1932

Abstract

Inspired by the medicinal properties of the plant and its principal component (−)-9-tetrahydrocannabinol (THC), researchers have developed a variety of compounds to modulate the endocannabinoid system in the human brain. Inhibitors of fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), which are the enzymes responsible for the inactivation of the endogenous cannabinoids anandamide and 2-arachidonoylglycerol, respectively, may exert therapeutic effects without inducing the adverse side effects associated with direct cannabinoid CB receptor stimulation by THC. Here we review the FAAH and MAGL inhibitors that have reached clinical trials, discuss potential caveats, and provide an outlook on where the field is headed.

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2021-01-06
2024-12-02
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Literature Cited

  1. 1. 
    Andre CM, Hausman JF, Guerriero G 2016. Cannabis sativa: the plant of the thousand and one molecules. Front. Plant Sci. 7:19
    [Google Scholar]
  2. 2. 
    Gaoni Y, Mechoulam R. 1964. Isolation, structure, and partial synthesis of an active constituent of hashish. J. Am. Chem. Soc. 86:81646–47
    [Google Scholar]
  3. 3. 
    Munro S, Thomas KL, Abu-Shaar M 1993. Molecular characterization of a peripheral receptor for cannabinoids. Nature 365:644161–65
    [Google Scholar]
  4. 4. 
    Matsuda LA, Lolait SJ, Brownstein MJ, Young AC, Bonner TI 1990. Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature 346:6284561–64
    [Google Scholar]
  5. 5. 
    Devane WA, Hanuš L, Breuer A, Pertwee RG, Stevenson LA et al. 1992. Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science 258:50901946–49
    [Google Scholar]
  6. 6. 
    Sugiura T, Kondo S, Sukagawa A, Nakane S, Shinoda A et al. 1995. 2-Arachidonoylglycerol: a possible endogenous cannabinoid receptor ligand in brain. Biochem. Biophys. Res. Commun. 215:189–97
    [Google Scholar]
  7. 7. 
    Di Marzo V, Petrosino S 2007. Endocannabinoids and the regulation of their levels in health and disease. Curr. Opin. Lipidol. 18:2129–40
    [Google Scholar]
  8. 8. 
    Cravatt BF, Giang DK, Mayfield SP, Boger DL, Lerner RA, Gilula NB 1996. Molecular characterization of an enzyme that degrades neuromodulatory fatty-acid amides. Nature 384:660483–87
    [Google Scholar]
  9. 9. 
    Dinh TP, Carpenter D, Leslie FM, Freund TF, Katona I et al. 2002. Brain monoglyceride lipase participating in endocannabinoid inactivation. PNAS 99:1610819–24
    [Google Scholar]
  10. 10. 
    Mechoulam R. 2019. The pharmacohistory of Cannabis sativa. Cannabinoids as Therapeutic Agents R Mechoulam 1–20 Boca Raton, FL: CRC Press
    [Google Scholar]
  11. 11. 
    Whiting PF, Wolff RF, Deshpande S, Di Nisio M, Duffy S et al. 2015. Cannabinoids for medical use: a systematic review and meta-analysis. J. Am. Med. Assoc. 313:242456–73
    [Google Scholar]
  12. 12. 
    Natl. Acad. Sci. Eng. Med. 2017. The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research Washington, DC: Natl. Acad. Press
    [Google Scholar]
  13. 13. 
    Sallan SE, Zinberg NE, Frei E 1975. Antiemetic effect of delta-9-tetrahydrocannabinol in patients receiving cancer chemotherapy. N. Engl. J. Med. 293:16795–97
    [Google Scholar]
  14. 14. 
    Machado Rocha FC, Stéfano SC, De Cássia Haiek R, Rosa Oliveira LMQ, Da Silveira DX 2008. Therapeutic use of Cannabis sativa on chemotherapy-induced nausea and vomiting among cancer patients: systematic review and meta-analysis. Eur. J. Cancer Care 17:5431–43
    [Google Scholar]
  15. 15. 
    Beal JE, Olson R, Laubenstein L, Morales JO, Bellman P et al. 1995. Dronabinol as a treatment for anorexia associated with weight loss in patients with AIDS. J. Pain Symptom Manag. 10:289–97
    [Google Scholar]
  16. 16. 
    Jatoi A, Windschitl HE, Loprinzi CL, Sloan JA, Dakhil SR et al. 2002. Dronabinol versus megestrol acetate versus combination therapy for cancer-associated anorexia: a North Central Cancer Treatment Group study. J. Clin. Oncol. 20:2567–73
    [Google Scholar]
  17. 17. 
    Volicer L, Stelly M, Morris J, McLaughlin J, Volicer BJ 1997. Effects of dronabinol on anorexia and disturbed behavior in patients with Alzheimer's disease. Int. J. Geriatr. Psychiatry 12:9913–19
    [Google Scholar]
  18. 18. 
    Compston A, Coles A. 2008. Multiple sclerosis. Lancet 372:96481502–17
    [Google Scholar]
  19. 19. 
    Rice J, Cameron M. 2017. Cannabinoids for treatment of MS symptoms: state of the evidence. Curr. Neurol. Neurosci. Rep. 18:850
    [Google Scholar]
  20. 20. 
    Baker D, Pryce G, Giovannoni G, Thompson AJ 2003. The therapeutic potential of cannabis. Lancet Neurol 2:5291–98
    [Google Scholar]
  21. 21. 
    Novotna A, Mares J, Ratcliffe S, Novakova I, Vachova M et al. 2011. A randomized, double-blind, placebo-controlled, parallel-group, enriched-design study of nabiximols* (Sativex®), as add-on therapy, in subjects with refractory spasticity caused by multiple sclerosis. Eur. J. Neurol. 18:91122–31
    [Google Scholar]
  22. 22. 
    Hill KP, Palastro MD, Johnson B, Ditre JW 2017. Cannabis and pain: a clinical review. Cannabis Cannabinoid Res 2:196–104
    [Google Scholar]
  23. 23. 
    Van De Donk T, Niesters M, Kowal MA, Olofsen E, Dahan A, Van Velzen M 2019. An experimental randomized study on the analgesic effects of pharmaceutical-grade cannabis in chronic pain patients with fibromyalgia. Pain 160:4860–69
    [Google Scholar]
  24. 24. 
    Ware MA, Wang T, Shapiro S, Robinson A, Ducruet T et al. 2010. Smoked cannabis for chronic neuropathic pain: a randomized controlled trial. CMAJ 182:14E649–701
    [Google Scholar]
  25. 25. 
    Buggy DJ, Toogood L, Maric S, Sharpe P, Lambert DG, Rowbotham DJ 2003. Lack of analgesic efficacy of oral δ-9-tetrahydrocannabinol in postoperative pain. Pain 106:1–2169–72
    [Google Scholar]
  26. 26. 
    Consroe P, Musty R, Rein J, Tillery W, Pertwee R 1997. The perceived effects of smoked cannabis on patients with multiple sclerosis. Eur. Neurol. 38:144–48
    [Google Scholar]
  27. 27. 
    Blake DR, Robson P, Ho M, Jubb RW, McCabe CS 2006. Preliminary assessment of the efficacy, tolerability and safety of a cannabis-based medicine (Sativex) in the treatment of pain caused by rheumatoid arthritis. Rheumatology 45:150–52
    [Google Scholar]
  28. 28. 
    Ware MA, Fitzcharles MA, Joseph L, Shir Y 2010. The effects of nabilone on sleep in fibromyalgia: results of a randomized controlled trial. Anesth. Analg. 110:2604–10
    [Google Scholar]
  29. 29. 
    Müller-Vahl KR, Schneider U, Koblenz A, Jöbges M, Kolbe H et al. 2002. Treatment of Tourette's syndrome with Δ9-tetrahydrocannabinol (THC): a randomized crossover trial. Pharmacopsychiatry 35:257–61
    [Google Scholar]
  30. 30. 
    Müller-Vahl KR, Schneider U, Prevedel H, Theloe K, Kolbe H et al. 2003. Δ9-Tetrahydrocannabinol (THC) is effective in the treatment of tics in Tourette syndrome: a 6-week randomized trial. J. Clin. Psychiatry 64:4459–65
    [Google Scholar]
  31. 31. 
    Sieradzan KA, Fox SH, Hill M, Dick JPR, Crossman AR, Brotchie JM 2001. Cannabinoids reduce levodopa-induced dyskinesia in Parkinson's disease: a pilot study. Neurology 57:112108–11
    [Google Scholar]
  32. 32. 
    Campos AC, Moreira FA, Gomes FV, del Bel EA, Guimarães FS 2012. Multiple mechanisms involved in the large-spectrum therapeutic potential of cannabidiol in psychiatric disorders. Philos. Trans. R. Soc. B Biol. Sci. 367:16073364–78
    [Google Scholar]
  33. 33. 
    Devinsky O, Cilio MR, Cross H, Fernandez-Ruiz J, French J et al. 2014. Cannabidiol: pharmacology and potential therapeutic role in epilepsy and other neuropsychiatric disorders. Epilepsia 55:6791–802
    [Google Scholar]
  34. 34. 
    Silvestro S, Mammana S, Cavalli E, Bramanti P, Mazzon E 2019. Use of cannabidiol in the treatment of epilepsy: efficacy and security in clinical trials. Molecules 24:81459
    [Google Scholar]
  35. 35. 
    Devinsky O, Cross JH, Laux L, Marsh E, Miller I et al. 2017. Trial of cannabidiol for drug-resistant seizures in the Dravet syndrome. N. Engl. J. Med. 376:212011–20
    [Google Scholar]
  36. 36. 
    Shannon S, Lewis N, Lee H, Hughes S 2019. Cannabidiol in anxiety and sleep: a large case series. Perm. J. 23:18–041
    [Google Scholar]
  37. 37. 
    Volkow ND, Baler RD, Compton WM, Weiss SRB 2014. Adverse health effects of marijuana use. N. Engl. J. Med. 370:232219–27
    [Google Scholar]
  38. 38. 
    Pacher P, Steffens S, Haskó G, Schindler TH, Kunos G 2018. Cardiovascular effects of marijuana and synthetic cannabinoids: the good, the bad, and the ugly. Nat. Rev. Cardiol. 15:3151–66
    [Google Scholar]
  39. 39. 
    Kumar RN, Chambers WA, Pertwee RG 2001. Pharmacological actions and therapeutic uses of cannabis and cannabinoids. Anaesthesia 56:111059–68
    [Google Scholar]
  40. 40. 
    Lichtman AH, Martin BR. 2005. Cannabinoid tolerance and dependence. Handb. Exp. Pharmacol. 168:691–717
    [Google Scholar]
  41. 41. 
    Grotenhermen F, Müller-Vahl K. 2012. The therapeutic potential of Cannabis and cannabinoids. Dtsch. Arztebl. Int. 109:29–30495–501
    [Google Scholar]
  42. 42. 
    Pertwee RG. 2006. The pharmacology of cannabinoid receptors and their ligands: an overview. Int. J. Obes. 30:S13–18
    [Google Scholar]
  43. 43. 
    Auwärter V, Dresen S, Weinmann W, Müller M, Pütz M, Ferreirós N 2009. ‘Spice’ and other herbal blends: harmless incense or cannabinoid designer drugs?. J. Mass Spectrom. 44:5832–37
    [Google Scholar]
  44. 44. 
    Iversen L. 2003. Cannabis and the brain. Brain 126:61252–70
    [Google Scholar]
  45. 45. 
    Piomelli D. 2003. The molecular logic of endocannabinoid signalling. Nat. Rev. Neurosci. 4:11873–84
    [Google Scholar]
  46. 46. 
    Mechoulam R, Parker LA. 2013. The endocannabinoid system and the brain. Annu. Rev. Psychol. 64:21–47
    [Google Scholar]
  47. 47. 
    Pacher P, Bátkai S, Kunos G 2006. The endocannabinoid system as an emerging target of pharmacotherapy. Pharmacol. Rev. 58:3389–462
    [Google Scholar]
  48. 48. 
    Herkenham M, Lynn AB, Little MD, Johnson MR, Melvin LS et al. 1990. Cannabinoid receptor localization in brain. PNAS 87:51932–36
    [Google Scholar]
  49. 49. 
    Katona I, Sperlágh B, Sík A, Käfalvi A, Vizi ES et al. 1999. Presynaptically located CB1 cannabinoid receptors regulate GABA release from axon terminals of specific hippocampal interneurons. J. Neurosci. 19:114544–58
    [Google Scholar]
  50. 50. 
    Katona I, Urbán GM, Wallace M, Ledent C, Jung KM et al. 2006. Molecular composition of the endocannabinoid system at glutamatergic synapses. J. Neurosci. 26:215628–37
    [Google Scholar]
  51. 51. 
    Bénard G, Massa F, Puente N, Lourenço J, Bellocchio L et al. 2012. Mitochondrial CB1 receptors regulate neuronal energy metabolism. Nat. Neurosci. 15:4558–64
    [Google Scholar]
  52. 52. 
    Castillo PE, Younts TJ, Chávez AE, Hashimotodani Y 2012. Endocannabinoid signaling and synaptic function. Neuron 76:170–81
    [Google Scholar]
  53. 53. 
    Busquets-Garcia A, Desprez T, Metna-Laurent M, Bellocchio L, Marsicano G, Soria-Gomez E 2015. Dissecting the cannabinergic control of behavior: The where matters. BioEssays 37:111215–25
    [Google Scholar]
  54. 54. 
    Howlett AC, Barth F, Bonner TI, Cabral G, Casellas P et al. 2002. International Union of Pharmacology. XXVII. Classification of cannabinoid receptors. Pharmacol. Rev. 54:2161–202
    [Google Scholar]
  55. 55. 
    Maccarrone M, Bab I, Bíró T, Cabral GA, Dey SK et al. 2015. Endocannabinoid signaling at the periphery: 50 years after THC. Trends Pharmacol. Sci. 36:5277–96
    [Google Scholar]
  56. 56. 
    Izzo AA, Sharkey KA. 2010. Cannabinoids and the gut: new developments and emerging concepts. Pharmacol. Ther. 126:121–38
    [Google Scholar]
  57. 57. 
    Howlett AC. 2005. Cannabinoid receptor signaling. Handb. Exp. Pharmacol. 168:53–79
    [Google Scholar]
  58. 58. 
    Ibsen MS, Connor M, Glass M 2017. Cannabinoid CB1 and CB2 receptor signaling and bias. Cannabis Cannabinoid Res 2:148–60
    [Google Scholar]
  59. 59. 
    Nguyen T, Li JX, Thomas BF, Wiley JL, Kenakin TP, Zhang Y 2017. Allosteric modulation: an alternate approach targeting the cannabinoid CB1 receptor. Med. Res. Rev. 37:3441–74
    [Google Scholar]
  60. 60. 
    Van Sickle MD, Duncan M, Kingsley PJ, Mouihate A, Urbani P et al. 2005. Identification and functional characterization of brainstem cannabinoid CB2 receptors. Science 310:5746329–32
    [Google Scholar]
  61. 61. 
    Felder CC, Joyce KE, Briley EM, Mansouri J, Mackie K et al. 1995. Comparison of the pharmacology and signal transduction of the human cannabinoid CB1 and CB2 receptors. Mol. Pharmacol. 48:3443–50
    [Google Scholar]
  62. 62. 
    Pacher P, Mechoulam R. 2011. Is lipid signaling through cannabinoid 2 receptors part of a protective system. ? Prog. Lipid Res. 50:2193–211
    [Google Scholar]
  63. 63. 
    Whiteside G, Lee G, Valenzano K 2007. The role of the cannabinoid CB2 receptor in pain transmission and therapeutic potential of small molecule CB2 receptor agonists. Curr. Med. Chem. 14:8917–36
    [Google Scholar]
  64. 64. 
    Mechoulam R, Ben-Shabat S, Hanus L, Ligumsky M, Kaminski NE et al. 1995. Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors. Biochem. Pharmacol. 50:183–90
    [Google Scholar]
  65. 65. 
    Mackie K, Devane WA, Hille B 1993. Anandamide, an endogenous cannabinoid, inhibits calcium currents as a partial agonist in N18 neuroblastoma cells. Mol. Pharmacol. 44:3498–503
    [Google Scholar]
  66. 66. 
    Gonsiorek W, Lunn C, Fan X, Narula S, Lundell D, Hipkin RW 2000. Endocannabinoid 2-arachidonyl glycerol is a full agonist through human type 2 cannabinoid receptor: antagonism by anandamide. Mol. Pharmacol. 57:51045–50
    [Google Scholar]
  67. 67. 
    Sugiura T, Kodaka T, Nakane S, Miyashita T, Kondo S et al. 1999. Evidence that the cannabinoid CB1 receptor is a 2-arachidonoylglycerol receptor: structure-activity relationship of 2-arachidonoylglycerol, ether-linked analogues, and related compounds. J. Biol. Chem. 274:52794–801
    [Google Scholar]
  68. 68. 
    Sugiura T, Kondo S, Kishimoto S, Miyashita T, Nakane S et al. 2000. Evidence that 2-arachidonoylglycerol but not N-palmitoylethanolamine or anandamide is the physiological ligand for the cannabinoid CB2 receptor: comparison of the agonistic activities of various cannabinoid receptor ligands in HL-60 cells. J. Biol. Chem. 275:1605–12
    [Google Scholar]
  69. 69. 
    Wilson RI, Kunos G, Nicoll RA 2001. Presynaptic specificity of endocannabinoid signaling in the hippocampus. Neuron 31:3453–62
    [Google Scholar]
  70. 70. 
    Kreitzer AC, Regehr WG. 2001. Retrograde inhibition of presynaptic calcium influx by endogenous cannabinoids at excitatory synapses onto Purkinje cells. Neuron 29:3717–27
    [Google Scholar]
  71. 71. 
    Kano M. 2014. Control of synaptic function by endocannabinoid-mediated retrograde signaling. Proc. Jpn. Acad. Ser. B Phys. Biol. Sci. 90:7235–50
    [Google Scholar]
  72. 72. 
    Zygmunt PM, Petersson J, Andersson DA, Chuang HH, Sørgård M et al. 1999. Vanilloid receptors on sensory nerves mediate the vasodilator action of anandamide. Nature 400:6743452–57
    [Google Scholar]
  73. 73. 
    Bouaboula M, Hilairet S, Marchand J, Fajas L, Le Fur G, Casellas P 2005. Anandamide induced PPARγ transcriptional activation and 3T3-L1 preadipocyte differentiation. Eur. J. Pharmacol. 517:3174–81
    [Google Scholar]
  74. 74. 
    Battista N, Maccarrone M. 2017. Basic mechanisms of synthesis and hydrolysis of major endocannabinoids. The Endocannabinoid System: Genetics, Biochemistry, Brain Disorders, and Therapy E Murillo-Rodríguez 1–23 London: Academic Press
    [Google Scholar]
  75. 75. 
    Cadas H, Gaillet S, Beltramo M, Venance L, Piomelli D 1996. Biosynthesis of an endogenous cannabinoid precursor in neurons and its control by calcium and cAMP. J. Neurosci. 16:123934–42
    [Google Scholar]
  76. 76. 
    Ogura Y, Parsons WH, Kamat SS, Cravatt BF 2016. A calcium-dependent acyltransferase that produces N-acyl phosphatidylethanolamines. Nat. Chem. Biol. 12:9669–71
    [Google Scholar]
  77. 77. 
    Cascio MG, Marini P. 2015. Biosynthesis and fate of endocannabinoids. Handb. Exp. Pharmacol. 231:39–58
    [Google Scholar]
  78. 78. 
    Okamoto Y, Morishita J, Tsuboi K, Tonai T, Ueda N 2004. Molecular characterization of a phospholipase D generating anandamide and its congeners. J. Biol. Chem. 279:75298–305
    [Google Scholar]
  79. 79. 
    Farooqui AA, Rammohan KW, Horrocks LA 1989. Isolation, characterization, and regulation of diacylglycerol lipases from the bovine brain. Ann. N. Y. Acad. Sci. 559:125–36
    [Google Scholar]
  80. 80. 
    Bisogno T, Howell F, Williams G, Minassi A, Cascio MG et al. 2003. Cloning of the first sn1-DAG lipases points to the spatial and temporal regulation of endocannabinoid signaling in the brain. J. Cell Biol. 163:3463–68
    [Google Scholar]
  81. 81. 
    Ueda H, Kobayashi T, Kishimoto M, Tsutsumi T, Okuyama H 1993. A possible pathway of phosphoinositide metabolism through EDTA‐insensitive phospholipase A1 followed by lysophosphoinositide‐specific phospholipase C in rat brain. J. Neurochem. 61:51874–81
    [Google Scholar]
  82. 82. 
    Yoshida T, Fukaya M, Uchigashima M, Miura E, Kamiya H et al. 2006. Localization of diacylglycerol lipase-α around postsynaptic spine suggests close proximity between production site of an endocannabinoid, 2-arachidonoyl-glycerol, and presynaptic cannabinoid CB1 receptor. J. Neurosci. 26:184740–51
    [Google Scholar]
  83. 83. 
    Deng H, van der Stelt M 2018. Chemical tools to modulate 2-arachidonoylglycerol biosynthesis. Biotechnol. Appl. Biochem. 65:19–15
    [Google Scholar]
  84. 84. 
    Castellani B, Diamanti E, Pizzirani D, Tardia P, Maccesi M et al. 2017. Synthesis and characterization of the first inhibitor of N-acylphosphatidylethanolamine phospholipase D (NAPE-PLD). Chem. Commun. 53:9512814–17
    [Google Scholar]
  85. 85. 
    Nicolussi S, Gertsch J. 2015. Endocannabinoid transport revisited. Vitam. Horm. 98:441–85
    [Google Scholar]
  86. 86. 
    Glaser ST, Abumrad NA, Fatade F, Kaczocha M, Studholme KM, Deutsch DG 2003. Evidence against the presence of an anandamide transporter. PNAS 100:74269–74
    [Google Scholar]
  87. 87. 
    Kaczocha M, Glaser ST, Deutsch DG 2009. Identification of intracellular carriers for the endocannabinoid anandamide. PNAS 106:156375–80
    [Google Scholar]
  88. 88. 
    Gabrielli M, Battista N, Riganti L, Prada I, Antonucci F et al. 2015. Active endocannabinoids are secreted on extracellular membrane vesicles. EMBO Rep 16:2213–20
    [Google Scholar]
  89. 89. 
    Maccarrone M. 2017. Metabolism of the endocannabinoid anandamide: Open questions after 25 years. Front. Mol. Neurosci. 10:166
    [Google Scholar]
  90. 90. 
    Chicca A, Nicolussi S, Bartholomäus R, Blunder M, Rey AA et al. 2017. Chemical probes to potently and selectively inhibit endocannabinoid cellular reuptake. PNAS 114:25E5006–15
    [Google Scholar]
  91. 91. 
    Kozak KR, Gupta RA, Moody JS, Ji C, Boeglin WE et al. 2002. 15-Lipoxygenase metabolism of 2-arachidonylglycerol: generation of a peroxisome proliferator-activated receptor α agonist. J. Biol. Chem. 277:2623278–86
    [Google Scholar]
  92. 92. 
    Edgemond WS, Hillard CJ, Falck JR, Kearn CS, Campbell WB 1998. Human platelets and polymorphonuclear leukocytes synthesize oxygenated derivatives of arachidonylethanolamide (anandamide): their affinities for cannabinoid receptors and pathways of inactivation. Mol. Pharmacol. 54:1180–88
    [Google Scholar]
  93. 93. 
    Yu M, Ives D, Ramesha CS 1997. Synthesis of prostaglandin E2 ethanolamide from anandamide by cyclooxygenase-2. J. Biol. Chem. 272:3421181–86
    [Google Scholar]
  94. 94. 
    Kozak KR, Rowlinson SW, Marnett LJ 2000. Oxygenation of the endocannabinoid, 2-arachidonylglycerol, to glyceryl prostaglandins by cyclooxygenase-2. J. Biol. Chem. 275:4333744–49
    [Google Scholar]
  95. 95. 
    Snider NT, Walker VJ, Hollenberg PF 2010. Oxidation of the endogenous cannabinoid arachidonoyl ethanolamide by the cytochrome P450 monooxygenases: physiological and pharmacological implications. Pharmacol. Rev. 62:1136–54
    [Google Scholar]
  96. 96. 
    Alhouayek M, Muccioli GG. 2014. COX-2-derived endocannabinoid metabolites as novel inflammatory mediators. Trends Pharmacol. Sci. 35:6284–92
    [Google Scholar]
  97. 97. 
    Blankman JL, Simon GM, Cravatt BF 2007. A comprehensive profile of brain enzymes that hydrolyze the endocannabinoid 2-arachidonoylglycerol. Chem. Biol. 14:121347–56
    [Google Scholar]
  98. 98. 
    Labar G, Bauvois C, Borel F, Ferrer JL, Wouters J, Lambert DM 2010. Crystal structure of the human monoacylglycerol lipase, a key actor in endocannabinoid signaling. Chembiochem 11:2218–27
    [Google Scholar]
  99. 99. 
    Ahn K, McKinney MK, Cravatt BF 2008. Enzymatic pathways that regulate endocannabinoid signaling in the nervous system. Chem. Rev. 108:51687–707
    [Google Scholar]
  100. 100. 
    Sasso O, Pontis S, Armirotti A, Cardinali G, Kovacs D et al. 2016. Endogenous N-acyl taurines regulate skin wound healing. PNAS 113:30E4397–406
    [Google Scholar]
  101. 101. 
    Alexander SPH. 2009. Fatty acid amide hydrolase (FAAH). Chem. Phys. Lipids. 108:1–7
    [Google Scholar]
  102. 102. 
    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. 281:4836569–78
    [Google Scholar]
  103. 103. 
    Karlsson M, Contreras JA, Hellman U, Tornqvist H, Holm C 1997. cDNA cloning, tissue distribution, and identification of the catalytic triad of monoglyceride lipase: evolutionary relationship to esterases, lysophospholipases, and haloperoxidases. J. Biol. Chem. 272:4327218–23
    [Google Scholar]
  104. 104. 
    Uhlén M, Fagerberg L, Hallström BM, Lindskog C, Oksvold P et al. 2015. Tissue-based map of the human proteome. Science 347:62201260419
    [Google Scholar]
  105. 105. 
    Hum. Protein Atlas. 2019. MGLL. Human Protein Atlas https://www.proteinatlas.org/ENSG00000074416-MGLL/tissue
    [Google Scholar]
  106. 106. 
    Rodríguez de Fonseca F, del Arco I, Bermudez-Silva FJ, Bilbao A, Cippitelli A, Navarro M 2005. The endocannabinoid system: physiology and pharmacology. Alcohol Alcohol 40:12–14
    [Google Scholar]
  107. 107. 
    Gulyas AI, Cravatt BF, Bracey MH, Dinh TP, Piomelli D et al. 2004. Segregation of two endocannabinoid-hydrolyzing enzymes into pre- and postsynaptic compartments in the rat hippocampus, cerebellum and amygdala. Eur. J. Neurosci. 20:2441–58
    [Google Scholar]
  108. 108. 
    Deutsch DG, Ueda N, Yamamoto S 2002. The fatty acid amide hydrolase (FAAH). Prostaglandins Leukot. Essent. Fat. Acids 66:2–3201–10
    [Google Scholar]
  109. 109. 
    Ahn K, Johnson DS, Mileni M, Beidler D, Long JZ et al. 2009. Discovery and characterization of a highly selective FAAH inhibitor that reduces inflammatory pain. Chem. Biol. 16:4411–20
    [Google Scholar]
  110. 110. 
    Jhaveri MD, Richardson D, Kendall DA, Barrett DA, Chapman V 2006. Analgesic effects of fatty acid amide hydrolase inhibition in a rat model of neuropathic pain. J. Neurosci. 26:5113318–27
    [Google Scholar]
  111. 111. 
    Lichtman AH, Leung D, Shelton CC, Saghatelian A, Hardouin C et al. 2004. Reversible inhibitors of fatty acid amide hydrolase that promote analgesia: evidence for an unprecedented combination of potency and selectivity. J. Pharmacol. Exp. Ther. 311:2441–48
    [Google Scholar]
  112. 112. 
    Kathuria S, Gaetani S, Fegley D, Valiño F, Duranti A et al. 2003. Modulation of anxiety through blockade of anandamide hydrolysis. Nat. Med. 9:176–81
    [Google Scholar]
  113. 113. 
    Schuelert N, Johnson MP, Oskins JL, Jassal K, Chambers MG, McDougall JJ 2011. Local application of the endocannabinoid hydrolysis inhibitor URB597 reduces nociception in spontaneous and chemically induced models of osteoarthritis. Pain 152:5975–81
    [Google Scholar]
  114. 114. 
    Jayamanne A, Greenwood R, Mitchell VA, Aslan S, Piomelli D, Vaughan CW 2006. Actions of the FAAH inhibitor URB597 in neuropathic and inflammatory chronic pain models. Br. J. Pharmacol. 147:3281–88
    [Google Scholar]
  115. 115. 
    Piomelli D, Tarzia G, Duranti A, Tontini A, Mor M et al. 2006. Pharmacological profile of the selective FAAH inhibitor KDS-4103 (URB597). CNS Drug Rev 12:121–38
    [Google Scholar]
  116. 116. 
    Colangeli R, Pierucci M, Benigno A, Campiani G, Butini S, Di Giovanni G 2017. The FAAH inhibitor URB597 suppresses hippocampal maximal dentate afterdischarges and restores seizure-induced impairment of short and long-term synaptic plasticity. Sci. Rep. 7:111152
    [Google Scholar]
  117. 117. 
    Kruk-Slomka M, Banaszkiewicz I, Slomka T, Biala G 2019. Effects of fatty acid amide hydrolase inhibitors acute administration on the positive and cognitive symptoms of schizophrenia in mice. Mol. Neurobiol. 56:117251–66
    [Google Scholar]
  118. 118. 
    Fidelman S, Mizrachi Zer-Aviv T, Lange R, Hillard CJ, Akirav I 2018. Chronic treatment with URB597 ameliorates post-stress symptoms in a rat model of PTSD. Eur. Neuropsychopharmacol. 28:5630–42
    [Google Scholar]
  119. 119. 
    Baker D, Pryce G, Croxford JL, Brown P, Pertwee RG et al. 2000. Cannabinoids control spasticity and tremor in a multiple sclerosis model. Nature 404:84–87
    [Google Scholar]
  120. 120. 
    Sun YX, Tsuboi K, Zhao LY, Okamoto Y, Lambert DM, Ueda N 2005. Involvement of N-acylethanolamine-hydrolyzing acid amidase in the degradation of anandamide and other N-acylethanolamines in macrophages. Biochim. Biophys. Acta 1736 3:211–20
    [Google Scholar]
  121. 121. 
    Karlsson M, Reue K, Xia YR, Lusis AJ, Langin D et al. 2001. Exon-intron organization and chromosomal localization of the mouse monoglyceride lipase gene. Gene 272:1–211–18
    [Google Scholar]
  122. 122. 
    Gil-Ordóñez A, Martín-Fontecha M, Ortega-Gutiérrez S, López-Rodríguez ML 2018. Monoacylglycerol lipase (MAGL) as a promising therapeutic target. Biochem. Pharmacol. 157:July18–32
    [Google Scholar]
  123. 123. 
    Baggelaar MP, Maccarrone M, van der Stelt M 2018. 2-Arachidonoylglycerol: a signaling lipid with manifold actions in the brain. Prog. Lipid Res. 71:May1–17
    [Google Scholar]
  124. 124. 
    Schlosburg JE, Blankman JL, Long JZ, Nomura DK, Pan B et al. 2010. Chronic monoacylglycerol lipase blockade causes functional antagonism of the endocannabinoid system. Nat. Neurosci. 13:91113–19
    [Google Scholar]
  125. 125. 
    Sciolino NR, Zhou W, Hohmann AG 2011. Enhancement of endocannabinoid signaling with JZL184, an inhibitor of the 2-arachidonoylglycerol hydrolyzing enzyme monoacylglycerol lipase, produces anxiolytic effects under conditions of high environmental aversiveness in rats. Pharmacol. Res. 64:3226–34
    [Google Scholar]
  126. 126. 
    Zhong P, Wang W, Pan B, Liu X, Zhang Z et al. 2014. Monoacylglycerol lipase inhibition blocks chronic stress-induced depressive-like behaviors via activation of mTOR signaling. Neuropsychopharmacology 39:71763–76
    [Google Scholar]
  127. 127. 
    Kinsey SG, Long JZ, O'Neal ST, Abdullah RA, Poklis JL et al. 2009. Blockade of endocannabinoid-degrading enzymes attenuates neuropathic pain. J. Pharmacol. Exp. Ther. 330:3902–10
    [Google Scholar]
  128. 128. 
    Ghosh S, Wise LE, Chen Y, Gujjar R, Mahadevan A et al. 2013. The monoacylglycerol lipase inhibitor JZL184 suppresses inflammatory pain in the mouse carrageenan model. Life Sci 92:8–9498–505
    [Google Scholar]
  129. 129. 
    Long JZ, Li W, Booker L, Burston JJ, Kinsey SG et al. 2009. Selective blockade of 2-arachidonoylglycerol hydrolysis produces cannabinoid behavioral effects. Nat. Chem. Biol. 5:137–44
    [Google Scholar]
  130. 130. 
    Alhouayek M, Masquelier J, Muccioli GG 2014. Controlling 2-arachidonoylglycerol metabolism as an anti-inflammatory strategy. Drug Discov. Today 19:3295–304
    [Google Scholar]
  131. 131. 
    Nomura DK, Morrison BE, Blankman JL, Long JZ, Kinsey SG et al. 2011. Endocannabinoid hydrolysis generates brain prostaglandins that promote neuroinflammation. Science 334:6057809–13
    [Google Scholar]
  132. 132. 
    Chen R, Zhang J, Wu Y, Wang D, Feng G et al. 2012. Monoacylglycerol lipase is a therapeutic target for Alzheimer's disease. Cell Rep 2:51329–39
    [Google Scholar]
  133. 133. 
    Chiurchiù V, van der Stelt M, Centonze D, Maccarrone M 2018. The endocannabinoid system and its therapeutic exploitation in multiple sclerosis: clues for other neuroinflammatory diseases. Prog. Neurobiol. 160:82–100
    [Google Scholar]
  134. 134. 
    Long JZ, Nomura DK, Vann RE, Walentiny DM, Booker L et al. 2009. Dual blockade of FAAH and MAGL identifies behavioral processes regulated by endocannabinoid crosstalk in vivo. PNAS 106:4820270–75
    [Google Scholar]
  135. 135. 
    Lodola A, Castelli R, Mor M, Rivara S 2015. Fatty acid amide hydrolase inhibitors: a patent review (2009–2014). Expert Opin. Ther. Pat. 25:111247–66
    [Google Scholar]
  136. 136. 
    Johnson DS, Stiff C, Lazerwith SE, Kesten SR, Fay LK et al. 2011. Discovery of PF-04457845: a highly potent, orally bioavailable, and selective urea FAAH inhibitor. ACS Med. Chem. Lett. 2:291–96
    [Google Scholar]
  137. 137. 
    Ahn K, Smith SE, Liimatta MB, Beidler D, Sadagopan N et al. 2011. Mechanistic and pharmacological characterization of PF-04457845: a highly potent and selective fatty acid amide hydrolase inhibitor that reduces inflammatory and noninflammatory pain. J. Pharmacol. Exp. Ther. 338:1114–24
    [Google Scholar]
  138. 138. 
    Doenni VM, Gray JM, Song CM, Patel S, Hill MN, Pittman QJ 2016. Deficient adolescent social behavior following early-life inflammation is ameliorated by augmentation of anandamide signaling. Brain. Behav. Immun. 58:237–47
    [Google Scholar]
  139. 139. 
    Panlilio LV, Thorndike EB, Nikas SP, Alapafuja SO, Bandiera T et al. 2016. Effects of fatty acid amide hydrolase (FAAH) inhibitors on working memory in rats. Psychopharmacology 233:101879–88
    [Google Scholar]
  140. 140. 
    Li GL, Winter H, Arends R, Jay GW, Le V et al. 2012. Assessment of the pharmacology and tolerability of PF-04457845, an irreversible inhibitor of fatty acid amide hydrolase-1, in healthy subjects. Br. J. Clin. Pharmacol. 73:5706–16
    [Google Scholar]
  141. 141. 
    Huggins JP, Smart TS, Langman S, Taylor L, Young T 2012. An efficient randomised, placebo-controlled clinical trial with the irreversible fatty acid amide hydrolase-1 inhibitor PF-04457845, which modulates endocannabinoids but fails to induce effective analgesia in patients with pain due to osteoarthritis of the knee. Pain 153:91837–46
    [Google Scholar]
  142. 142. 
    D'Souza DC, Cortes-Briones J, Creatura G, Bluez G, Thurnauer H et al. 2019. Efficacy and safety of a fatty acid amide hydrolase inhibitor (PF-04457845) in the treatment of cannabis withdrawal and dependence in men: a double-blind, placebo-controlled, parallel group, phase 2a single-site randomised controlled trial. Lancet Psychiatry 6:135–45
    [Google Scholar]
  143. 143. 
    Mayo LM, Asratian A, Lindé J, Morena M, Haataja R et al. 2020. Elevated anandamide, enhanced recall of fear extinction, and attenuated stress responses following inhibition of fatty acid amide hydrolase: a randomized, controlled experimental medicine trial. Biol. Psychiatry 87:6538–47
    [Google Scholar]
  144. 144. 
    Griebel G, Stemmelin J, Lopez-Grancha M, Fauchey V, Slowinski F et al. 2018. The selective reversible FAAH inhibitor, SSR411298, restores the development of maladaptive behaviors to acute and chronic stress in rodents. Sci. Rep. 8:12416
    [Google Scholar]
  145. 145. 
    Sanofi. 2013. NCT00822744. A randomized, double-blind, placebo-controlled dose-finding study to evaluate the efficacy, safety and tolerability of SSR411298 in elderly patients with MDD Sanofi Clin. Rep., Sanofi, Bridgewater, NJ:
    [Google Scholar]
  146. 146. 
    Sanofi. 2013. NCT01439919. A randomized, double-blind, parallel-group, placebo-controlled study to assess the clinical benefit of SSR411298 as adjunctive treatment for persistent cancer pain Sanofi Clin. Rep., Sanofi Bridgewater, NJ:
    [Google Scholar]
  147. 147. 
    Watabiki T, Tsuji N, Kiso T, Ozawa T, Narazaki F, Kakimoto S 2017. In vitro and in vivo pharmacological characterization of ASP8477: a novel highly selective fatty acid amide hydrolase inhibitor. Eur. J. Pharmacol. 815:42–48
    [Google Scholar]
  148. 148. 
    Schaffler K, Yassen A, Reeh P, Passier P 2018. A randomized, double-blind, placebo- and active comparator-controlled phase I study of analgesic/antihyperalgesic properties of ASP8477, a fatty acid amide hydrolase inhibitor, in healthy female subjects. Pain Med 19:61206–18
    [Google Scholar]
  149. 149. 
    Bradford D, Stirling A, Ernault E, Liosatos M, Tracy K et al. 2017. The MOBILE study—a phase IIa enriched enrollment randomized withdrawal trial to assess the analgesic efficacy and safety of ASP8477, a fatty acid amide hydrolase inhibitor, in patients with peripheral neuropathic pain. Pain Med 18:122388–400
    [Google Scholar]
  150. 150. 
    Roughley S, Walls S, Hart T, Parsons R, Brough P et al. 2009. Azetidine derivatives WO Patent 2009/109743
    [Google Scholar]
  151. 151. 
    Pawsey S, Wood M, Browne H, Donaldson K, Christie M, Warrington S 2016. Safety, tolerability and pharmacokinetics of FAAH inhibitor V158866: a double-blind, randomised, placebo-controlled phase I study in healthy volunteers. Drugs R D 16:2181–91
    [Google Scholar]
  152. 152. 
    Keith J, Liu J. 2011. Modulators of fatty acid amide hydrolase WO Patent 2011/139951
    [Google Scholar]
  153. 153. 
    Keith JM, Jones WM, Tichenor M, Liu J, Seierstad M et al. 2015. Preclinical characterization of the FAAH inhibitor JNJ-42165279. ACS Med. Chem. Lett. 6:121204–8
    [Google Scholar]
  154. 154. 
    Bonifácio M-J, Sousa F, Aires C, Loureiro A, Fernandes-Lopes C et al. 2020. Preclinical pharmacological evaluation of the fatty acid amide hydrolase inhibitor BIA 10-2474. Br. J. Pharmacol. 177:212342
    [Google Scholar]
  155. 155. 
    Postnov A, Schmidt ME, Pemberton DJ, de Hoon J, van Hecken A et al. 2018. Fatty acid amide hydrolase inhibition by JNJ-42165279: a multiple-ascending dose and a positron emission tomography study in healthy volunteers. Clin. Transl. Sci. 11:4397–404
    [Google Scholar]
  156. 156. 
    Liu P, Hamill TG, Chioda M, Chobanian H, Fung S et al. 2013. Discovery of MK-3168: a PET tracer for imaging brain fatty acid amide hydrolase. ACS Med. Chem. Lett. 4:6509–13
    [Google Scholar]
  157. 157. 
    Kerbrat A, Ferré JC, Fillatre P, Ronzière T, Vannier S et al. 2016. Acute neurologic disorder from an inhibitor of fatty acid amide hydrolase. N. Engl. J. Med. 375:181717–25
    [Google Scholar]
  158. 158. 
    Van Esbroeck ACM, Janssen APA, Cognetta AB, Ogasawara D, Shpak G et al. 2017. Activity-based protein profiling reveals off-target proteins of the FAAH inhibitor BIA 10-2474. Science 356:63421084–87
    [Google Scholar]
  159. 159. 
    Deng H, Li W. 2019. Monoacylglycerol lipase inhibitors: modulators for lipid metabolism in cancer malignancy, neurological and metabolic disorders. Acta Pharm. Sin. B 10:4582–602
    [Google Scholar]
  160. 160. 
    Granchi C, Caligiuri I, Minutolo F, Rizzolio F, Tuccinardi T 2017. A patent review of monoacylglycerol lipase (MAGL) inhibitors (2013–2017). Expert Opin. Ther. Pat. 27:121341–51
    [Google Scholar]
  161. 161. 
    Cisar JS, Weber OD, Clapper JR, Blankman JL, Henry CL et al. 2018. Identification of ABX-1431, a selective inhibitor of monoacylglycerol lipase and clinical candidate for treatment of neurological disorders. J. Med. Chem. 61:209062–84
    [Google Scholar]
  162. 162. 
    Jiang M, van der Stelt M 2018. Activity-based protein profiling delivers selective drug candidate ABX-1431, a monoacylglycerol lipase inhibitor, to control lipid metabolism in neurological disorders. J. Med. Chem. 61:209059–61
    [Google Scholar]
  163. 163. 
    Pacher P, Kogan NM, Mechoulam R 2020. Beyond THC and endocannabinoids. Annu. Rev. Pharmacol. Toxicol. 60:637–59
    [Google Scholar]
  164. 164. 
    Di Marzo V. 2018. New approaches and challenges to targeting the endocannabinoid system. Nat. Rev. Drug Discov. 17:9623–39
    [Google Scholar]
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