1932

Abstract

The endocannabinoids are lipid-derived messengers that play a diversity of regulatory roles in mammalian physiology. Dysfunctions in their activity have been implicated in various disease conditions, attracting attention to the endocannabinoid system as a possible source of therapeutic drugs. This signaling complex has three components: the endogenous ligands, anandamide and 2-arachidonoyl--glycerol (2-AG); a set of enzymes and transporters that generate, eliminate, or modify such ligands; and selective cell surface receptors that mediate their biological actions. We provide an overview of endocannabinoid formation, deactivation, and biotransformation and outline the properties and therapeutic potential of pharmacological agents that interfere with those processes. We describe small-molecule inhibitors that target endocannabinoid-producing enzymes, carrier proteins that transport the endocannabinoids into cells, and intracellular endocannabinoid-metabolizing enzymes. We briefly discuss selected agents that simultaneous-ly interfere with components of the endocannabinoid system and with other functionally related signaling pathways.

Keyword(s): DGLendocannabinoidFAAHMGLNAPE-PLDTHC
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2022-01-06
2024-06-19
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Literature Cited

  1. 1. 
    Mechoulam R, Ben-Shabat S, Hanuš 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]
  2. 2. 
    Sugiura T, Kondo S, Sukagawa A, Nakane S, Shinoda A et al. 1995. 2-Arachidonoylgylcerol: a possible endogenous cannabinoid receptor ligand in brain. Biochem. Biophys. Res. Commun. 215:189–97
    [Google Scholar]
  3. 3. 
    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]
  4. 4. 
    Fu J, Gaetani S, Oveisi F, Lo Verme J, Serrano A et al. 2003. Oleylethanolamide regulates feeding and body weight through activation of the nuclear receptor PPAR-α. Nature 425:695390–93
    [Google Scholar]
  5. 5. 
    Lo Verme J, Fu J, Astarita G, La Rana G, Russo R et al. 2005. The nuclear receptor peroxisome proliferator-activated receptor α mediates the anti-inflammatory actions of palmitoylethanolamide. Mol. Pharmacol. 67:115–19
    [Google Scholar]
  6. 6. 
    Hansen HS, Rosenkilde MM, Holst JJ, Schwartz TW. 2012. GPR119 as a fat sensor. Trends Pharmacol. Sci. 33:7374–81
    [Google Scholar]
  7. 7. 
    Pertwee RG. 2012. Targeting the endocannabinoid system with cannabinoid receptor agonists: pharmacological strategies and therapeutic possibilities. Philos. Trans. R. Soc. B 367: 1607.3353–63
    [Google Scholar]
  8. 8. 
    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]
  9. 9. 
    Wang J, Okamoto Y, Morishita J, Tsuboi K, Miyatake A, Ueda N. 2006. Functional analysis of the purified anandamide-generating phospholipase D as a member of the metallo-β-lactamase family. J. Biol. Chem. 281:1812325–35
    [Google Scholar]
  10. 10. 
    Magotti P, Bauer I, Igarashi M, Babagoli M, Marotta R et al. 2015. Structure of human N-acylphosphatidylethanolamine-hydrolyzing phospholipase D: regulation of fatty acid ethanolamide biosynthesis by bile acids. Structure 23:3598–604
    [Google Scholar]
  11. 11. 
    Beltramo M, Stella N, Calignano A, Lin SY, Makriyannis A, Piomelli D. 1997. Functional role of high-affinity anandamide transport, as revealed by selective inhibition. Science 277:53291094–97
    [Google Scholar]
  12. 12. 
    Hillard CJ, Edgemond WS, Jarrahian A, Campbell WB. 1997. Accumulation of N-arachidonoylethanolamine (anandamide) into cerebellar granule cells occurs via facilitated diffusion. J. Neurochem. 69:2631–38
    [Google Scholar]
  13. 13. 
    Piomelli D, Beltramo M, Glasnapp S, Lin SY, Goutopoulos A et al. 1999. Structural determinants for recognition and translocation by the anandamide transporter. PNAS 96:105802–7
    [Google Scholar]
  14. 14. 
    Fegley D, Kathuria S, Mercier R, Li C, Goutopoulos A et al. 2004. Anandamide transport is independent of fatty-acid amide hydrolase activity and is blocked by the hydrolysis-resistant inhibitor AM1172. PNAS 101:238756–61
    [Google Scholar]
  15. 15. 
    Kaczocha M, Hermann A, Glaser ST, Bojesen IN, Deutsch DG. 2006. 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. 281:149066–75
    [Google Scholar]
  16. 16. 
    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]
  17. 17. 
    Ortar G, Ligresti A, De Petrocellis L, Morera E, Di Marzo V. 2003. Novel selective and metabolically stable inhibitors of anandamide cellular uptake. Biochem. Pharmacol. 65:91473–81
    [Google Scholar]
  18. 18. 
    Kaczocha M, Glaser ST, Deutsch DG 2009. Identification of intracellular carriers for the endocannabinoid anandamide. PNAS 106:156375–80
    [Google Scholar]
  19. 19. 
    Oddi S, Fezza F, Pasquariello N, D'Agostino A, Catanzaro G et al. 2009. Molecular identification of albumin and Hsp70 as cytosolic anandamide-binding proteins. Chem. Biol. 16:6624–32
    [Google Scholar]
  20. 20. 
    Spector AA. 1975. Fatty acid binding to plasma albumin. J. Lipid Res. 16:3165–79
    [Google Scholar]
  21. 21. 
    Desarnaud F, Cadas H, Piomelli D. 1995. Anandamide amidohydrolase activity in rat brain microsomes: identification and partial characterization. J. Biol. Chem. 270:116030–35
    [Google Scholar]
  22. 22. 
    Hillard CJ, Wilkison DM, Edgemond WS, Campbell WB. 1995. Characterization of the kinetics and distribution of N-arachidonylethanolamine (anandamide) hydrolysis by rat brain. Biochim. Biophys. Acta Lipids Lipid Metab. 1257:3249–56
    [Google Scholar]
  23. 23. 
    Ueda N, Kurahashi Y, Yamamoto S, Tokunaga T. 1995. Partial purification and characterization of the porcine brain enzyme hydrolyzing and synthesizing anandamide. J. Biol. Chem. 270:4023823–27
    [Google Scholar]
  24. 24. 
    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]
  25. 25. 
    McKinney MK, Cravatt BE. 2005. Structure and function of fatty acid amide hydrolase. Annu. Rev. Biochem. 74:411–32
    [Google Scholar]
  26. 26. 
    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]
  27. 27. 
    Habib AM, Okorokov AL, Hill MN, Bras JT, Lee MC et al. 2019. Microdeletion in a FAAH pseudogene identified in a patient with high anandamide concentrations and pain insensitivity. Br. J. Anaesth. 123:2e249–53
    [Google Scholar]
  28. 28. 
    Saghatelian A, McKinney MK, Bandell M, Patapoutian A, Cravatt BF. 2006. A FAAH-regulated class of N-acyl taurines that activates TRP ion channels. Biochemistry 45:309007–15
    [Google Scholar]
  29. 29. 
    Stella N, Schweitzer P, Piomelli D. 1997. A second endogenous cannabinoid that modulates long-term potentiation. Nature 388:6644773–78
    [Google Scholar]
  30. 30. 
    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]
  31. 31. 
    Jung KM, Astarita G, Zhu C, Wallace M, Mackie K, Piomelli D. 2007. A key role for diacylglycerol lipase-α in metabotropic glutamate receptor–dependent endocannabinoid mobilization. Mol. Pharmacol. 72:3612–21
    [Google Scholar]
  32. 32. 
    Gao Y, Vasilyev DV, Goncalves MB, Howell FV, Hobbs C et al. 2010. Loss of retrograde endocannabinoid signaling and reduced adult neurogenesis in diacylglycerol lipase knock-out mice. J. Neurosci. 30:62017–24
    [Google Scholar]
  33. 33. 
    Shin M, Buckner A, Prince J, Bullock TNJ, Hsu KL. 2019. Diacylglycerol lipase-β is required for TNF-α response but not CD8+ T cell priming capacity of dendritic cells. Cell Chem. Biol. 26:71036–41.e3
    [Google Scholar]
  34. 34. 
    Bell RL, Kennerly DA, Stanford N, Majerus PW 1979. Diglyceride lipase: a pathway for arachidonate release from human platelets. PNAS 76:73238–41
    [Google Scholar]
  35. 35. 
    Beltramo M, Piomelli D. 2000. Carrier-mediated transport and enzymatic hydrolysis of the endogenous cannabinoid 2-arachidonylglycerol. Neuroreport 11:61231–35
    [Google Scholar]
  36. 36. 
    Nicolussi S, Gertsch J. 2015. Endocannabinoid transport revisited. Vitam. Horm. 98:441–85
    [Google Scholar]
  37. 37. 
    Tornqvist H, Belfrage P. 1976. Purification and some properties of a monoacylglycerol hydrolyzing enzyme of rat adipose tissue. J. Biol. Chem. 251:3813–19
    [Google Scholar]
  38. 38. 
    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]
  39. 39. 
    Dinh TP, Kathuria S, Piomelli D. 2004. RNA interference suggests a primary role for monoacylglycerol lipase in the degradation of the endocannabinoid 2-arachidonoylglycerol. Mol. Pharmacol. 66:51260–64
    [Google Scholar]
  40. 40. 
    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]
  41. 41. 
    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]
  42. 42. 
    Bertrand T, Augé F, Houtmann J, Rak A, Vallée F et al. 2010. Structural basis for human monoglyceride lipase inhibition. J. Mol. Biol. 396:3663–73
    [Google Scholar]
  43. 43. 
    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]
  44. 44. 
    Schalk-Hihi C, Schubert C, Alexander R, Bayoumy S, Clemente JC et al. 2011. Crystal structure of a soluble form of human monoglyceride lipase in complex with an inhibitor at 1.35 Å resolution. Protein Sci. 20:4670–83
    [Google Scholar]
  45. 45. 
    Dotsey EY, Jung KM, Basit A, Wei D, Daglian J et al. 2015. Peroxide-dependent MGL sulfenylation regulates 2-AG-mediated endocannabinoid signaling in brain neurons. Chem. Biol. 22:5619–28
    [Google Scholar]
  46. 46. 
    Scalvini L, Vacondio F, Bassi M, Pala D, Lodola A et al. 2016. Free-energy studies reveal a possible mechanism for oxidation-dependent inhibition of MGL. Sci. Rep. 6:31046
    [Google Scholar]
  47. 47. 
    Saario SM, Salo OMH, Nevalainen T, Poso A, Laitinen JT et al. 2005. Characterization of the sulfhydryl-sensitive site in the enzyme responsible for hydrolysis of 2-arachidonoyl-glycerol in rat cerebellar membranes. Chem. Biol. 12:6649–56
    [Google Scholar]
  48. 48. 
    Zvonok N, Williams J, Johnston M, Pandarinathan L, Janero DR et al. 2008. Full mass spectrometric characterization of human monoacylglycerol lipase generated by large-scale expression and single-step purification. J. Proteome Res. 7:52158–64
    [Google Scholar]
  49. 49. 
    Goparaju SK, Ueda N, Taniguchi K, Yamamoto S. 1999. Enzymes of porcine brain hydrolyzing 2-arachidonoylglycerol, an endogenous ligand of cannabinoid receptors. Biochem. Pharmacol. 57:4417–23
    [Google Scholar]
  50. 50. 
    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]
  51. 51. 
    Marrs WR, Blankman JL, Horne EA, Thomazeau A, Lin YH et al. 2010. The serine hydrolase ABHD6 controls the accumulation and efficacy of 2-AG at cannabinoid receptors. Nat. Neurosci. 13:8951–57
    [Google Scholar]
  52. 52. 
    Blankman JL, Long JZ, Trauger SA, Siuzdak G, Cravatt BF 2013. ABHD12 controls brain lysophosphatidylserine pathways that are deregulated in a murine model of the neurodegenerative disease PHARC. PNAS 110:41500–5
    [Google Scholar]
  53. 53. 
    Miller MR, Mannowetz N, Iavarone AT, Safavi R, Gracheva EO et al. 2016. Unconventional endocannabinoid signaling governs sperm activation via the sex hormone progesterone. Science 352:6285555–59
    [Google Scholar]
  54. 54. 
    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]
  55. 55. 
    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]
  56. 56. 
    Urquhart P, Nicolaou A, Woodward DF. 2015. Endocannabinoids and their oxygenation by cyclo-oxygenases, lipoxygenases and other oxygenases. Biochim. Biophys. Acta Mol. Cell Biol. Lipids 1851:4366–76
    [Google Scholar]
  57. 57. 
    Kingsley PJ, Rouzer CA, Morgan AJ, Patel S, Marnett LJ. 2019. Aspects of prostaglandin glycerol ester biology. Adv. Exp. Med. Biol. 1161:77–88
    [Google Scholar]
  58. 58. 
    Hermanson DJ, Gamble-George JC, Marnett LJ, Patel S 2014. Substrate-selective COX-2 inhibition as a novel strategy for therapeutic endocannabinoid augmentation. Trends Pharmacol. Sci. 35:7358–67
    [Google Scholar]
  59. 59. 
    Ueda N, Yamamoto K, Kurahashi Y, Yamamoto S, Ogawa M et al. 1995. Oxygenation of arachidonylethanolamide (anandamide) by lipoxygenases. Adv. Prostaglandin Thromboxane Leukotriene Res. 23:163–65
    [Google Scholar]
  60. 60. 
    McDougle DR, Kambalyal A, Meling DD, Das A. 2014. Endocannabinoids anandamide and 2-arachidonoylglycerol are substrates for human CYP2J2 epoxygenase. J. Pharmacol. Exp. Ther. 351:3616–27
    [Google Scholar]
  61. 61. 
    McDougle DR, Watson JE, Abdeen AA, Adili R, Caputo MP et al. 2017. Anti-inflammatory ω-3 endocannabinoid epoxides. PNAS 114:30E6034–43
    [Google Scholar]
  62. 62. 
    Carnevale LN, Das A. 2019. Novel anti-inflammatory and vasodilatory ω-3 endocannabinoid epoxide regioisomers. Adv. Exp. Med. Biol. 1161:219–32
    [Google Scholar]
  63. 63. 
    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]
  64. 64. 
    Petersen G, Pedersen AH, Pickering DS, Begtrup M, Hansen HS. 2009. Effect of synthetic and natural phospholipids on N-acylphosphatidylethanolamine-hydrolyzing phospholipase D activity. Chem. Phys. Lipids 162:1/253–61
    [Google Scholar]
  65. 65. 
    Griebel G, Pichat P, Beeske S, Leroy T, Redon N et al. 2015. Selective blockade of the hydrolysis of the endocannabinoid 2-arachidonoylglycerol impairs learning and memory performance while producing antinociceptive activity in rodents. Sci. Rep. 5:7642
    [Google Scholar]
  66. 66. 
    Calignano A, La Rana G, Giuffrida A, Piomelli D 1998. Control of pain initiation by endogenous cannabinoids. Nature 394:6690277–81
    [Google Scholar]
  67. 67. 
    Scott SA, Spencer CT, O'Reilly MC, Brown KA, Lavieri RR et al. 2015. Discovery of desketoraloxifene analogues as inhibitors of mammalian, Pseudomonas aeruginosa, and NAPE phospholipase D enzymes. ACS Chem. Biol. 10:2421–32
    [Google Scholar]
  68. 68. 
    Aggarwal G, Zarrow JE, Mashhadi Z, Robb Flynn C, Vinson P et al. 2020. Symmetrically substituted dichlorophenes inhibit N-acyl-phosphatidylethanolamine phospholipase D. J. Biol. Chem. 295:217289–300
    [Google Scholar]
  69. 69. 
    Mock ED, Mustafa M, Gunduz-Cinar O, Cinar R, Petrie GN et al. 2020. Discovery of a NAPE-PLD inhibitor that modulates emotional behavior in mice. Nat. Chem. Biol. 16:6667–75
    [Google Scholar]
  70. 70. 
    Stebbins KJ, Broadhead AR, Cabrera G, Correa LD, Messmer D et al. 2017. In vitro and in vivo pharmacology of NXT629, a novel and selective PPARα antagonist. Eur. J. Pharmacol. 809:130–40
    [Google Scholar]
  71. 71. 
    Maccarrone M, Barboni B, Paradisi A, Bernabò NN, Gasperi V et al. 2005. Characterization of the endocannabinoid system in boar spermatozoa and implications for sperm capacitation and acrosome reaction. J. Cell Sci. 118:194393–404
    [Google Scholar]
  72. 72. 
    Maccarrone M, Valensise H, Bari M, Lazzarin N, Romanini C, Finazzi-Agrò A. 2000. Relation between decreased anandamide hydrolase concentrations in human lymphocytes and miscarriage. Lancet 355:92121326–29
    [Google Scholar]
  73. 73. 
    Ortar G, Bisogno T, Ligresti A, Morera E, Nalli M, Di Marzo V. 2008. Tetrahydrolipstatin analogues as modulators of endocannabinoid 2-arachidonoylglycerol metabolism. J. Med. Chem. 51:216970–79
    [Google Scholar]
  74. 74. 
    Bisogno T, Cascio MG, Saha B, Mahadevan A, Urbani P et al. 2006. Development of the first potent and specific inhibitors of endocannabinoid biosynthesis. Biochim. Biophys. Acta Mol. Cell Biol. Lipids 1761:2205–12
    [Google Scholar]
  75. 75. 
    Appiah KK, Blat Y, Robertson BJ, Pearce BC, Pedicord DL et al. 2014. Identification of small molecules that selectively inhibit diacylglycerol lipase-α activity. J. Biomol. Screen. 19:4595–605
    [Google Scholar]
  76. 76. 
    Janssen FJ, Deng H, Baggelaar MP, Allarà M, van der Wel T et al. 2014. Discovery of glycine sulfonamides as dual inhibitors of sn-1-diacylglycerol lipase α and α/β-hydrolase domain 6. J. Med. Chem. 57:156610–22
    [Google Scholar]
  77. 77. 
    Chupak LS, Zheng X, Hu S, Huang Y, Ding M et al. 2016. Structure activity relationship studies on chemically non-reactive glycine sulfonamide inhibitors of diacylglycerol lipase. Bioorg. Med. Chem. 24:71455–68
    [Google Scholar]
  78. 78. 
    Baggelaar MP, Chameau PJP, Kantae V, Hummel J, Hsu KL et al. 2015. Highly selective, reversible inhibitor identified by comparative chemoproteomics modulates diacylglycerol lipase activity in neurons. J. Am. Chem. Soc. 137:278851–57
    [Google Scholar]
  79. 79. 
    Ogasawara D, Deng H, Viader A, Baggelaar MP, Breman A et al. 2016. Rapid and profound rewiring of brain lipid signaling networks by acute diacylglycerol lipase inhibition. PNAS 113:126–33
    [Google Scholar]
  80. 80. 
    Powell DR, Gay JP, Wilganowski N, Doree D, Savelieva KV et al. 2015. Diacylglycerol lipase α knockout mice demonstrate metabolic and behavioral phenotypes similar to those of cannabinoid receptor 1 knockout mice. Front. Endocrinol. 6:86
    [Google Scholar]
  81. 81. 
    Christensen R, Kristensen PK, Bartels EM, Bliddal H, Astrup A. 2007. Efficacy and safety of the weight-loss drug rimonabant: a meta-analysis of randomised trials. Lancet 370:96001706–13
    [Google Scholar]
  82. 82. 
    Cota D, Sandoval DA, Olivieri M, Prodi E, D'Alessio DA et al. 2009. Food intake–independent effects of CB1 antagonism on glucose and lipid metabolism. Obesity 17:81641–45
    [Google Scholar]
  83. 83. 
    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]
  84. 84. 
    De Petrocellis L, Bisogno T, Davis JB, Pertwee RG, Di Marzo V. 2000. Overlap between the ligand recognition properties of the anandamide transporter and the VR1 vanilloid receptor: inhibitors of anandamide uptake with negligible capsaicin-like activity. FEBS Lett 483:152–56
    [Google Scholar]
  85. 85. 
    López-Rodríguez ML, Viso A, Ortega-Gutiérrez S, Lastres-Becker I, González S et al. 2001. Design, synthesis and biological evaluation of novel arachidonic acid derivatives as highly potent and selective endocannabinoid transporter inhibitors. J. Med. Chem. 44:264505–8
    [Google Scholar]
  86. 86. 
    Giuffrida A, Rodríguez de Fonseca F, Nava F, Loubet-Lescoulié P, Piomelli D. 2000. Elevated circulating levels of anandamide after administration of the transport inhibitor, AM404. Eur. J. Pharmacol. 408:2161–68
    [Google Scholar]
  87. 87. 
    Bortolato M, Campolongo P, Mangieri RA, Scattoni ML, Frau R et al. 2006. Anxiolytic-like properties of the anandamide transport inhibitor AM404. Neuropsychopharmacology 31:122652–59
    [Google Scholar]
  88. 88. 
    La Rana G, Russo R, Campolongo P, Bortolato M, Mangieri RA et al. 2006. Modulation of neuropathic and inflammatory pain by the endocannabinoid transport inhibitor AM404 [N-(4-hydroxyphenyl)-eicosa-5,8,11,14-tetraenamide]. J. Pharmacol. Exp. Ther. 317:31365–71
    [Google Scholar]
  89. 89. 
    Patel S, Roelke CT, Rademacher DJ, Cullinan WE, Hillard CJ. 2004. Endocannabinoid signaling negatively modulates stress-induced activation of the hypothalamic-pituitary-adrenal axis. Endocrinology 145:125431–38
    [Google Scholar]
  90. 90. 
    Del Arco I, Navarro M, Bilbao A, Ferrer B, Piomelli D, Rodríguez de Fonseca F. 2002. Attenuation of spontaneous opiate withdrawal in mice by the anandamide transport inhibitor AM404. Eur. J. Pharmacol. 454:1103–4
    [Google Scholar]
  91. 91. 
    Schindler CW, Scherma M, Redhi GH, Vadivel SK, Makriyannis A et al. 2016. Self-administration of the anandamide transport inhibitor AM404 by squirrel monkeys. Psychopharmacology 233:101867–77
    [Google Scholar]
  92. 92. 
    Justinova Z, Mangieri RA, Bortolato M, Chefer SI, Mukhin AG et al. 2008. Fatty acid amide hydrolase inhibition heightens anandamide signaling without producing reinforcing effects in primates. Biol. Psychiatry 64:11930–37
    [Google Scholar]
  93. 93. 
    Nicolussi S, Viveros-Paredes JM, Gachet MS, Rau M, Flores-Soto ME et al. 2014. Guineensine is a novel inhibitor of endocannabinoid uptake showing cannabimimetic behavioral effects in BALB/c mice. Pharmacol. Res. 80:52–65
    [Google Scholar]
  94. 94. 
    Chicca A, Nicolussi S, Bartholomäus R, Blunder M, Aparisi Rey A et al. 2017. Chemical probes to potently and selectively inhibit endocannabinoid cellular reuptake. PNAS 114:25E5006–15
    [Google Scholar]
  95. 95. 
    Reynoso-Moreno I, Chicca A, Flores-Soto ME, Viveros-Paredes JM, Gertsch J. 2018. The endocannabinoid reuptake inhibitor WOBE437 is orally bioavailable and exerts indirect polypharmacological effects via different endocannabinoid receptors. Front. Mol. Neurosci. 11:180
    [Google Scholar]
  96. 96. 
    Bortolato M, Campolongo P, Mangieri RA, Scattoni ML, Frau R et al. 2006. Anxiolytic-like properties of the anandamide transport inhibitor AM404. Neuropsychopharmacology 31:122652–59
    [Google Scholar]
  97. 97. 
    Fernandez-Espejo E, Caraballo I, Rodríguez de Fonseca F, Ferrer B, El Banoua F et al. 2004. Experimental Parkinsonism alters anandamide precursor synthesis, and functional deficits are improved by AM404: a modulator of endocannabinoid function. Neuropsychopharmacology 29:61134–42
    [Google Scholar]
  98. 98. 
    Laine K, Järvinen T, Savinainen J, Laitinen JT, Pate DW, Järvinen K. 2001. Effects of topical anandamide-transport inhibitors, AM404 and olvanil, on intraocular pressure in normotensive rabbits. Pharm. Res. 18:4494–99
    [Google Scholar]
  99. 99. 
    Boger DL, Sato H, Lerner AE, Hedrick MP, Fecik RA et al. 2000. Exceptionally potent inhibitors of fatty acid amide hydrolase: the enzyme responsible for degradation of endogenous oleamide and anandamide. PNAS 97:105044–49
    [Google Scholar]
  100. 100. 
    Boger DL, Miyauchi H, Hedrick MP. 2001. α-Keto heterocycle inhibitors of fatty acid amide hydrolase: carbonyl group modification and α-substitution. Bioorg. Med. Chem. Lett. 11:121517–20
    [Google Scholar]
  101. 101. 
    Mileni M, Kamtekar S, Wood DC, Benson TE, Cravatt BF, Stevens RC. 2010. Crystal structure of fatty acid amide hydrolase bound to the carbamate inhibitor URB597: discovery of a deacylating water molecule and insight into enzyme inactivation. J. Mol. Biol. 400:4743–54
    [Google Scholar]
  102. 102. 
    Gobbi G, Bambico FR, Mangieri R, Bortolato M, Campolongo P et al. 2005. Antidepressant-like activity and modulation of brain monoaminergic transmission by blockade of anandamide hydrolysis. PNAS 102:5118620–25
    [Google Scholar]
  103. 103. 
    Bortolato M, Mangieri RA, Fu J, Kim JH, Arguello O et al. 2007. Antidepressant-like activity of the fatty acid amide hydrolase inhibitor URB597 in a rat model of chronic mild stress. Biol. Psychiatry 62:101103–10
    [Google Scholar]
  104. 104. 
    Clapper JR, Moreno-Sanz G, Russo R, Guijarro A, Vacondio F et al. 2010. Anandamide suppresses pain initiation through a peripheral endocannabinoid mechanism. Nat. Neurosci. 13:101265–70
    [Google Scholar]
  105. 105. 
    Tuo W, Leleu-Chavain N, Spencer J, Sansook S, Millet R, Chavatte P. 2017. Therapeutic potential of fatty acid amide hydrolase, monoacylglycerol lipase, and N-acylethanolamine acid amidase inhibitors. J. Med. Chem. 60:14–46
    [Google Scholar]
  106. 106. 
    Keith JM, Apodaca R, Xiao W, Seierstad M, Pattabiraman K et al. 2008. Thiadiazolopiperazinyl ureas as inhibitors of fatty acid amide hydrolase. Bioorg. Med. Chem. Lett. 18:174838–43
    [Google Scholar]
  107. 107. 
    Ahn K, Johnson DS, Fitzgerald LR, Liimatta M, Arendse A et al. 2007. Novel mechanistic class of fatty acid amide hydrolase inhibitors with remarkable selectivity. Biochemistry 46:4513019–30
    [Google Scholar]
  108. 108. 
    Patel S, Hill MN, Cheer JF, Wotjak CT, Holmes A. 2017. The endocannabinoid system as a target for novel anxiolytic drugs. Neurosci. Biobehav. Rev. 76:Part A56–66
    [Google Scholar]
  109. 109. 
    Dincheva I, Drysdale AT, Hartley CA, Johnson DC, Jing D et al. 2015. FAAH genetic variation enhances fronto-amygdala function in mouse and human. Nat. Commun. 6:6395
    [Google Scholar]
  110. 110. 
    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]
  111. 111. 
    Paulus MP, Stein MB, Simmons AN, Risbrough VB, Halter R, Chaplan SR. 2020. The effects of FAAH inhibition on the neural basis of anxiety-related processing in healthy male subjects: a randomized clinical trial. Neuropsychopharmacology 46:51011–19
    [Google Scholar]
  112. 112. 
    Schmidt ME, Liebowitz MR, Stein MB, Grunfeld J, Van Hove I et al. 2020. The effects of inhibition of fatty acid amide hydrolase (FAAH) by JNJ-42165279 in social anxiety disorder: a double-blind, randomized, placebo-controlled proof-of-concept study. Neuropsychopharmacology 46:51004–10
    [Google Scholar]
  113. 113. 
    Justinova Z, Panlilio LV, Moreno-Sanz G, Redhi GH, Auber A et al. 2015. Effects of fatty acid amide hydrolase (FAAH) inhibitors in non-human primate models of nicotine reward and relapse. Neuropsychopharmacology 40:92185–97
    [Google Scholar]
  114. 114. 
    Melis M, Pistis M, Perra S, Muntoni AL, Pillolla G, Gessa GL. 2004. Endocannabinoids mediate presynaptic inhibition of glutamatergic transmission in rat ventral tegmental area dopamine neurons through activation of CB1 receptors. J. Neurosci. 24:153–62
    [Google Scholar]
  115. 115. 
    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]
  116. 116. 
    Finn DP, Haroutounian S, Hohmann AG, Krane E, Soliman N, Rice ASC. 2021. Cannabinoids, the endocannabinoid system, and pain. Pain 162:Suppl. 1S5–25
    [Google Scholar]
  117. 117. 
    Greenbaum L, Tegeder I, Barhum Y, Melamed E, Roditi Y, Djaldetti R. 2012. Contribution of genetic variants to pain susceptibility in Parkinson disease. Eur. J. Pain 16:91243–50
    [Google Scholar]
  118. 118. 
    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]
  119. 119. 
    Wagenlehner FME, van Till JWO, Houbiers JGA, Martina RV, Cerneus DP et al. 2017. Fatty acid amide hydrolase inhibitor treatment in men with chronic prostatitis/chronic pelvic pain syndrome: an adaptive double-blind, randomized controlled trial. Urology 103:191–97
    [Google Scholar]
  120. 120. 
    Wortley MA, Adcock JJ, Dubuis ED, Maher SA, Bonvini SJ et al. 2017. Targeting fatty acid amide hydrolase as a therapeutic strategy for antitussive therapy. Eur. Respir. J. 50:31700782
    [Google Scholar]
  121. 121. 
    Habib AM, Okorokov AL, Hill MN, Bras JT, Lee MC et al. 2019. Microdeletion in a FAAH pseudogene identified in a patient with high anandamide concentrations and pain insensitivity. Br. J. Anaesth. 123:2e249–53
    [Google Scholar]
  122. 122. 
    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]
  123. 123. 
    FDA (US Food Drug Adm.). FDA finds drugs under investigation in the U.S. related to French BIA 10-2474 drug do not pose similar safety risks News Release, FDA Washington, DC.: https://www.fda.gov/drugs/drug-safety-and-availability/fda-finds-drugs-under-investigation-us-related-french-bia-10-2474-drug-do-not-pose-similar-safety
    [Google Scholar]
  124. 124. 
    Hohmann AG, Suplita RL, Bolton NM, Neely MH, Fegley D et al. 2005. An endocannabinoid mechanism for stress-induced analgesia. Nature 435:70451108–12
    [Google Scholar]
  125. 125. 
    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]
  126. 126. 
    Niphakis MJ, Cognetta AB, Chang JW, Buczynski MW, Parsons LH et al. 2013. Evaluation of NHS carbamates as a potent and selective class of endocannabinoid hydrolase inhibitors. ACS Chem. Neurosci. 4:91322–32
    [Google Scholar]
  127. 127. 
    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]
  128. 128. 
    McAllister LA, Butler CR, Mente S, O'Neil SV, Fonseca KR et al. 2018. Discovery of trifluoromethyl glycol carbamates as potent and selective covalent monoacylglycerol lipase (MAGL) inhibitors for treatment of neuroinflammation. J. Med. Chem. 61:73008–26
    [Google Scholar]
  129. 129. 
    Zvonok N, Pandarinathan L, Williams J, Johnston M, Karageorgos I et al. 2008. Covalent inhibitors of human monoacylglycerol lipase: ligand-assisted characterization of the catalytic site by mass spectrometry and mutational analysis. Chem. Biol. 15:8854–62
    [Google Scholar]
  130. 130. 
    Castelli R, Scalvini L, Vacondio F, Lodola A, Anselmi M et al. 2020. Benzisothiazolinone derivatives as potent allosteric monoacylglycerol lipase inhibitors that functionally mimic sulfenylation of regulatory cysteines. J. Med. Chem. 63:31261–80
    [Google Scholar]
  131. 131. 
    Hernández-Torres G, Cipriano M, Hedén E, Björklund E, Canales A et al. 2014. A reversible and selective inhibitor of monoacylglycerol lipase ameliorates multiple sclerosis. Angew. Chem. Int. Ed. 53:5013765–70
    [Google Scholar]
  132. 132. 
    Aghazadeh Tabrizi M, Baraldi PG, Baraldi S, Ruggiero E, De Stefano L et al. 2018. Discovery of 1,5-diphenylpyrazole-3-carboxamide derivatives as potent, reversible, and selective monoacylglycerol lipase (MAGL) inhibitors. J. Med. Chem. 61:31340–54
    [Google Scholar]
  133. 133. 
    Bononi G, Granchi C, Lapillo M, Giannotti M, Nieri D et al. 2018. Discovery of long-chain salicylketoxime derivatives as monoacylglycerol lipase (MAGL) inhibitors. Eur. J. Med. Chem. 157:817–36
    [Google Scholar]
  134. 134. 
    Aida J, Fushimi M, Kusumoto T, Sugiyama H, Arimura N et al. 2018. Design, synthesis, and evaluation of piperazinyl pyrrolidin-2-ones as a novel series of reversible monoacylglycerol lipase inhibitors. J. Med. Chem. 61:209205–17
    [Google Scholar]
  135. 135. 
    Wyatt RM, Fraser I, Welty N, Lord B, Wennerholm M et al. 2020. Pharmacologic characterization of JNJ-42226314, [1-(4-fluorophenyl)indol-5-yl]-[3-[4-(thiazole-2-carbonyl) piperazin-1-yl]azetidin-1-yl]methanone, a reversible, selective, and potent monoacylglycerol lipase inhibitor. J. Pharmacol. Exp. Ther. 372:3339–53
    [Google Scholar]
  136. 136. 
    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]
  137. 137. 
    Guindon J, Lai Y, Takacs SM, Bradshaw HB, Hohmann AG. 2013. Alterations in endocannabinoid tone following chemotherapy-induced peripheral neuropathy: effects of endocannabinoid deactivation inhibitors targeting fatty-acid amide hydrolase and monoacylglycerol lipase in comparison to reference analgesics following cisplatin treatment. Pharmacol. Res. 67:194–109
    [Google Scholar]
  138. 138. 
    Shonesy BC, Bluett RJ, Ramikie TS, Báldi R, Hermanson DJ et al. 2014. Genetic disruption of 2-arachidonoylglycerol synthesis reveals a key role for endocannabinoid signaling in anxiety modulation. Cell Rep 9:51644–53
    [Google Scholar]
  139. 139. 
    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]
  140. 140. 
    Bluett RJ, Báldi R, Haymer A, Gaulden AD, Hartley ND et al. 2017. Endocannabinoid signalling modulates susceptibility to traumatic stress exposure. Nat. Commun. 8:14782
    [Google Scholar]
  141. 141. 
    Ivy D, Palese F, Vozella V, Fotio Y, Yalcin A et al. 2020. Cannabinoid CB2 receptors mediate the anxiolytic-like effects of monoacylglycerol lipase inhibition in a rat model of predator-induced fear. Neuropsychopharmacology 45:81330–38
    [Google Scholar]
  142. 142. 
    Oleson EB, Beckert MV, Morra JT, Lansink CS, Cachope R et al. 2012. Endocannabinoids shape accumbal encoding of cue-motivated behavior via CB1 receptor activation in the ventral tegmentum. Neuron 73:2360–73
    [Google Scholar]
  143. 143. 
    McReynolds JR, Doncheck EM, Li Y, Vranjkovic O, Graf EN et al. 2018. Stress promotes drug seeking through glucocorticoid-dependent endocannabinoid mobilization in the prelimbic cortex. Biol. Psychiatry 84:285–94
    [Google Scholar]
  144. 144. 
    Brindisi M, Maramai S, Gemma S, Brogi S, Grillo A et al. 2016. Development and pharmacological characterization of selective blockers of 2-arachidonoyl glycerol degradation with efficacy in rodent models of multiple sclerosis and pain. J. Med. Chem. 59:62612–32
    [Google Scholar]
  145. 145. 
    Pasquarelli N, Engelskirchen M, Hanselmann J, Endres S, Porazik C et al. 2017. Evaluation of monoacylglycerol lipase as a therapeutic target in a transgenic mouse model of ALS. Neuropharmacology 124:157–69
    [Google Scholar]
  146. 146. 
    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]
  147. 147. 
    Piro JR, Benjamin DI, Duerr JM, Pi YQ, Gonzales C et al. 2012. A dysregulated endocannabinoid-eicosanoid network supports pathogenesis in a mouse model of Alzheimer's disease. Cell Rep 1:6617–23
    [Google Scholar]
  148. 148. 
    Aymerich MS, Rojo-Bustamante E, Molina C, Celorrio M, Sánchez-Arias JA, Franco R. 2016. Neuroprotective effect of JZL184 in MPP+-treated SH-SY5Y cells through CB2 receptors. Mol. Neurobiol. 53:42312–19
    [Google Scholar]
  149. 149. 
    Nomura DK, Long JZ, Niessen S, Hoover HS, Ng SW, Cravatt BF. 2010. Monoacylglycerol lipase regulates a fatty acid network that promotes cancer pathogenesis. Cell 140:149–61
    [Google Scholar]
  150. 150. 
    Owens RA, Mustafa MA, Ignatowska-Jankowska BM, Damaj MI, Beardsley PM et al. 2017. Inhibition of the endocannabinoid-regulating enzyme monoacylglycerol lipase elicits a CB1 receptor–mediated discriminative stimulus in mice. Neuropharmacology 125:80–86
    [Google Scholar]
  151. 151. 
    Thomas G, Betters JL, Lord CC, Brown AL, Marshall S et al. 2013. The serine hydrolase ABHD6 is a critical regulator of the metabolic syndrome. Cell Rep 5:2508–20
    [Google Scholar]
  152. 152. 
    Li W, Blankman JL, Cravatt BF. 2007. A functional proteomic strategy to discover inhibitors for uncharacterized hydrolases. J. Am. Chem. Soc. 129:319594–95
    [Google Scholar]
  153. 153. 
    Patel JZ, Nevalainen TJ, Savinainen JR, Adams Y, Laitinen T et al. 2015. Optimization of 1,2,5-thiadiazole carbamates as potent and selective ABHD6 inhibitors. ChemMedChem 10:2253–65
    [Google Scholar]
  154. 154. 
    Poursharifi P, Attané C, Mugabo Y, Al-Mass A, Ghosh A et al. 2020. Adipose ABHD6 regulates tolerance to cold and thermogenic programs. JCI Insight 5:24e140294
    [Google Scholar]
  155. 155. 
    Zhao S, Mugabo Y, Iglesias J, Xie L, Delghingaro-Augusto V et al. 2014. α/β-Hydrolase domain-6-accessible monoacylglycerol controls glucose-stimulated insulin secretion. Cell Metab 19:6993–1007
    [Google Scholar]
  156. 156. 
    Fisette A, Tobin S, Décarie-Spain L, Bouyakdan K, Peyot ML et al. 2016. α/β-Hydrolase domain 6 in the ventromedial hypothalamus controls energy metabolism flexibility. Cell Rep 17:51217–26
    [Google Scholar]
  157. 157. 
    Zhao S, Mugabo Y, Ballentine G, Attane C, Iglesias J et al. 2016. α/β-Hydrolase domain 6 deletion induces adipose browning and prevents obesity and type 2 diabetes. Cell Rep 14:122872–88
    [Google Scholar]
  158. 158. 
    Deng H, Li W. 2020. Therapeutic potential of targeting α/β-hydrolase domain–containing 6 (ABHD6). Eur. J. Med. Chem. 198:112353
    [Google Scholar]
  159. 159. 
    Naidu PS, Booker L, Cravatt BF, Lichtman AH. 2009. Synergy between enzyme inhibitors of fatty acid amide hydrolase and cyclooxygenase in visceral nociception. J. Pharmacol. Exp. Ther. 329:148–56
    [Google Scholar]
  160. 160. 
    Bertolacci L, Romeo E, Veronesi M, Magotti P, Albani C et al. 2013. A binding site for nonsteroidal anti-inflammatory drugs in fatty acid amide hydrolase. J. Am. Chem. Soc. 135:122–25
    [Google Scholar]
  161. 161. 
    Sasso O, Migliore M, Habrant D, Armirotti A, Albani C et al. 2015. Multitarget fatty acid amide hydrolase/cyclooxygenase blockade suppresses intestinal inflammation and protects against nonsteroidal anti-inflammatory drug–dependent gastrointestinal damage. FASEB J 29:62616–27
    [Google Scholar]
  162. 162. 
    Sasso O, Wagner K, Morisseau C, Inceoglu B, Hammock BD, Piomelli D. 2015. Peripheral FAAH and soluble epoxide hydrolase inhibitors are synergistically antinociceptive. Pharmacol. Res. 97:7–15
    [Google Scholar]
  163. 163. 
    Wagner KM, McReynolds CB, Schmidt WK, Hammock BD. 2017. Soluble epoxide hydrolase as a therapeutic target for pain, inflammatory and neurodegenerative diseases. Pharmacol. Ther. 180:62–76
    [Google Scholar]
  164. 164. 
    Kodani SD, Wan D, Wagner KM, Hwang SH, Morisseau C, Hammock BD. 2018. Design and potency of dual soluble epoxide hydrolase/fatty acid amide hydrolase inhibitors. ACS Omega 3:1014076–86
    [Google Scholar]
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