The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Benjamin F Cravatt - One of the best experts on this subject based on the ideXlab platform.
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effects of Fatty Acid Amide hydrolase faah inhibitors on working memory in rats
Psychopharmacology, 2016Co-Authors: Leigh V. Panlilio, Steven R. Goldberg, Benjamin F Cravatt, Alexandros Makriyannis, Spyros P Nikas, Shakiru O Alapafuja, Tiziano Bandiera, Daniele Piomelli, Eric B Thorndike, Zuzana JustinovaAbstract:Rationale Manipulations of the endocannabinoid system could potentially produce therapeutic effects with minimal risk of adverse cannabis-like side effects. Inhibitors of Fatty Acid Amide hydrolase (FAAH) increase endogenous levels of the cannabinoid-receptor agonist, anandAmide, and show promise for treating a wide range of disorders. However, their effects on learning and memory have not been fully characterized.
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Evidence for distinct roles in catalysis for residues of the serine-serine-lysine catalytic triad of Fatty Acid Amide hydrolase
2015Co-Authors: Michele K Mckinney, Benjamin F CravattAbstract:Fatty Acid Amide hydrolase (FAAH) is a mammalian amidase signature enzyme that inactivates neuromodu-latory Fatty Acid Amides, including the endogenous can-nabinoid anandAmide and the sleep-inducing substance oleAmide. The recent determination of the three-dimen-sional structures of FAAH and two distantly related bac-terial amidase signature enzymes indicates that these enzymes employ an unusual serine-serine-lysine triad for catalysis (Ser-241/Ser-217/Lys-142 in FAAH). Mu-tagenesis of each of the triad residues in FAAH has been shown to severely reduce amidase activity; however, how these residues contribute, both individually and in cooperation, to catalysis remains unclear. Here, through a combination of site-directed mutagenesis, enzyme ki-netics, and chemical labeling experiments, we provid
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disruption of Fatty Acid Amide hydrolase activity prevents the effects of chronic stress on anxiety and amygdalar microstructure
Molecular Psychiatry, 2013Co-Authors: Benjamin F Cravatt, Cecilia J. Hillard, John M Keith, Matthew N Hill, Shobha Anil Kumar, Sarah B Filipski, Moriah Iverson, Kara L Stuhr, Sumantra ChattarjiAbstract:Disruption of Fatty Acid Amide hydrolase activity prevents the effects of chronic stress on anxiety and amygdalar microstructure
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rat and human Fatty Acid Amide hydrolases overt similarities and hidden differences
Biochimica et Biophysica Acta, 2012Co-Authors: Almerinda Di Venere, Enrico Dainese, Filomena Fezza, Beatrice Clotilde Angelucci, Alessandro Finazziagro, Nicola Rosato, Benjamin F Cravatt, Mauro MaccarroneAbstract:Abstract Fatty Acid Amide hydrolase (FAAH) is a membrane protein that plays a relevant role in the metabolism of Fatty Acid Amides and esters. It degrades important neurotransmitters such as oleAmide and anandAmide, and it has been involved in a number of human pathological conditions, representing therefore a valuable target for biochemical and pharmacological research. In this study, we have investigated in vitro the structure–function relationship of rat and human FAAHs. In particular circular dichroism, fluorescence spectroscopy and light scattering measurements have been performed, in order to characterize the structural features of the two proteins, both in the presence and absence of the irreversible inhibitor methoxyarachidonyl-fluorophosphonate. The results demonstrate that the structural dynamics of the two FAAHs are different, despite their high sequence homology and overall similarity in temperature-dependence. Additionally, membrane binding and kinetic assays of both FAAHs indicate that also the functional properties of the two enzymes are different in their interaction with lipid bilayers and with exogenous inhibitors. These findings suggest that pre-clinical studies of FAAH-dependent human diseases based only on animal models should be interpreted with caution, and that the efficacy of new drugs targeted to FAAH should be tested in vitro, on both rat and human enzymes.
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inhibiting Fatty Acid Amide hydrolase normalizes endotoxin induced enhanced gastrointestinal motility in mice
British Journal of Pharmacology, 2012Co-Authors: Mohammad Bashashati, Spyros P Nikas, Jodianne T Wood, Shakiru O Alapafuja, Grzegorz Godlewski, Martin Storr, Jie Liu, Catherine M Keenan, Hong Zhang, Benjamin F CravattAbstract:BACKGROUND AND PURPOSE Gastrointestinal (GI) motility is regulated in part by Fatty Acid ethanolAmides (FAEs), including the endocannabinoid (EC) anandAmide (AEA). The actions of FAEs are terminated by Fatty Acid Amide hydrolase (FAAH). We investigated the actions of the novel FAAH inhibitor AM3506 on normal and enhanced GI motility. EXPERIMENTAL APPROACH We examined the effect of AM3506 on electrically-evoked contractility in vitro and GI transit and colonic faecal output in vivo, in normal and FAAH-deficient mice treated with saline or LPS (100 µg·kg−1, i.p.), in the presence and absence of cannabinoid (CB) receptor antagonists. mRNA expression was measured by quantitative real time-PCR, EC levels by liquid chromatography-MS and FAAH activity by the conversion of [3H]-AEA to [3H]-ethanolamine in intestinal extracts. FAAH expression was examined by immunohistochemistry. KEY RESULTS FAAH was dominantly expressed in the enteric nervous system; its mRNA levels were higher in the ileum than the colon. LPS enhanced ileal contractility in the absence of overt inflammation. AM3506 reversed the enhanced electrically-evoked contractions of the ileum through CB1 and CB2 receptors. LPS increased the rate of upper GI transit and faecal output. AM3506 normalized the enhanced GI transit through CB1 and CB2 receptors and faecal output through CB1 receptors. LPS did not increase GI transit in FAAH-deficient mice. CONCLUSIONS AND IMPLICATIONS Inhibiting FAAH normalizes various parameters of GI dysmotility in intestinal pathophysiology. Inhibition of FAAH represents a new approach to the treatment of disordered intestinal motility.
Dale L Boger - One of the best experts on this subject based on the ideXlab platform.
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the discovery and development of inhibitors of Fatty Acid Amide hydrolase faah
Bioorganic & Medicinal Chemistry Letters, 2011Co-Authors: Katerina Otrubova, Cyrine Ezzili, Dale L BogerAbstract:A summary of the discovery and advancement of inhibitors of Fatty Acid Amide hydrolase (FAAH) is presented.
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Fatty Acid Amide signaling molecules.
Bioorganic & Medicinal Chemistry Letters, 2010Co-Authors: Cyrine Ezzili, Katerina Otrubova, Dale L BogerAbstract:Key studies leading to the discovery and definition of the role of endogenous Fatty Acid Amide signaling molecules are summarized.
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x ray crystallographic analysis of alpha ketoheterocycle inhibitors bound to a humanized variant of Fatty Acid Amide hydrolase
Journal of Medicinal Chemistry, 2010Co-Authors: Mauro Mileni, Cyrine Ezzili, Benjamin F Cravatt, Joie Garfunkle, Scott F Kimball, Raymond C Stevens, Dale L BogerAbstract:Three cocrystal X-ray structures of the α-ketoheterocycle inhibitors 3−5 bound to a humanized variant of Fatty Acid Amide hydrolase (FAAH) are disclosed and comparatively discussed alongside those of 1 (OL-135) and its isomer 2. These five X-ray structures systematically probe each of the three active site regions key to substrate or inhibitor binding: (1) the conformationally mobile acyl chain-binding pocket and membrane access channel responsible for Fatty Acid Amide substrate and inhibitor acyl chain binding, (2) the atypical active site catalytic residues and surrounding oxyanion hole that covalently binds the core of the α-ketoheterocycle inhibitors captured as deprotonated hemiketals mimicking the tetrahedral intermediate of the enzyme-catalyzed reaction, and (3) the cytosolic port and its uniquely important imbedded ordered water molecules and a newly identified anion binding site. The detailed analysis of their key active site interactions and their implications on the interpretation of the availa...
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potent and selective α ketoheterocycle based inhibitors of the anandAmide and oleAmide catabolizing enzyme Fatty Acid Amide hydrolase
Journal of Medicinal Chemistry, 2007Co-Authors: Anthony F Romero, Inkyu Hwang, Benjamin F Cravatt, Richard Apodaca, Scott F Kimball, Donmienne Leung, Thomas J Rayl, Heather Hoover, Guy J Breitenbucher, Dale L BogerAbstract:A study of the structure-activity relationships (SAR) of 2f (OL-135), a potent inhibitor of Fatty Acid Amide hydrolase (FAAH), is detailed, targeting the 5-position of the oxazole. Examination of a series of substituted benzene derivatives (12-14) revealed that the optimal position for substitution was the meta-position with selected members approaching or exceeding the potency of 2f. Concurrent with these studies, the effect of substitution on the pyridine ring of 2f was also examined. A series of small, nonaromatic C5-substituents was also explored and revealed that the K(i) follows a well-defined correlation with the Hammett sigma(p) constant (rho = 3.01, R2 = 0.91) in which electron-withdrawing substituents enhance potency, leading to inhibitors with K(i)s as low as 400 pM (20n). Proteomic-wide screening of the inhibitors revealed that most are exquisitely selective for FAAH over all other mammalian proteases, reversing the 100-fold preference of 20a (C5 substituent = H) for the enzyme TGH.
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elucidation of Fatty Acid Amide hydrolase inhibition by potent α ketoheterocycle derivatives from monte carlo simulations
Journal of the American Chemical Society, 2005Co-Authors: Cristiano Ruch Werneck Guimaraes, Dale L Boger, William L JorgensenAbstract:Fatty Acid Amide hydrolase (FAAH) is a serine hydrolase responsible for the degradation of anandAmide, an endogenous cannabinoid agonist, and oleAmide, a sleep-inducing lipid. Recently, Boger and co-workers reported a potent, selective, and efficacious class of reversible α-ketoheterocycle inhibitors of FAAH that produce analgesia in animal models (J. Med. Chem. 2005, 48, 1849−1856; Bioorg. Med. Chem. Lett. 2005, 15, 1423−1428). Key aspects of the structure−activity data are addressed here through computational analysis of FAAH inhibition using Monte Carlo (MC) simulations in conjunction with free energy perturbation (FEP) calculations. The MC/FEP simulations demonstrate that incorporation of pyridine at the C5 position of the 2-keto-oxazole and 2-keto-1,3,4-oxadiazole derivatives significantly enhances binding affinity by formation of a hydrogen-bonded array between the pyridyl nitrogen and Lys142 and Thr236. The results also attribute the activity boost upon substitution of oxazole by oxadiazole to redu...
Daniele Piomelli - One of the best experts on this subject based on the ideXlab platform.
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effects of Fatty Acid Amide hydrolase faah inhibitors on working memory in rats
Psychopharmacology, 2016Co-Authors: Leigh V. Panlilio, Steven R. Goldberg, Benjamin F Cravatt, Alexandros Makriyannis, Spyros P Nikas, Shakiru O Alapafuja, Tiziano Bandiera, Daniele Piomelli, Eric B Thorndike, Zuzana JustinovaAbstract:Rationale Manipulations of the endocannabinoid system could potentially produce therapeutic effects with minimal risk of adverse cannabis-like side effects. Inhibitors of Fatty Acid Amide hydrolase (FAAH) increase endogenous levels of the cannabinoid-receptor agonist, anandAmide, and show promise for treating a wide range of disorders. However, their effects on learning and memory have not been fully characterized.
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applying a multitarget rational drug design strategy the first set of modulators with potent and balanced activity toward dopamine d3 receptor and Fatty Acid Amide hydrolase
Chemical Communications, 2014Co-Authors: Alessio De Simone, G F Ruda, Clara Albani, Glauco Tarozzo, Tiziano Bandiera, Daniele Piomelli, Andrea Cavalli, Giovanni BottegoniAbstract:Combining computer-assisted drug design and synthetic efforts, we generated compounds with potent and balanced activities toward both D3 dopamine receptor and Fatty Acid Amide hydrolase (FAAH) enzyme. By concurrently modulating these targets, our compounds hold great potential toward exerting a disease-modifying effect on nicotine addiction and other forms of compulsive behavior.
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Quantum Mechanics/Molecular Mechanics Modeling of Fatty Acid Amide Hydrolase Reactivation Distinguishes Substrate from Irreversible Covalent Inhibitors
2013Co-Authors: Alessio Lodola, Daniele Piomelli, Silvia Rivara, Giorgio Tarzia, Luigi Capoferri, Adrian Mulholland, Marco MorAbstract:Carbamate and urea derivatives are important classes of Fatty Acid Amide hydrolase (FAAH) inhibitors that carbamoylate the active-site nucleophile Ser241. In the present work, the reactivation mechanism of carbamoylated FAAH is investigated by means of a quantum mechanics/molecular mechanics (QM/MM) approach. The potential energy surfaces for decarbamoylation of FAAH covalent adducts, derived from the O-aryl carbamate URB597 and from the N-piperazinylurea JNJ1661610, were calculated and compared to that for deacylation of FAAH acylated by the substrate oleAmide. Calculations show that a carbamic group bound to Ser241 prevents efficient stabilization of transition states of hydrolysis, leading to large increments in the activation barrier. Moreover, the energy barrier for the piperazine carboxylate was significantly lower than that for the cyclohexyl carbamate derived from URB597. This is consistent with experimental data showing slowly reversible FAAH inhibition for the N-piperazinylurea inhibitor and irreversible inhibition for URB597
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identification and characterization of carprofen as a multitarget Fatty Acid Amide hydrolase cyclooxygenase inhibitor
Journal of Medicinal Chemistry, 2012Co-Authors: Angelo D Favia, Clara Albani, Glauco Tarozzo, Daniele Piomelli, Mauro Dionisi, Rita Scarpelli, Damien Habrant, Marco Migliore, Sine Mandrup Bertozzi, Andrea CavalliAbstract:Pain and inflammation are major therapeutic areas for drug discovery. Current drugs for these pathologies have limited efficacy, however, and often cause a number of unwanted side effects. In the present study, we identify the nonsteroidal anti-inflammatory drug carprofen as a multitarget-directed ligand that simultaneously inhibits cyclooxygenase-1 (COX-1), COX-2, and Fatty Acid Amide hydrolase (FAAH). Additionally, we synthesized and tested several derivatives of carprofen, sharing this multitarget activity. This may result in improved analgesic efficacy and reduced side effects (Naidu et al. J. Pharmacol. Exp. Ther.2009, 329, 48–56; Fowler, C. J.; et al. J. Enzyme Inhib. Med. Chem.2012, in press; Sasso et al. Pharmacol. Res.2012, 65, 553). The new compounds are among the most potent multitarget FAAH/COX inhibitors reported so far in the literature and thus may represent promising starting points for the discovery of new analgesic and anti-inflammatory drugs.
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structure property relationships of a class of carbamate based Fatty Acid Amide hydrolase faah inhibitors chemical and biological stability
ChemMedChem, 2009Co-Authors: Federica Vacondio, Alessio Lodola, Silvia Rivara, Claudia Silva, Alessandro Fioni, Andrea Duranti, Andrea Tontini, Silvano Sanchini, Jason R Clapper, Daniele PiomelliAbstract:Cyclohexylcarbamic Acid aryl esters are a class of Fatty Acid Amide Hydrolase (FAAH) inhibitors, which includes the reference compound URB597. The reactivity of their carbamate fragment is involved in pharmacological activity and may affect pharmacokinetic and toxicological properties. We conducted in vitro stability experiments in chemical and biological environments to investigate the structure-stability relationships in this class of compounds. The results show that electrophilicity of the carbamate influences its chemical stability, as suggested by the relation between the rate constant of alkaline hydrolysis (log kpH9) and the energy of lowest unoccupied molecular orbital (LUMO). Introduction of small, electron donor substituents at conjugated positions of the O-aryl moiety increased overall hydrolytic stability of the carbamate group without affecting FAAH inhibitory potency, whereas peripheral nonconjugated hydrophilic groups, which favor FAAH recognition, helped reducing oxidative metabolism in the liver.
Alessio Lodola - One of the best experts on this subject based on the ideXlab platform.
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Nonempirical Energetic Analysis of Reactivity and Covalent Inhibition of Fatty Acid Amide Hydrolase
2016Co-Authors: Ewa I. Chudyk, Alessio Lodola, Marco Mor, Edyta Dyguda-kazimierowicz, Karol M. Langner, Andrzej W. Sokalski, Jitnapa Sirirak, Adrian J. MulhollandAbstract:Fatty Acid Amide hydrolase (FAAH) is a member of the amidase signature family and is responsible for the hydrolytic deactivation of Fatty Acid Amide neuromodulators, such as anandAmide. FAAH carries an unusual catalytic triad consisting of Lys-Ser-Ser, which uniquely enables the enzyme to cleave Amides and esters at similar rates. The acylation of 9Z-octadecenAmide (oleAmide, a FAAH reference substrate) has been widely investigated by computational methods, and those have shown that conformational fluctuations of the active site affect the reaction barrier. Empirical descriptors have been devised to provide a possible mechanistic explanation for such conformational effects, but a first-principles understanding is still missing. A comparison of FAAH acylation with a reference reaction in water suggests that transition-state stabilization is crucial for catalysis because the activation energy barrier falls by 6 kcal/mol in the presence of the active site. With this in mind, we have analyzed the enzymatic reaction using the differential transition-state stabilization (DTSS) approach to determine key active-site residues for lowering the barrier. We examined several QM/MM structures at the MP2 level of theory and analyzed catalytic effects with a variation–perturbation partitioning of the interaction energy into electrostatic multipole and penetration, exchange, delocalization, and correlation terms. Three residues – Thr236, Ser218, and one water molecule – appear to be essential for the stabilization of the transition state, a conclusion that is also reflected by catalytic fields and agrees with site-directed mutagenesis data. An analogous analysis for URB524, URB618, and URB694 (three potent representatives of covalent, carbamate-based FAAH inhibitors) confirms the importance of the residues involved in oleAmide acylation, providing insight for future inhibitor design
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Fatty Acid Amide hydrolase inhibitors a patent review 2009 2014
Expert Opinion on Therapeutic Patents, 2015Co-Authors: Alessio Lodola, Riccardo Castelli, Marco Mor, Silvia RivaraAbstract:Introduction: Fatty Acid Amide hydrolase (FAAH) is a key enzyme responsible for the degradation of the endocannabinoid anandAmide. FAAH inactivation is emerging as a strategy to treat several CNS and peripheral diseases, including inflammation and pain. The search for effective FAAH inhibitors has thus become a key focus in present drug discovery.Areas covered: Patents and patent applications published from 2009 to 2014 in which novel chemical classes are claimed to inhibit FAAH.Expert opinion: FAAH is a promising target for treating many disease conditions including pain, inflammation and mood disorders. In the last few years, remarkable efforts have been made to develop new FAAH inhibitors (either reversible and irreversible) characterized by excellent potency and selectivity, to complete the arsenal of tools for modulating FAAH activity. The failure of PF-04457845 in a Phase II study on osteoarthritis pain has not flattened the interest in FAAH inhibitors. New clinical trials on ‘classical’ FAAH inhibi...
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Quantum Mechanics/Molecular Mechanics Modeling of Fatty Acid Amide Hydrolase Reactivation Distinguishes Substrate from Irreversible Covalent Inhibitors
2013Co-Authors: Alessio Lodola, Daniele Piomelli, Silvia Rivara, Giorgio Tarzia, Luigi Capoferri, Adrian Mulholland, Marco MorAbstract:Carbamate and urea derivatives are important classes of Fatty Acid Amide hydrolase (FAAH) inhibitors that carbamoylate the active-site nucleophile Ser241. In the present work, the reactivation mechanism of carbamoylated FAAH is investigated by means of a quantum mechanics/molecular mechanics (QM/MM) approach. The potential energy surfaces for decarbamoylation of FAAH covalent adducts, derived from the O-aryl carbamate URB597 and from the N-piperazinylurea JNJ1661610, were calculated and compared to that for deacylation of FAAH acylated by the substrate oleAmide. Calculations show that a carbamic group bound to Ser241 prevents efficient stabilization of transition states of hydrolysis, leading to large increments in the activation barrier. Moreover, the energy barrier for the piperazine carboxylate was significantly lower than that for the cyclohexyl carbamate derived from URB597. This is consistent with experimental data showing slowly reversible FAAH inhibition for the N-piperazinylurea inhibitor and irreversible inhibition for URB597
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structure property relationships of a class of carbamate based Fatty Acid Amide hydrolase faah inhibitors chemical and biological stability
ChemMedChem, 2009Co-Authors: Federica Vacondio, Alessio Lodola, Silvia Rivara, Claudia Silva, Alessandro Fioni, Andrea Duranti, Andrea Tontini, Silvano Sanchini, Jason R Clapper, Daniele PiomelliAbstract:Cyclohexylcarbamic Acid aryl esters are a class of Fatty Acid Amide Hydrolase (FAAH) inhibitors, which includes the reference compound URB597. The reactivity of their carbamate fragment is involved in pharmacological activity and may affect pharmacokinetic and toxicological properties. We conducted in vitro stability experiments in chemical and biological environments to investigate the structure-stability relationships in this class of compounds. The results show that electrophilicity of the carbamate influences its chemical stability, as suggested by the relation between the rate constant of alkaline hydrolysis (log kpH9) and the energy of lowest unoccupied molecular orbital (LUMO). Introduction of small, electron donor substituents at conjugated positions of the O-aryl moiety increased overall hydrolytic stability of the carbamate group without affecting FAAH inhibitory potency, whereas peripheral nonconjugated hydrophilic groups, which favor FAAH recognition, helped reducing oxidative metabolism in the liver.
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qm mm modelling of oleAmide hydrolysis in Fatty Acid Amide hydrolase faah reveals a new mechanism of nucleophile activation
Chemical Communications, 2005Co-Authors: Alessio Lodola, Daniele Piomelli, Johannes Cornelius Herma, Giorgio Tarzia, Adria J MulhollandAbstract:Fatty Acid Amide hydrolase (FAAH), a promising target for the treatment of several central and peripheral nervous system disorders, such as anxiety, pain and hypertension, has an unusual catalytic site, and its mechanism has been uncertain; hybrid quantum mechanics/molecular mechanics (QM/MM) calculations reveal a new mechanism of nucleophile activation (involving a Lys–Ser–Ser catalytic triad), with potentially crucial insights for the design of potent and selective inhibitors.
Aron H Lichtman - One of the best experts on this subject based on the ideXlab platform.
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the role of Fatty Acid Amide hydrolase inhibition in nicotine reward and dependence
Life Sciences, 2013Co-Authors: Pretal P Muldoon, Aron H Lichtman, Loren H Parsons, Imad M DamajAbstract:The endogenous cannabinoid anandAmide (AEA) exerts the majority of its effects at CB1 and CB2 receptors and is degraded by Fatty Acid Amide hydrolase (FAAH). FAAH KO mice and animals treated with FAAH inhibitors are impaired in their ability to hydrolyze AEA and other non-cannabinoid lipid signaling molecules, such as oleoylethanolAmide (OEA) and palmitoylethanolAmide (PEA). AEA and these other substrates activate non-cannabinoid receptor systems, including TRPV1 and PPAR-α receptors. In this mini review, we describe the functional consequences of FAAH inhibition on nicotine reward and dependence as well as the underlying endocannabinoid and non-cannabinoid receptor systems mediating these effects. Interestingly, FAAH inhibition seems to mediate nicotine dependence differently in mice and rats. Indeed, pharmacological and genetic FAAH disruption in mice enhances nicotine reward and withdrawal. However, in rats, pharmacological blockade of FAAH significantly inhibits nicotine reward and has no effect in nicotine withdrawal. Studies suggest that non-cannabinoid mechanisms may play a role in these species differences.
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targeting Fatty Acid Amide hydrolase faah to treat pain and inflammation
Aaps Journal, 2009Co-Authors: Joel E Schlosburg, Steven G. Kinsey, Aron H LichtmanAbstract:The endogenous cannabinoid N-arachidonoyl ethanolamine (anandAmide; AEA) produces most of its pharmacological effects by binding and activating CB1 and CB2 cannabinoid receptors within the CNS and periphery. However, the actions of AEA are short lived because of its rapid catabolism by Fatty Acid Amide hydrolase (FAAH). Indeed, FAAH knockout mice as well as animals treated with FAAH inhibitors are severely impaired in their ability to hydrolyze AEA as well as a variety of noncannabinoid lipid signaling molecules and consequently possess greatly elevated levels of these endogenous ligands. In this mini review, we describe recent research that has investigated the functional consequences of inhibiting this enzyme in a wide range of animal models of inflammatory and neuropathic pain states. FAAH-compromised animals reliably display antinociceptive and anti-inflammatory phenotypes with a similar efficacy as direct-acting cannabinoid receptor agonists, such as Δ9-tetrahydrocannabinol (THC), the primary psychoactive constituent of Cannabis sativa. Importantly, FAAH blockade does not elicit any apparent psychomimetic effects associated with THC or produce reinforcing effects that are predictive of human drug abuse. The beneficial effects caused by FAAH blockade in these models are predominantly mediated through the activation of CB1 and/or CB2 receptors, though noncannabinoid mechanisms of actions can also play contributory or even primary roles. Collectively, the current body of scientific literature suggests that activating the endogenous cannabinoid system by targeting FAAH is a promising strategy to treat pain and inflammation but lacks untoward side effects typically associated with Cannabis sativa.
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evaluation of Fatty Acid Amide hydrolase inhibition in murine models of emotionality
Psychopharmacology, 2007Co-Authors: Pattipati S Naidu, Billy R. Martin, Benjamin F Cravatt, S A Varvel, Aron H LichtmanAbstract:Rationale Manipulations of the endocannabinoid/Fatty Acid Amide hydrolase (FAAH) signaling systems result in conflicting and paradoxical effects in rodent models of emotional reactivity.
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Fatty Acid Amide hydrolase mice exhibit an increased sensitivity to the disruptive effects of anandAmide or oleAmide in a working memory water maze task
Journal of Pharmacology and Experimental Therapeutics, 2006Co-Authors: S A Varvel, Benjamin F Cravatt, April E Engram, Aron H LichtmanAbstract:Although recent evidence suggests that Fatty Acid Amide hydrolase (FAAH) may represent a potential therapeutic target, few published studies have investigated FAAH or its Fatty Acid Amide substrates (FAAs) in animal models of learning and memory. Therefore, our primary goal was to determine whether FAAH (–/–) mice, which possess elevated levels of anandAmide and other FAAs, would display altered performance in four Morris water maze tasks: acquisition of a hidden fixed platform, reversal learning, working memory, and probe trials. FAAH (–/–) mice failed to exhibit deficits in any task; in fact, they initially acquired the working memory task more rapidly than FAAH (+/+) mice. The second goal of this study was to investigate whether the FAAH inhibitor OL-135 (1-oxo-1[5-(2-pyridyl)-2-yl]-7-phenylheptane), anandAmide, other FAAs, and methanandAmide would affect working memory in both genotypes. FAAH (–/–), but not (+/+), mice displayed working memory impairments following exogenous administration of anandAmide (ED50 = 6 mg/kg) or oleAmide (50 mg/kg). However, the central cannabinoid receptor (CB1) receptor antagonist SR141716 [ N -(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1 H -pyrazole-3-carboxAmide HCl] only blocked the disruptive effects of anandAmide. MethanandAmide, which is not metabolized by FAAH, disrupted working memory performance in both genotypes (ED50 = 10 mg/kg), suggesting that CB1 receptor signaling is unaltered by FAAH deletion. In contrast, OL-135 and other FAAs failed to affect working memory in either genotype. These results suggest that FAAH deletion does not impair spatial learning but may enhance acquisition under certain conditions. More generally, FAAH may represent a novel therapeutic target that circumvents the undesirable cognitive side effects commonly associated with direct-acting cannabinoid agonists.
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mice lacking Fatty Acid Amide hydrolase exhibit a cannabinoid receptor mediated phenotypic hypoalgesia
Pain, 2004Co-Authors: Aron H Lichtman, Christopher C Shelton, Tushar Advani, Benjamin F CravattAbstract:Abstract Although the N-arachidonoyl ethanolamine (anandAmide) binds to cannabinoid receptors and has been implicated in the suppression of pain, its rapid catabolism in vivo by Fatty Acid Amide hydrolase (FAAH) has presented a challenge in investigating the physiological functions of this endogenous cannabinoid. In order to test whether anandAmide and other non-cannabinoid Fatty Amides modulate nociception, we compared FAAH (+/+) and (−/−) mice in the tail immersion, hot plate, and formalin tests, as well as for thermal hyperalgesia in the carrageenan and the chronic constriction injury (CCI) models. FAAH (−/−) mice exhibited a CB1 receptor-mediated phenotypic hypoalgesia in thermal nociceptive tests. These mice also exhibited CB1 receptor-mediated hypoalgesia in both phases of the formalin test accompanied with a phenotypic anti-edema effect, which was not blocked by either CB1 or CB2 antagonists. Additionally, FAAH (−/−) mice displayed thermal anti-hyperalgesic and anti-inflammatory effects in the carrageenan model that were mediated, in part, by CB2, but not CB1 receptors. In contrast, no genotype differences in pain behavior were evident following CCI, which was instead found to obliterate the phenotypic hypoalgesia displayed by FAAH (−/−) mice in the tail immersion and hot plate tests, suggesting that nerve injury may promote adaptive changes in these animals. Collectively, these findings demonstrate a cannabinoid receptor-mediated analgesic phenotype in FAAH (−/−) mice. In more general terms, these findings suggest that selective inhibitors of FAAH might represent a viable pharmacological approach for the clinical treatment of pain disorders.
