesis And Evaluation Of Paracetamol Esters As Novel Fatty Acid Amide Hydrolase Inhibitors.
V. Onnis, C. Congiu, E. Björklund, F. Hempel, E. Söderström, C. Fowler
Published 2010 · Chemistry, Medicine
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Fatty acid amide hydrolase (FAAH) is the key hydrolytic enzyme for the endogenous cannabinoid receptor ligand anandamide. The synthesis and evaluation for their FAAH inhibitory activities of a series of 18 paracetamol esters are described. Structure-activity relationship studies indicated that the ester (33) with a 2-(4-(2-(trifluoromethyl)pyridin-4-ylamino)phenyl)acetic acid substituent was the most potent analogue in this series. The compound inhibited FAAH activity in a competitive manner with a K(i) value of 0.16 microM. The compound was also able to inhibit the FAAH activity in rat basophilic leukemia cells as assessed by measuring either the hydrolysis of anandamide, the FAAH-dependent cellular accumulation of anandamide, or the FAAH-dependent recycling of tritium to the cell membranes. The compound also inhibited the activity of monoacylglycerol lipase (MGL), the enzyme responsible for the hydrolysis of the endogenous cannabinoid receptor ligand 2-arachidonoylglycerol, with an IC(50) value of 1.9 microM. It is concluded that the compound may be a useful template for the design of potent novel inhibitors of FAAH.
This paper references
The palmitoylethanolamide family: a new class of anti-inflammatory agents?
D. Lambert (2002)
Endocannabinoids in the treatment of mood disorders: evidence from animal models.
F. Bambico (2009)
Carrier-mediated uptake of the endogenous cannabinoid anandamide in RBL-2H3 cells.
F. Rakhshan (2000)
Efficient Reagents for the Synthesis of 5-, 7-, and 5,7-Substituted Indoles Starting from Aromatic Amines: Scope and Limitations.
J. Ezquerra (1997)
Selective blockade of 2-arachidonoylglycerol hydrolysis produces cannabinoid behavioral effects
J. Z. Long (2009)
Valdecoxib: Assessment of Cyclooxygenase-2 Potency and Selectivity
J. Gierse (2005)
Proteins regulating the biosynthesis and inactivation of neuromodulatory fatty acid amides.
M. Patricelli (2001)
Synthesis and biological properties of 3methyl10propargyl5 , 8dideazafolic acid
J. Ezquerra (1989)
Modifications of the ethanolamine head in N-palmitoylethanolamine: synthesis and evaluation of new agents interfering with the metabolism of anandamide.
S. Vandevoorde (2003)
Nonsteroidal antiinflammatory agents. 2. [(Heteroarylamino)phenyl]alkanoic acids.
K. Hino (1983)
Substituted 2-thioxoimidazolidin-4-ones and imidazolidine-2,4-diones as fatty acid amide hydrolase inhibitors templates.
G. Muccioli (2006)
The endocannabinoid system: drug targets, lead compounds, and potential therapeutic applications.
D. Lambert (2005)
Activation of peroxisome proliferator-activated receptor isoforms and inhibition of prostaglandin H(2) synthases by ibuprofen, naproxen, and indomethacin.
M. S. Jaradat (2001)
Ibuprofen inhibits rat brain deamidation of anandamide at pharmacologically relevant concentrations. Mode of inhibition and structure-activity relationship.
C. Fowler (1997)
Synthesis and quantitative structure-activity relationship of fatty acid amide hydrolase inhibitors: modulation at the N-portion of biphenyl-3-yl alkylcarbamates.
M. Mor (2008)
Differential inhibition of prostaglandin endoperoxide synthase (cyclooxygenase) isozymes by aspirin and other non-steroidal anti-inflammatory drugs.
E. Meade (1993)
Isolation and structure of a brain constituent that binds to the cannabinoid receptor.
W. Devane (1992)
Chemical characterization of a family of brain lipids that induce sleep.
B. Cravatt (1995)
Inhibition of fatty acid amide hydrolase, a key endocannabinoid metabolizing enzyme, by analogues of ibuprofen and indomethacin.
S. Holt (2007)
Role of fatty acid amide hydrolase in the transport of the endogenous cannabinoid anandamide.
T. Day (2001)
Oleylethanolamide regulates feeding and body weight through activation of the nuclear receptor PPAR-α
J. Fu (2003)
Trihaloacetylated enol ethers : general synthetic procedure and heterocyclic ring closure reactions with hydroxylamine
A. Colla (1991)
Inhibition of monoacylglycerol lipase and fatty acid amide hydrolase by analogues of 2‐arachidonoylglycerol
N. Ghafouri (2004)
Targeting Fatty Acid Amide Hydrolase (FAAH) to Treat Pain and Inflammation
J. Schlosburg (2008)
pressure, body temperature, and locomotor activity in rats
S. Huitron-Resendiz (2001)
The synthesis and biological evaluation of para-substituted phenolic N-alkyl carbamates as endocannabinoid hydrolyzing enzyme inhibitors.
Anna Minkkilae (2009)
Inhibitors of proteases and amide hydrolases that employ an alpha-ketoheterocycle as a key enabling functionality.
B. Maryanoff (2008)
Discovery of a potent, selective, and efficacious class of reversible alpha-ketoheterocycle inhibitors of fatty acid amide hydrolase effective as analgesics.
D. Boger (2005)
The endocannabinoid system: from biology to therapy.
M. Bifulco (2009)
Analgesic actions of N‐arachidonoyl‐serotonin, a fatty acid amide hydrolase inhibitor with antagonistic activity at vanilloid TRPV1 receptors
S. Maione (2007)
Effect of Oleamide on Sleep and Its Relationship to Blood Pressure, Body Temperature, and Locomotor Activity in Rats
S. Huitrón-Reséndiz (2001)
A simple stopped assay for fatty acid amide hydrolase avoiding the use of a chloroform extraction phase.
L. Boldrup (2004)
Characterization of the sleep-wake patterns in mice lacking fatty acid amide hydrolase.
S. Huitrón-Reséndiz (2004)
Mice lacking fatty acid amide hydrolase exhibit a cannabinoid receptor-mediated phenotypic hypoalgesia
A. Lichtman (2004)
Molecular characterization of an enzyme that degrades neuromodulatory fatty-acid amides
B. Cravatt (1996)
Reversible, temperature-dependent, and AM404-inhibitable adsorption of anandamide to cell culture wells as a confounding factor in release experiments.
M. Karlsson (2004)
vanillylamides , ethanolamides , and arachidonic acid amides of anti - inflammatory and analgesic drug substances as TRPV 1 ligands
S. Maione (2008)
Effects of pH on the inhibition of fatty acid amidohydrolase by ibuprofen
S. Holt (2001)
Endocannabinoid Research Group . Development of a potent inhibitor of 2arachidonoylglycerol hydrolysis with antinociceptive activity in vivo
G. G. Muccioli (2009)
Endocannabinoid and serotonergic systems are needed for acetaminophen-induced analgesia
C. Mallet (2008)
Design, synthesis, and structure-activity relationships of alkylcarbamic acid aryl esters, a new class of fatty acid amide hydrolase inhibitors.
G. Tarzia (2003)
A comprehensive profile of brain enzymes that hydrolyze the endocannabinoid 2-arachidonoylglycerol.
J. Blankman (2007)
Fatty acid amide hydrolase: a gate-keeper of the endocannabinoid system.
F. Fezza (2008)
analgesic activity of paracetamol is prevented by the blockade of cannabinoid CB1 receptors.Eur
M. Dani (2006)
Inhibition of fatty acid amide hydrolase by kaempferol and related naturally occurring flavonoids
L. Thors (2008)
Overview of the chemical families of fatty acid amide hydrolase and monoacylglycerol lipase inhibitors.
S. Vandevoorde (2008)
Bisarylimidazolyl fatty acid amide hydrolase inhibitors
S.-Y. Sit (2002)
CAY10499, a Novel Monoglyceride Lipase Inhibitor Evidenced by an Expeditious MGL Assay
G. Muccioli (2008)
Functional role of high-affinity anandamide transport, as revealed by selective inhibition.
M. Beltramo (1997)
Inhibition of the cellular uptake of anandamide by genistein and its analogue daidzein in cells with different levels of fatty acid amide hydrolase‐driven uptake
L. Thors (2007)
Discovery and development of fatty acid amide hydrolase (FAAH) inhibitors.
M. Seierstad (2008)
A Role for Caveolae/Lipid Rafts in the Uptake and Recycling of the Endogenous Cannabinoid Anandamide*
M. J. McFarland (2004)
Functional disassociation of the central and peripheral fatty acid amide signaling systems.
B. Cravatt (2004)
Novel inhibitors of fatty acid amide hydrolase.
S. Sit (2007)
Supersensitivity to anandamide and enhanced endogenous cannabinoid signaling in mice lacking fatty acid amide hydrolase
B. Cravatt (2001)
Design, synthesis, and in vitro evaluation of carbamate derivatives of 2-benzoxazolyl- and 2-benzothiazolyl-(3-hydroxyphenyl)-methanones as novel fatty acid amide hydrolase inhibitors.
Mikko J. Myllymäki (2007)
The local antinociceptive effects of paracetamol in neuropathic pain are mediated by cannabinoid receptors.
M. Dani (2007)
Fatty acid amide hydrolase: biochemistry, pharmacology, and therapeutic possibilities for an enzyme hydrolyzing anandamide, 2-arachidonoylglycerol, palmitoylethanolamide, and oleamide.
C. Fowler (2001)
Modulation of anxiety through blockade of anandamide hydrolysis
S. Kathuria (2003)
Head group analogs of arachidonylethanolamide, the endogenous cannabinoid ligand.
A. Khanolkar (1996)
Attenuation of Allergic Contact Dermatitis Through the Endocannabinoid System
B. Thiers (2008)
Exploration of a fundamental substituent effect of alpha-ketoheterocycle enzyme inhibitors: Potent and selective inhibitors of fatty acid amide hydrolase.
Jessica Demartino (2008)
The anandamide transport inhibitor AM404 activates vanilloid receptors.
P. Zygmunt (2000)
The cannabinoid CB1 receptor and the endocannabinoid anandamide: possible antidepressant targets.
F. Bambico (2008)
New potential anticancer agents based on the anthranilic acid scaffold: synthesis and evaluation of biological activity.
C. Congiu (2005)
Delineation of a fundamental alpha-ketoheterocycle substituent effect for use in the design of enzyme inhibitors.
F. Romero (2006)
Conversion of Acetaminophen to the Bioactive N-Acylphenolamine AM404 via Fatty Acid Amide Hydrolase-dependent Arachidonic Acid Conjugation in the Nervous System*
E. Högestätt (2005)
Folate analogues altered in theC 9N 10 bridge region : N ’ Otosylisohomofolic acid and N ’ Otosylisohomoaminopterin J
M. G. Colleen O’Neal Nair (1978)
Nonsteroid drug selectivities for cyclo-oxygenase-1 rather than cyclo-oxygenase-2 are associated with human gastrointestinal toxicity: a full in vitro analysis.
T. Warner (1999)
Anandamide Uptake Is Consistent with Rate-limited Diffusion and Is Regulated by the Degree of Its Hydrolysis by Fatty Acid Amide Hydrolase*
M. Kaczocha (2006)
Characterization of the sulfhydryl-sensitive site in the enzyme responsible for hydrolysis of 2-arachidonoyl-glycerol in rat cerebellar membranes.
S. Saario (2005)
The analgesic activity of paracetamol is prevented by the blockade of cannabinoid CB1 receptors.
A. Ottani (2006)
An anorexic lipid mediator regulated by feeding
F. D. Fonseca (2001)
Recent advances in the cannabinoids
Donald L. Hertzog (2004)
Control of pain initiation by endogenous cannabinoids
A. Calignano (1998)
Molecular characterization of human and mouse fatty acid amide hydrolases.
D. Giang (1997)
Brain monoglyceride lipase participating in endocannabinoid inactivation
T. V. Dinh (2002)
Fatty acid amide hydrolase: an emerging therapeutic target in the endocannabinoid system.
B. Cravatt (2003)
New analgesics synthetically derived from the paracetamol metabolite N-(4-hydroxyphenyl)-(5Z,8Z,11Z,14Z)-icosatetra-5,8,11,14-enamide.
Christian Sinning (2008)
Optimization of the central heterocycle of alpha-ketoheterocycle inhibitors of fatty acid amide hydrolase.
Joie Garfunkle (2008)
Modulation of Neuropathic and Inflammatory Pain by the Endocannabinoid Transport Inhibitor AM404 [N-(4-Hydroxyphenyl)-eicosa-5,8,11,14-tetraenamide]
G. La Rana (2006)
Substrate specificity and stereoselectivity of rat brain microsomal anandamide amidohydrolase.
W. Lang (1999)
Novel mechanistic class of fatty acid amide hydrolase inhibitors with remarkable selectivity.
K. Ahn (2007)
Anxiolytic Effects in Mice of a Dual Blocker of Fatty Acid Amide Hydrolase and Transient Receptor Potential Vanilloid Type-1 Channels
V. Micale (2009)
The potency of the fatty acid amide hydrolase inhibitor URB597 is dependent upon the assay pH.
Ben Paylor (2006)
Structure-activity relationships of alpha-ketooxazole inhibitors of fatty acid amide hydrolase.
Christophe Hardouin (2007)
Potent and selective alpha-ketoheterocycle-based inhibitors of the anandamide and oleamide catabolizing enzyme, fatty acid amide hydrolase.
F. Romero (2007)
This paper is referenced by
Involvement of Fatty Acid Amide Hydrolase and Fatty Acid Binding Protein 5 in the Uptake of Anandamide by Cell Lines with Different Levels of Fatty Acid Amide Hydrolase Expression: A Pharmacological Study
E. Björklund (2014)
Inhibitory properties of ibuprofen and its amide analogues towards the hydrolysis and cyclooxygenation of the endocannabinoid anandamide
C. Fowler (2013)
Chapter 2 – Ring Synthesis
P. Keller (2013)
Inhibition of Endocannabinoid Metabolism by the Metabolites of Ibuprofen and Flurbiprofen
Jessica Karlsson (2014)
Semisynthesis of a novel benzotriazole-trachylobane derivative from ent-7α-acetoxi-trachyloban-18-oic acid
Thaís de Almeida Santos (2018)
Characterisation of (R)-2-(2-Fluorobiphenyl-4-yl)-N-(3-Methylpyridin-2-yl)Propanamide as a Dual Fatty Acid Amide Hydrolase: Cyclooxygenase Inhibitor
S. Gouveia-Figueira (2015)
The anti‐inflammatory compound palmitoylethanolamide inhibits prostaglandin and hydroxyeicosatetraenoic acid production by a macrophage cell line
L. Gabrielsson (2017)
Reversible competitive α-ketoheterocycle inhibitors of fatty acid amide hydrolase containing additional conformational constraints in the acyl side chain: orally active, long-acting analgesics.
Cyrine Ezzili (2011)
The endocannabinoid system : a translational study from Achilles tendinosis to cyclooxygenase
Emmelie Björklund (2014)
Cannabidiol Improves Vasorelaxation in Zucker Diabetic Fatty Rats through Cyclooxygenase Activation
A. J. Wheal (2014)
Chiral 1,3,4-oxadiazol-2-ones as highly selective FAAH inhibitors.
Jayendra Z Patel (2013)
Inhibitors of the endocannabinoid-degrading enzymes, or how to increase endocannabinoid's activity by preventing their hydrolysis.
Marion Feledziak (2012)
Design, Synthesis, and Characterization of α-Ketoheterocycles That Additionally Target the Cytosolic Port Cys269 of Fatty Acid Amide Hydrolase
K. Otrubova (2014)
X-ray crystallographic analysis of alpha-ketoheterocycle inhibitors bound to a humanized variant of fatty acid amide hydrolase.
Mauro Mileni (2010)
A Double Whammy: Targeting Both Fatty Acid Amide Hydrolase (FAAH) and Cyclooxygenase (COX) To Treat Pain and Inflammation
R. Scarpelli (2016)
Class 3.4–6 Hydrolases, Lyases, Isomerases, Ligases
Antje Chang (2013)
Novel propanamides as fatty acid amide hydrolase inhibitors.
Alessandro Deplano (2017)
2-Amino-5-arylbenzoxazole derivatives as potent inhibitors of fatty acid amide hydrolase (FAAH)
M. A. Estiarte (2012)
Inhibition of fatty acid amide hydrolase and cyclooxygenase by the N-(3-methylpyridin-2-yl)amide derivatives of flurbiprofen and naproxen.
Mariateresa Cipriano (2013)
The endocannabinoid anandamide causes endothelium-dependent vasorelaxation in human mesenteric arteries
Christopher P. Stanley (2016)
The discovery and development of inhibitors of fatty acid amide hydrolase (FAAH).
K. Otrubova (2011)
TRPV1 modulators: Synthesis and in vitro evaluation of 1-heteroaryl piperidinecarboxamide and piperazinylurea derivatives.
C. Congiu (2015)
Intramolecular interactions, isomerization and vibrational frequencies of two paracetamol analogues: A spectroscopic and a computational approach.
R. Viana (2016)