Pain and beyond: fatty acid amides and fatty acid amide hydrolase inhibitors in cardiovascular and metabolic diseases

Drug Discovery Today

Volumn 14, Issue 23-24, 2009, Pages 1098-1111

  Pillarisetti, Sivaram ^a   Alexander, Christopher W ^a   Khanna, Ish ^a  

^a Reddy US Therapeutics   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

7 PHENYL 1 [5 (2 PYRIDINYL) 2 OXAZOLYL] 1 HEPTANONE; ANANDAMIDE; CAPSAICIN; CYCLOHEXYLCARBAMIC ACID 3' CARBAMOYLBIPHENYL 3 YL ESTER; FATTY ACID AMIDASE; FATTY ACID AMIDASE INHIBITOR; JNJ 1661010; LY 2183240; N OLEOYLETHANOLAMINE; N STEAROYLETHANOLAMINE; PALMIDROL; PF 622; PF 750; RIMONABANT; SA 41129; SSR 411298; UNCLASSIFIED DRUG; URB 524;

ALLOSTERISM; ANALGESIA; ANTIINFLAMMATORY ACTIVITY; ANXIETY DISORDER; CARDIOVASCULAR DISEASE; CHOLESTASIS; CLINICAL TRIAL; DEPRESSION; DIABETES MELLITUS; DRUG STRUCTURE; ENTERITIS; ENZYME SPECIFICITY; ESSENTIAL HYPERTENSION; FOOD INTAKE; HEART INFARCTION; HEART PROTECTION; HUMAN; HYDROLYSIS; HYPERTENSION; INFLAMMATION; METABOLIC DISORDER; NAUSEA AND VOMITING; NEUROPATHIC PAIN; NOCICEPTION; NONHUMAN; OBESITY; PAIN; PARKINSON DISEASE; PROTEIN FUNCTION; PROTEIN STRUCTURE; PRURITUS; REVIEW; SLEEP DISORDER; STOMACH EMPTYING; STRUCTURE ACTIVITY RELATION; TOBACCO DEPENDENCE;

AMIDES; AMIDOHYDROLASES; ANIMALS; CARDIOVASCULAR DISEASES; CENTRAL NERVOUS SYSTEM DISEASES; ENDOCANNABINOIDS; FATTY ACIDS; HUMANS; METABOLIC DISEASES; OBESITY; PAIN; RECEPTORS, CANNABINOID;

EID: 71749089107     PISSN: 13596446     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.drudis.2009.08.002     Document Type: Review

References (170)

1. Farrell E.K., and Merkler D.J. Biosynthesis, degradation and pharmacological importance of the fatty acid amides. Drug Discov. Today 13 (2008) 558-568
2. Walker J.M., et al. Targeted lipidomics: fatty acid amides and pain modulation. Prostaglandins Other Lipid Mediat. 77 (2005) 35-45
3. Devane W.A., et al. Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science 18 (1992) 1946-1949
4. Movahed P., et al. Endogenous unsaturated C18 N-acylethanolamines are vanilloid receptor (TRPV1) agonists. J. Biol. Chem. 280 (2005) 38496-38504
5. Caldwell J.E.A. The amino acid conjugations. In: Gram T.E. (Ed). Extrahepatic Metabolism of Drugs and Other Compounds (1980), Spectrum Publications 453-492
6. Arafat E.S., et al. Identification of fatty acid amides in human plasma. Life Sci. 45 (1989) 1679-1687
7. Cravatt B.F., et al. Chemical characterization of a family of brain lipids that induce sleep. Science 268 (1995) 1506-1509
8. Mechoulam R., et al. Endocannabinoids. Eur. J. Pharmacol. 359 (1998) 1-18
9. Di Marzo V., et al. Endocannabinoids and related compounds: walking back and forth between plant natural products and animal physiology. Chem. Biol. 14 (2007) 741-756
10. Starowicz K., et al. Biochemistry and pharmacology of endovanilloids. Pharmacol. Ther. 114 (2007) 13-33
11. Walker J.M., et al. Pain modulation by release of the endogenous cannabinoid anandamide. Proc. Natl. Acad. Sci. U. S. A. 96 (1999) 12198-12203
12. Murillo-Rodríguez E., et al. Anandamide modulates sleep and memory in rats. Brain Res. 812 (1998) 270-274
13. Crawley J.N., et al. Anandamide, an endogenous ligand of the cannabinoid receptor, induces hypomotility and hypothermia in vivo in rodents. Pharmacol. Biochem. Behav. 46 (1993) 967-972
14. Walker J.M., et al. Endocannabinoids and related fatty acid derivatives in pain modulation. Chem. Phys. Lipids 121 (2002) 159-172
15. Suardíaz M., et al. Analgesic properties of oleoylethanolamide (OEA) in visceral and inflammatory pain. Pain 133 (2007) 99-110
16. Strangman N.M. Evidence for a role of endogenous cannabinoids in the modulation of acute and tonic pain sensitivity. Brain Res. 813 (1998) 323-328
17. Patricelli M.P., and Cravatt B.F. Proteins regulating the biosynthesis and inactivation of neuromodulatory fatty acid amides. Vitam. Horm. 62 (2001) 95-131
18. Sugiura T., et al. Biosynthesis and degradation of anandamide and 2-arachidonoylglycerol and their possible physiological significance. Prostaglandins Leukot. Essent. Fatty Acids 66 (2002) 173-192
19. Leung D., et al. Inactivation of N-acyl phosphatidylethanolamine phospholipase D reveals multiple mechanisms for the biosynthesis of endocannabinoids. Biochemistry 45 (2006) 4720-4726
20. 2+ influx via TRPV1 channels. EMBO J. 24 (2005) 3026-3037
21. Ross R.A. Anandamide and vanilloid TRPV1 receptors. Br. J. Pharmacol. 140 (2003) 790-801
22. Saghatelian A., et al. A FAAH-regulated class of N-acyl taurines that activates TRP ion channels. Biochemistry 45 (2006) 9007-9015
23. Wang X., et al. Oleoylethanolamide excites vagal sensory neurones, induces visceral pain and reduces short-term food intake in mice via capsaicin receptor TRPV1. J. Physiol. 564 (2005) 541-547
24. Costa B., et al. The endogenous fatty acid amide, palmitoylethanolamide, has anti-allodynic and anti-hyperalgesic effects in a murine model of neuropathic pain: involvement of CB(1). TRPV1 and PPARgamma receptors and neurotrophic factors. Pain 139 (2008) 541-550
25. Sun Y., et al. Cannabinoid activation of PPAR alpha; a novel neuroprotective mechanism. Br. J. Pharmacol. 152 (2007) 734-743
26. O'Sullivan S.E. Cannabinoids go nuclear: evidence for activation of peroxisome proliferator-activated receptors. Br. J. Pharmacol. 152 (2007) 576-582
27. Overton H.A., et al. Deorphanization of a G protein-coupled receptor for oleoylethanolamide and its use in the discovery of small-molecule hypophagic agents. Cell Metab. 3 (2006) 167-175
28. Ross R.A. The enigmatic pharmacology of GPR55. Trends Pharmacol. Sci. 30 (2009) 156-163
29. Ho W.S., et al. 'Entourage' effects of N-palmitoylethanolamide and N-oleoylethanolamide on vasorelaxation to anandamide occur through TRPV1 receptors. Br. J. Pharmacol. 155 (2008) 837-846
30. Smart D., et al. 'Entourage' effects of N-acyl ethanolamines at human vanilloid receptors. Comparison of effects upon anandamide-induced vanilloid receptor activation and upon anandamide metabolism. Br. J. Pharmacol. 136 (2002) 452-458
31. Massi P., et al. Cannabinoids, immune system and cytokine network. Curr. Pharm. Des. 12 (2006) 3135-3146
32. Ashton J.C. Cannabinoids for the treatment of inflammation. Curr. Opin. Investig. Drugs 8 (2007) 373-384
33. D'Argenio G., et al. Up-regulation of anandamide levels as an endogenous mechanism and a pharmacological strategy to limit colon inflammation. FASEB J. 20 (2006) 568-570
34. Lambert D.M., et al. The palmitoylethanolamide family: a new class of anti-inflammatory agents?. Curr. Med. Chem. 9 (2002) 663-674
35. Conti S., et al. Antiinflammatory action of endocannabinoid palmitoylethanolamide and the synthetic cannabinoid nabilone in a model of acute inflammation in the rat. Br. J. Pharmacol. 135 (2002) 181-187
36. Re G., et al. Palmitoylethanolamide, endocannabinoids and related cannabimimetic compounds in protection against tissue inflammation and pain: potential use in companion animals. Vet. J. 173 (2007) 21-30
37. Lo Verme J., et al. The nuclear receptor peroxisome proliferator-activated receptor-alpha mediates the anti-inflammatory actions of palmitoylethanolamide. Mol. Pharmacol. 67 (2005) 15-19
38. Costa B., et al. Therapeutic effect of the endogenous fatty acid amide, palmitoylethanolamide, in rat acute inflammation: inhibition of nitric oxide and cyclo-oxygenase systems. Br. J. Pharmacol. 137 (2002) 413-420
39. Lambert D.M., and Di Marzo V. The palmitoylethanolamide and oleamide enigmas: are these two fatty acid amides cannabimimetic?. Curr. Med. Chem. 6 (1999) 757-773
40. Berdyshev E.V., et al. Influence of fatty acid ethanolamides and δ9-tetrahydrocannabinol on cytokine and arachidonate release by mononuclear cells. Eur. J. Pharmacol. 330 (1997) 231-240
41. Berdyshev E., et al. Effects of cannabinoid receptor ligands on LPS-induced pulmonary inflammation in mice. Life Sci. 63 (1998) PL125-PL129
42. D'Agostino G., et al. Acute intracerebroventricular administration of palmitoylethanolamide, an endogenous peroxisome proliferator-activated receptor-alpha agonist, modulates carrageenan-induced paw edema in mice. J. Pharmacol. Exp. Ther. 322 (2007) 1137-1143
43. Dalle Carbonare M., et al. A saturated N-acylethanolamine other than N-palmitoyl ethanolamine with anti-inflammatory properties: a neglected story. J. Neuroendocrinol. 20 (2008) 26-34
44. Cummings D.E., and Overduin J. Gastrointestinal regulation of food intake. J. Clin. Invest. 117 (2007) 13-23
45. Chaudhri O., et al. Gastrointestinal hormones regulating appetite. Philos. Trans. R. Soc. Lond. B: Biol. Sci. 361 (2006) 1187-1209
46. Capasso R., and Izzo A.A. Gastrointestinal regulation of food intake: general aspects and focus on anandamide and oleoylethanolamide. J. Neuroendocrinol. 20 (2008) 39-46
47. Pinto L., et al. Endocannabinoids and the gut. Prostaglandins Leukot. Essent. Fatty Acids 66 (2002) 333-341
48. Di Marzo V., et al. The role of endocannabinoids in the regulation of gastric emptying: alterations in mice fed a high-fat diet. Br. J. Pharmacol. 153 (2008) 1272-1280
49. Aviello G., et al. Inhibitory effect of the anorexic compound oleoylethanolamide on gastric emptying in control and overweight mice. J. Mol. Med. 86 (2008) 413-422
50. Fu J., et al. Food intake regulates oleoylethanolamide formation and degradation in the proximal small intestine. J. Biol. Chem. 282 (2007) 1518-1528
51. Fu J., et al. Oleylethanolamide regulates feeding and body weight through activation of the nuclear receptor PPAR-alpha. Nature 425 (2003) 90-93
52. Astarita G., et al. Pharmacological characterization of hydrolysis-resistant analogs of oleoylethanolamide with potent anorexiant properties. J. Pharmacol. Exp. Ther. 318 (2006) 563-570
53. Guzmán M., et al. Oleoylethanolamide stimulates lipolysis by activating the nuclear receptor peroxisome proliferator-activated receptor alpha (PPAR-alpha). J. Biol. Chem. 279 (2004) 27849-27854
54. Matias I., et al. Role and regulation of acylethanolamides in energy balance: focus on adipocytes and beta-cells. Br. J. Pharmacol. 152 (2007) 676-690
55. Overton H.A., et al. GPR119, a novel G protein-coupled receptor target for the treatment of type 2 diabetes and obesity. Br. J. Pharmacol. 153 (2008) S76-S81
56. Blüher M., et al. Dysregulation of the peripheral and adipose tissue endocannabinoid system in human abdominal obesity. Diabetes 55 (2006) 3053-3060
57. Matias I., et al. Regulation, function, and dysregulation of endocannabinoids in models of adipose and beta-pancreatic cells and in obesity and hyperglycemia. J. Clin. Endocrinol. Metab. 91 (2006) 3171-3180
58. Sipe J.C., et al. Overweight and obesity associated with a missense polymorphism in fatty acid amide hydrolase (FAAH). Int. J. Obes. (Lond.) 29 (2005) 755-759
59. Jensen D.P., et al. The functional Pro129Thr variant of the FAAH gene is not associated with various fat accumulation phenotypes in a population-based cohort of 5,801 whites. J. Mol. Med. 85 (2007) 445-449
60. Papazoglou D., et al. The fatty acid amide hydrolase (FAAH) Pro129Thr polymorphism is not associated with severe obesity in Greek subjects. Horm. Metab. Res. 40 (2008) 907-910
61. Hillard C.J. Endocannabinoids and vascular function. J. Pharmacol. Exp. Ther. 294 (2000) 27-32
62. Kunos G., et al. Endocannabinoids as cardiovascular modulators. Chem. Phys. Lipids 108 (2000) 159-168
63. Randall M.D., et al. Cardiovascular effects of cannabinoids. Pharmacol. Ther. 95 (2002) 191-202
64. Randall M.D., et al. The complexities of the cardiovascular actions of cannabinoids. Br. J. Pharmacol. 142 (2004) 20-26
65. Wagner J.A., et al. Cardiovascular actions of cannabinoids and their generation during shock. J. Mol. Med. 76 (1998) 824-836
66. Deutsch D.G., et al. Production and physiological actions of anandamide in the vasculature of the rat kidney. J. Clin. Invest. 100 (1997) 1538-1546
67. Lagneux C., and Lamontagne D. Involvement of cannabinoids in the cardioprotection induced by lipopolysaccharide. Br. J. Pharmacol. 132 (2001) 793-796
68. Joyeux M., et al. Endocannabinoids are implicated in the infarct size-reducing effect conferred by heat stress preconditioning in isolated rat hearts. Cardiovasc. Res. 55 (2002) 619-625
69. Hajrasouliha A.R., et al. Endogenous cannabinoids contribute to remote ischemic preconditioning via cannabinoid CB2 receptors in the rat heart. Eur. J. Pharmacol. 579 (2008) 246-252
70. Hiley C.R., and Hoi P.M. Oleamide: a fatty acid amide signaling molecule in the cardiovascular system?. Cardiovasc. Drug Rev. 25 (2007) 46-60
71. Glaser S.T., et al. Anandamide transport: a critical review. Life Sci. 77 (2005) 1584-1604
72. Piomelli D., et al. Structural determinants for recognition and translocation by the anandamide transporter. Proc. Natl. Acad. Sci. U. S. A. 96 (1999) 5802-5807
73. Kaczocha M., et al. Anandamide uptake is consistent with rate-limited diffusion and is regulated by the degree of its hydrolysis by fatty acid amide hydrolase. J. Biol. Chem. 281 (2006) 9066-9075
74. McKinney M.K., and Cravatt B.F. Structure and function of fatty acid amide hydrolase. Annu. Rev. Biochem. 74 (2005) 411-432
75. Kaczocha M., et al. Identification of intracellular carriers for the endocannabinoid anandamide. Proc. Natl. Acad. Sci. U. S. A. 106 (2009) 6375-6380
76. Desarnaud F., et al. Anandamide amidohydrolase activity in rat brain microsomes. Identification and partial characterization. J. Biol. Chem. 270 (1995) 6030-6035
77. Matsuda S., et al. Metabolism of anandamide, an endogenous cannabinoid receptor ligand, in porcine ocular tissues. Exp. Eye Res. 64 (1997) 707-711
78. Watanabe K., et al. Distribution and characterization of anandamide amidohydrolase in mouse brain and liver. Life Sci. 62 (1998) 1223-1239
79. Maccarrone M., et al. Down-regulation of anandamide hydrolase in mouse uterus by sex hormones. Eur. J. Biochem. 267 (2000) 2991-2997
80. Bobrov M.Y., et al. Hydrolysis of anandamide and eicosapentanoic acid ethanolamide in mouse splenocytes. Biochemistry (Mosc.) 65 (2000) 615-619
81. Bari M., et al. New insights into endocannabinoid degradation and its therapeutic potential. Mini Rev. Med. Chem. 6 (2006) 257-268
82. Cravatt B.F., et al. Supersensitivity to anandamide and enhanced endogenous cannabinoid signaling in mice lacking fatty acid amide hydrolase. Proc. Natl. Acad. Sci. U. S. A. 98 (2001) 9371-9376
83. Pacher P., et al. Hemodynamic profile, responsiveness to anandamide, and baroreflex sensitivity of mice lacking fatty acid amide hydrolase. Am. J. Physiol. Heart Circ. Physiol. 289 (2005) H533-541
84. Di Marzo V., et al. The anandamide membrane transporter. Structure-activity relationships of anandamide and oleoylethanolamine analogs with phenyl rings in the polar head group region. Bioorg. Med. Chem. 12 (2004) 5161-5169
85. Lichtman A.H., et al. Mice lacking fatty acid amide hydrolase exhibit a cannabinoid receptor-mediated phenotypic hypoalgesia. Pain 109 (2004) 319-327
86. Moreira F.A., et al. Reduced anxiety-like behaviour induced by genetic and pharmacological inhibition of the endocannabinoid-degrading enzyme fatty acid amide hydrolase (FAAH) is mediated by CB1 receptors. Neuropharmacology 54 (2008) 141-150
87. Massa F., et al. The endogenous cannabinoid system protects against colonic inflammation. J. Clin. Invest. 113 (2004) 1202-1209
88. Bátkai S., et al. Decreased age-related cardiac dysfunction, myocardial nitrative stress, inflammatory gene expression, and apoptosis in mice lacking fatty acid amide hydrolase. Am. J. Physiol. Heart Circ. Physiol. 293 (2007) H909-H918
89. Patricelli M.P., and Cravatt B.F. Fatty acid amide hydrolase competitively degrades bioactive amides and esters through a nonconventional catalytic mechanism. Biochemistry 38 (1999) 14125-14130
90. Bracey M.H., et al. Structural adaptations in a membrane enzyme that terminates endocannabinoid signaling. Science 298 (2002) 1793-1796
91. McKinney M.K., and Cravatt B.F. Evidence for distinct roles in catalysis for residues of the serine-serine-lysine catalytic triad of fatty acid amide hydrolase. J. Biol. Chem. 278 (2003) 37393-37399
92. Mileni M., et al. Structure-guided inhibitor design for human FAAH by interspecies active site conversion. Proc. Natl. Acad. Sci. U. S. A. 105 (2008) 12820-12824
93. Wei B.Q., et al. A second fatty acid amide hydrolase with variable distribution among placental mammals. J. Biol. Chem. 281 (2006) 36569-36578
94. Seierstad M., and Breitenbucher J.G. Discovery and development of fatty acid amide hydrolase (FAAH) inhibitors. J. Med. Chem. 51 (2008) 7327-7343
95. Vandevoorde S. Overview of the chemical families of fatty acid amide hydrolase and monoacylglycerol lipase inhibitors. Curr. Top. Med. Chem. 8 (2008) 247-267
96. Di Marzo V. Targeting the endocannabinoid system: to enhance or reduce?. Nat. Rev. Drug Discov. 7 (2008) 438-455
97. Labar G., and Michaux C. Fatty acid amide hydrolase: from characterization to therapeutics. Chem. Biodivers. 4 (2007) 1882-1902
98. Lambert D.M., and Fowler C.J. The endocannabinoid system: drug targets, lead compounds, and potential therapeutic applications. J. Med. Chem. 48 (2005) 5059-5087
99. Bisogno T., et al. Fatty acid amide hydrolase, an enzyme with many bioactive substrates. Possible therapeutic implications. Curr. Pharm. Des. 8 (2002) 533-547
100. Deutsch D.G., et al. Methyl arachidonyl fluorophosphonate: a potent irreversible inhibitor of anandamide amidase. Biochem. Pharmacol. 53 (1997) 255-260
101. De Petrocellis L., et al. The activity of anandamide at vanilloid VR1 receptors requires facilitated transport across the cell membrane and is limited by intracellular metabolism. J. Biol. Chem. 276 (2001) 12856-12863
102. Bisogno T., et al. Arachidonoylserotonin and other novel inhibitors of fatty acid amide hydrolase. Biochem. Biophys. Res. Commun. 248 (1998) 515-522
103. Kathuria S., et al. Modulation of anxiety through blockade of anandamide hydrolysis. Nat. Med. 9 (2003) 76-81
104. Mor M., et al. Synthesis and quantitative structure-activity relationship of fatty acid amide hydrolase inhibitors: modulation at the N-portion of biphenyl-3-yl alkycarbamates. J. Med. Chem. 51 (2008) 3487-3498
105. Mor M., et al. Cyclohexylcarbamic acid 3′- or 4′-substituted biphenyl-3-yl esters as fatty acid amide hydrolase inhibitors: synthesis, quantitative structure-activity relationships, and molecular modeling studies. J. Med. Chem. 47 (2004) 4998-5008
106. Clinicaltrials.gov http://clinicaltrials.gov/ct2/show/NCT00822744, (accessed March 10, 2009). An eight week study of SSR411298 as treatment for major depressive disorder in elderly patients (FIDELIO)
107. Sit, S. et al. (2003) (Oxime)carbamoyl fatty acid amide hydrolase inhibitors. WO, 2003065989 A2
108. Sit S.Y., et al. Novel inhibitors of fatty acid amide hydrolase. Bioorg. Med. Chem. Lett. 17 (2007) 3287-3291
109. Edwards P.D., et al. Peptidyl alpha-ketoheterocyclic inhibitors of human neutrophil elastase. 3. In vitro and in vivo potency of a series of peptidyl alpha-ketobenzoxazoles. J. Med. Chem. 38 (1995) 3972-3982
110. Zhang D., et al. Fatty acid amide hydrolase inhibitors display broad selectivity and inhibit multiple carboxylesterases as off-targets. Neuropharmacology 52 (2007) 1095-1105
111. Ortar G., et al. Carbamoyl tetrazoles as inhibitors of endocannabinoid inactivation: a critical revisitation. Eur. J. Med. Chem. 43 (2008) 62-72
112. Keith J.M., et al. Thiadiazolopiperazinyl ureas as inhibitors of fatty acid amide hydrolase. Bioorg. Med. Chem. Lett. 18 (2008) 4838-4843
113. Ahn K., et al. Novel mechanistic class of fatty acid amide hydrolase inhibitors with remarkable selectivity. Biochemistry 46 (2007) 13019-13030
114. Johnson D.S. Fatty acid amide hydrolase (FAAH) inhibitors for the treatment of inflammatory pain. Presented at the 9th Winter Conference on Medicinal & Bioorganic Chemistry (2009)
115. Urbach A., et al. 3-Alkenyl-2-azetidinones as fatty acid amide hydrolase inhibitors. Bioorg. Med. Chem. Lett. 18 (2008) 4163-4167
116. Poppitz W., et al. Synthesis and activity of 1,3,5-triphenylimidazolidine-2,4-diones and 1,3,5-triphenyl-2-thioxoimidazolidin-4-ones: characterization of new CB1 cannabinoid receptor inverse agonists/antagonists. J. Med. Chem. 49 (2006) 872-882
117. Muccioli G.G., et al. Substituted 2-thioxo-4-imidazolidinones and imidazolidine-2,4-diones as fatty acid amide hydrolase inhibitors templates. J. Med. Chem. 49 (2006) 417-425
118. Romero F.A., et al. Potent and selective α-ketoheterocycle-based inhibitors of the anandamide and oleamide catabolizing enzyme, fatty acid amide hydrolase. J. Med. Chem. 50 (2007) 1058-1068
119. Kimball F.S., et al. Optimization of α-ketooxazole inhibitors of fatty acid amide hydrolase. J. Med. Chem. 51 (2008) 937-947
120. Garfunkle J., et al. Optimization of the central heterocycle of α-ketoheterocycle inhibitors of fatty acid amide hydrolase. J. Med. Chem. 51 (2008) 4392-4403
121. Boger D.L., et al. Discovery of a potent, selective, and efficacious class of reversible α-ketoheterocycle inhibitors of fatty acid amide hydrolase effective as analgesics. J. Med. Chem. 48 (2005) 1849-1856
122. Boger D.L., et al. Exceptionally potent inhibitors of fatty acid amide hydrolase: the enzyme responsible for degradation of endogenous oleamide and anandamide. Proc. Natl. Acad. Sci. U. S. A. 97 (2000) 5044-5049
123. Leung D., et al. Discovering potent and selective reversible inhibitors of enzymes in complex proteomes. Nat. Biotechnol. 21 (2003) 687-691
124. Leung D., et al. Discovery of an exceptionally potent and selective class of fatty acid amide hydrolase inhibitors enlisting proteome-wide selectivity screening: concurrent optimization of enzyme inhibitor potency and selectivity. Bioorg. Med. Chem. Lett. 15 (2005) 1423-1428
125. Timmons A., et al. Novel ketooxazole based inhibitors of fatty acid amide hydrolase (FAAH). Bioorg. Med. Chem. Lett. 18 (2008) 2109-2113
126. Wang X., et al. Synthesis and evaluation of benzothiazole-based analogues as novel, potent, and selective fatty acid amide hydrolase inhibitors. J. Med. Chem. 52 (2009) 170-180
127. Schlosburg J.E., et al. Targeting fatty acid amide hydrolase (FAAH) to treat pain and inflammation. AAPS J. 11 (2009) 39-44
128. Tham C.S., et al. Inhibition of microglial fatty acid amide hydrolase modulates LPS stimulated release of inflammatory mediators. FEBS Lett. 581 (2007) 2899-2904
129. Capasso R., et al. Cannabidiol, extracted from Cannabis sativa, selectively inhibits inflammatory hypermotility in mice. Br. J. Pharmacol. 154 (2008) 1001-1008
130. Schirra J., et al. GLP-1 regulates gastroduodenal motility involving cholinergic pathways. Neurogastroenterol. Motil. 21 (2009) 609-618
131. Lauffer L.M., et al. GPR119 is essential for oleoylethanolamide-induced glucagon-like peptide-1 secretion from the intestinal enteroendocrine L-cell. Diabetes 58 (2009) 1058-1066
132. Jayamanne A., et al. Actions of the FAAH inhibitor URB597 in neuropathic and inflammatory chronic pain models. Br. J. Pharmacol. 147 (2006) 281-288
133. Bátkai S., et al. Endocannabinoids acting at cannabinoid-1 receptors regulate cardiovascular function in hypertension. Circulation 110 (2004) 1996-2002
134. Wang H., et al. Fatty acid amide hydrolase deficiency limits early pregnancy events. J. Clin. Invest. 116 (2006) 2122-2131
135. Maione S., et al. Analgesic actions of N-arachidonoyl-serotonin; a fatty acid amide hydrolase inhibitor with antagonistic activity at vanilloid TRPV1 receptors. Br. J. Pharmacol. 150 (2007) 766-781
136. Chang L., et al. Inhibition of fatty acid amide hydrolase produces analgesia by multiple mechanisms. Br. J. Pharmacol. 148 (2006) 102-113
137. 2 antinociceptive effects of several novel compounds in the PPQ stretch test in mice. Eur. J. Pharmacol. 546 (2006) 60-68
138. Karbarz M.J., et al. Biochemical and biological properties of 4-(3-phenyl-[1,2,4] thiadiazol-5-yl)-piperazine-1-carboxylic acid phenylamide, a mechanism-based inhibitor of fatty acid amide hydrolase. Anesth. Analg. 108 (2009) 316-329
139. Sit S.Y., and Xie K. Preparation of bisarylimidazolyl fatty acid amide hydrolase inhibitors for treatment of pain. PCT Int. Appl. 98 (2006) 2002087569
140. Jhaveri M.D., et al. Analgesic effects of fatty acid amide hydrolase inhibition in a rat model of neuropathic pain. J. Neurosci. 26 (2006) 13318-13327
141. Russo R., et al. The fatty acid amide hydrolase inhibitor URB597 (cyclohexylcarbamic acid 3′-carbamoylbiphenyl-3-yl ester) reduces neuropathic pain after oral administration in mice. J. Pharmacol. Exp. Ther. 322 (2007) 236-242
142. Sagar D.R., et al. Inhibition of fatty acid amide hydrolase produces PPAR-α-mediated analgesia in a rat model of inflammatory pain. Br. J. Pharmacol. 155 (2008) 1297-1306
143. Jhaveri M.D., et al. Inhibition of fatty acid amide hydrolase and cyclooxygenase-2 increases levels of endocannabinoid related molecules and produces analgesia via peroxisome proliferator-activated receptor-alpha in a model of inflammatory pain. Neuropharmacology 55 (2008) 85-93
144. Hasanein P., et al. Effects of URB597 as an inhibitor of fatty acid amide hydrolase on modulation of nociception in a rat model of cholestasis. Eur. J. Pharmacol. 591 (2008) 132-135
145. Holt S., et al. Inhibitors of fatty acid amide hydrolase reduce carrageenan-induced hind paw inflammation in pentobarbital-treated mice: comparison with indomethacin and possible involvement of cannabinoid receptors. Br. J. Pharmacol. 146 (2005) 467-476
146. Storr M.A., et al. Targeting endocannabinoid degradation protects against experimental colitis in mice: involvement of CB1 and CB2 receptors. J. Mol. Med. 86 (2008) 925-936
147. Piomelli D., et al. Pharmacological profile of the selective FAAH inhibitor KDS-4103 (URB597). CNS Drug Rev. 12 (2006) 21-38
148. Patel S., and Hillard C.J. Pharmacological evaluation of cannabinoid receptor ligands in a mouse model of anxiety: further evidence for an anxiolytic role for endogenous cannabinoid signaling. J. Pharmacol. Exp. Ther. 318 (2006) 304-311
149. Hill M.N., et al. Estrogen recruits the endocannabinoid system to modulate emotionality. Psychoneuroendocrinology 32 (2007) 350-357
150. Lisboa S.F., et al. Activation of cannabinoid CB1 receptors in the dorsolateral periaqueductal gray induces anxiolytic effects in rats submitted to the Vogel conflict test. Eur. J. Pharmacol. 593 (2008) 73-78
151. Scherma M., et al. The endogenous cannabinoid anandamide has effects on motivation and anxiety that are revealed by fatty acid amide hydrolase (FAAH) inhibition. Neuropharmacology 54 (2008) 129-140
152. Gobbi G., et al. Antidepressant-like activity and modulation of brain monoaminergic transmission by blockade of anandamide hydrolysis. Proc. Natl. Acad. Sci. U. S. A. 102 (2005) 18620-18625
153. Bortolato M., et al. Antidepressant-like activity of the fatty acid amide hydrolase inhibitor URB597 in a rat model of chronic mild stress. Biol. Psychiatry 62 (2007) 1103-1110
154. Cross-Mellor S.K., et al. Effects of the FAAH inhibitor, URB597, and anandamide on lithium-induced taste reactivity responses: a measure of nausea in the rat. Psychopharmacology (Berl.) 190 (2007) 135-143
155. Rock E.M., et al. The effect of cannabidiol and URB597 on conditioned gaping (a model of nausea) elicited by a lithium-paired context in the rat. Psychopharmacology (Berl.) 196 (2008) 389-395
156. Parker L.A., et al. The FAAH inhibitor URB-597 interferes with cisplatin- and nicotine-induced vomiting in the Suncus murinus (house musk shrew). Physiol. Behav. 97 (2009) 121-124
157. Kreitzer A.C., and Malenka R.C. Endocannabinoid-mediated rescue of striatal LTD and motor deficits in Parkinson's disease models. Nature 445 (2007) 643-647
158. Morgese M.G., et al. Anti-dyskinetic effects of cannabinoids in a rat model of Parkinson's disease: role of CB1 and TRPV1 receptors. Exp. Neurol. 208 (2007) 110-119
159. Schlosburg J.E., et al. Endocannabinoid modulation of scratching response in an acute allergenic model: a new prospective neural therapeutic target for pruritus. J. Pharmacol. Exp. Ther. 329 (2009) 314-323
160. Scherma M., et al. Inhibition of anandamide hydrolysis by cyclohexyl carbamic acid 3′-carbamoyl-3-yl ester (URB597) reverses abuse-related behavioral and neurochemical effects of nicotine in rats. J. Pharmacol. Exp. Ther. 327 (2008) 482-490
161. Facci L., et al. Mast cells express a peripheral cannabinoid receptor with differential sensitivity to anandamide and palmitoylethanolamide. Proc. Natl. Acad. Sci. U. S. A. 92 (1995) 3376-3380
162. Katayama K., et al. Distribution of anandamide amidohydrolase in rat tissues with special reference to small intestine. Biochim. Biophys. Acta 1347 (1997) 212-218
163. Pinto L., et al. Endocannabinoids as physiological regulators of colonic propulsion in mice. Gastroenterology 123 (2002) 227-234
164. Fu J., et al. Oleoylethanolamide, an endogenous PPAR-alpha agonist, lowers body weight and hyperlipidemia in obese rats. Neuropharmacology 48 (2005) 1147-1153
165. White R., et al. Mechanisms of anandamide-induced vasorelaxation in rat isolated coronary arteries. Br. J. Pharmacol. 134 (2001) 921-929
166. Egertová M., et al. A new perspective on cannabinoid signalling: complementary localization of fatty acid amide hydrolase, and the CB1 receptor in rat brain. Proc. R. Soc. Lond. B: Biol. Sci. 265 (1998) 2081-2085
167. Yazulla S., et al. Immunochemical localization of cannabinoid CB1 receptor and fatty acid amide hydrolase in rat retina. J. Comp. Neurol. 415 (1999) 80-90
168. Moore S.A., et al. Identification of a high-affinity binding site involved in the transport of endocannabinoids. Proc. Natl. Acad. Sci. U. S. A. 102 (2005) 17852-17857
169. Alexander J.P., and Cravatt B.F. The putative endocannabinoid transport blocker LY2183240 is a potent inhibitor of FAAH and several other brain serine hydrolases. J. Am. Chem. Soc. 128 (2006) 9699-9704
170. Lichtman A.H., et al. Reversible inhibitors of fatty acid amide hydrolase that promote analgesia: evidence for an unprecedented combination of potency and selectivity. J. Pharmacol. Exp. Ther. 311 (2004) 441-448