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Inhibitory Properties Of Ibuprofen And Its Amide Analogues Towards The Hydrolysis And Cyclooxygenation Of The Endocannabinoid Anandamide

C. Fowler, E. Björklund, A. Lichtman, P. S. Naidu, C. Congiu, V. Onnis
Published 2013 · Chemistry, Medicine

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A dual-action cyclooxygenase (COX)–fatty acid amide hydrolase (FAAH) inhibitor may have therapeutic usefulness as an analgesic, but a key issue is finding the right balance of inhibitory effects. This can be done by the design of compounds exhibiting different FAAH/COX-inhibitory potencies. In the present study, eight ibuprofen analogues were investigated. Ibuprofen (1), 2-(4-Isobutylphenyl)-N-(2-(3-methylpyridin-2-ylamino)-2-oxoethyl)propanamide (9) and N-(3-methylpyridin-2-yl)-2-(4′-isobutylphenyl)propionamide (2) inhibited FAAH with IC50 values of 134, 3.6 and 0.52 µM respectively. The corresponding values for COX-1 were ~29, ~50 and ~60 µM, respectively. Using arachidonic acid as substrate, the compounds were weak inhibitors of COX-2. However, when anandamide was used as COX-2 substrate, potency increased, with approximate IC50 values of ~6, ~10 and ~19 µM, respectively. Compound 2 was confirmed to be active in vivo in a murine model of visceral nociception, but the effects of the compound were not blocked by CB receptor antagonists.
This paper references
Designed Multiple Ligands. An Emerging Drug Discovery Paradigm
R. Morphy (2006)
Synthesis of Prostaglandin E2 Ethanolamide from Anandamide by Cyclooxygenase-2*
M. Yu (1997)
Increased sensitivity to inhibition by ibuprofen and flurbiprofen upon reduction of extrabut not intracellular pH
S Holt (2003)
Amino acid determinants in cyclooxygenase-2 oxygenation of the endocannabinoid anandamide.
K. Kozak (2003)
The Nuclear Receptor Peroxisome Proliferator-Activated Receptor-α Mediates the Anti-Inflammatory Actions of Palmitoylethanolamide
J. Lo Verme (2005)
Anandamide suppresses pain initiation through a peripheral endocannabinoid mechanism
Jason R. Clapper (2010)
Regulation of Inflammatory Pain by Inhibition of Fatty Acid Amide Hydrolase
P. S. Naidu (2010)
Endocannabinoid and serotonergic systems are needed for acetaminophen-induced analgesia
C. Mallet (2008)
Non-cannabinoid CB1, non-cannabinoid CB2 antinociceptive effects of several novel compounds in the PPQ stretch test in mice.
V. Haller (2006)
The Structural Basis of Endocannabinoid Oxygenation by Cyclooxygenase-2*
A. J. Vecchio (2011)
The case for the development of novel analgesic agents targeting both fatty acid amide hydrolase and either cyclooxygenase or TRPV1
C. Fowler (2009)
Synthesis and evaluation of paracetamol esters as novel fatty acid amide hydrolase inhibitors.
V. Onnis (2010)
Spinal anti-nociceptive effects of cyclooxygenase inhibition during inflammation: Involvement of prostaglandins and endocannabinoids. Pain 2010;148:26–35
A Telleria-Diaz (2010)
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)
Inhibition of fatty acid amide hydrolase, a key endocannabinoid metabolizing enzyme, by analogues of ibuprofen and indomethacin.
S. Holt (2007)
Antinociceptive activity of the endogenous fatty acid amide, palmitylethanolamide.
A. Calignano (2001)
Mice lacking fatty acid amide hydrolase exhibit a cannabinoid receptor-mediated phenotypic hypoalgesia
A. Lichtman (2004)
A simple stopped assay for fatty acid amide hydrolase avoiding the use of a chloroform extraction phase.
L. Boldrup (2004)
R-Flurbiprofen Reduces Neuropathic Pain in Rodents by Restoring Endogenous Cannabinoids
P. Bishay (2010)
Effects of COX‐2 inhibition on spinal nociception: the role of endocannabinoids
L. E. Staniaszek (2010)
Local interactions between anandamide, an endocannabinoid, and ibuprofen, a nonsteroidal anti-inflammatory drug, in acute and inflammatory pain
J. Guindon (2006)
A role for endocannabinoids in indomethacin-induced spinal antinociception.
H. Gühring (2002)
Synthesis of ibuprofen heterocyclic amides and investigation of their analgesic and toxicological properties.
M. Cocco (2003)
Chemistry around imidazopyrazine and ibuprofen: discovery of novel fatty acid amide hydrolase (FAAH) inhibitors.
Frédéric De Wael (2010)
Anandamide amidohydrolase reacting with 2‐arachidonoylglycerol, another cannabinoid receptor ligand
S. Goparaju (1998)
Synergy between Enzyme Inhibitors of Fatty Acid Amide Hydrolase and Cyclooxygenase in Visceral Nociception
P. S. Naidu (2009)
Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs.
J. Vane (1971)
Intrathecally applied flurbiprofen produces an endocannabinoid‐dependent antinociception in the rat formalin test
M. Ates (2003)
Differential Sensitivity and Mechanism of Inhibition of COX-2 Oxygenation of Arachidonic Acid and 2-Arachidonoylglycerol by Ibuprofen and Mefenamic Acid†
J. J. Prusakiewicz (2009)
Acidic Nonsteroidal Anti-inflammatory Drugs Inhibit Rat Brain Fatty Acid Amide Hydrolase in a pH-dependent Manner
C. Fowler (2003)
Differential inhibition of prostaglandin endoperoxide synthase (cyclooxygenase) isozymes by aspirin and other non-steroidal anti-inflammatory drugs.
E. Meade (1993)
Partnering between monomers of cyclooxygenase-2 homodimers.
C. Yuan (2006)
Modulation of NSAID-induced antinociceptive and anti-inflammatory effects by alpha2-adrenoceptor agonists with gastroprotective effects.
N. Jain (2002)
Ibuprofen inhibits rat brain deamidation of anandamide at pharmacologically relevant concentrations. Mode of inhibition and structure-activity relationship.
C. Fowler (1997)
Anandamide metabolism by fatty acid amide hydrolase in intact C6 glioma cells. Increased sensitivity to inhibition by ibuprofen and flurbiprofen upon reduction of extra- but not intracellular pH
S. Holt (2003)
Spinal antinociceptive effects of cyclooxygenase inhibition during inflammation: Involvement of prostaglandins and endocannabinoids
A. Telleria-Diaz (2010)
(R)-Profens are substrate-selective inhibitors of endocannabinoid oxygenation by COX-2.
Kelsey C. Duggan (2011)

This paper is referenced by
Endocannabinoid metabolism : the impact of inflammatory factors and pharmacological inhibitors
Jessica Karlsson (2018)
Ibuprofen: from invention to an OTC therapeutic mainstay
K. Rainsford (2013)
Structure and surface analysis of ibuprofen-organotin conjugate: Potential anti-cancer drug candidacy of the compound is proven by in-vitro DNA binding and cytotoxicity studies
Shahid Iqbal Farooqi (2020)
The fatty acid amide hydrolase and cyclooxygenase-inhibitory properties of novel amide derivatives of carprofen.
Alessandro Deplano (2020)
TRPV1 modulators: Synthesis and in vitro evaluation of 1-heteroaryl piperidinecarboxamide and piperazinylurea derivatives.
C. Congiu (2015)
Advances in the discovery of fatty acid amide hydrolase inhibitors: what does the future hold?
D. Fazio (2020)
New approaches and challenges to targeting the endocannabinoid system
V. Marzo (2018)
Benzylamides and piperazinoarylamides of ibuprofen as fatty acid amide hydrolase inhibitors
Alessandro Deplano (2019)
NSAIDs: eNdocannabinoid stimulating anti-inflammatory drugs?
C. Fowler (2012)
Conference on ‘ PUFA mediators : implications for human health ’ Symposium 3 : Cannabinoids in human health Endocannabinoid system and pain : an introduction
J. Burston (2014)
Interaction of the N-(3-Methylpyridin-2-yl)amide Derivatives of Flurbiprofen and Ibuprofen with FAAH: Enantiomeric Selectivity and Binding Mode
Jessica Karlsson (2015)
Potent multitarget FAAH-COX inhibitors: Design and structure-activity relationship studies.
Marco Migliore (2016)
COX inhibitors: a patent review (2011 – 2014)
S. Consalvi (2015)
Preemptive and Preventive Systemic Anti-Inflammatory Drugs for Dental Sensitivity Control in-Office Bleaching
J. Públio (2018)
PNS1300365 106..117
James J Burston (2014)
Identification and characterization of carprofen as a multitarget fatty acid amide hydrolase/cyclooxygenase inhibitor.
Angelo D. Favia (2012)
Identification and characterization of carprofen as a multi-target FAAH / COX inhibitor
Angelo D. Favia (2013)
PharmGKB summary: ibuprofen pathways
Liudmila L. Mazaleuskaya (2015)
A Double Whammy: Targeting Both Fatty Acid Amide Hydrolase (FAAH) and Cyclooxygenase (COX) To Treat Pain and Inflammation
R. Scarpelli (2016)
Inhibition of fatty acid amide hydrolase and cyclooxygenase by the N-(3-methylpyridin-2-yl)amide derivatives of flurbiprofen and naproxen.
Mariateresa Cipriano (2013)
Chiral 1,3,4-oxadiazol-2-ones as highly selective FAAH inhibitors.
Jayendra Z Patel (2013)
Evaluation of Anti‐inflammatory and Analgesic Effects of Synthesized Derivatives of Ibuprofen
J. Wang (2015)
Novel propanamides as fatty acid amide hydrolase inhibitors.
Alessandro Deplano (2017)
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)
Stimulation of brain glucose uptake by cannabinoid CB2 receptors and its therapeutic potential in Alzheimer's disease
A. Köfalvi (2016)
The Potential of Inhibitors of Endocannabinoid Metabolism for Drug Development: A Critical Review.
C. Fowler (2015)
The endocannabinoid system : a translational study from Achilles tendinosis to cyclooxygenase
Emmelie Björklund (2014)
Exploring the fatty acid amide hydrolase and cyclooxygenase inhibitory properties of novel amide derivatives of ibuprofen
Alessandro Deplano (2020)
A Personal Retrospective: Elevating Anandamide (AEA) by Targeting Fatty Acid Amide Hydrolase (FAAH) and the Fatty Acid Binding Proteins (FABPs)
D. Deutsch (2016)
Endocannabinoid system and pain: an introduction.
J. Burston (2014)
Non-opioid Analgesics and the Endocannabinoid System
R. D. Topuz (2020)
Inhibition of FAAH, TRPV1, and COX2 by NSAID-serotonin conjugates.
Tyler M. Rose (2014)
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