Endocannabinoids Part I: Molecular basis of endocannabinoid formation, action and inactivation and development of selective inhibitors

Expert Opinion on Therapeutic Targets

Volumn 5, Issue 2, 2001, Pages 241-265

  Di Marzo, Ovincenzo ^a   De Petrocellis, Luciano ^b   Bisogno, Tiziana ^a  

^a Istituto per la Chimica di Molecole di Interesse Biologico   (Italy)

^b CNR   (Italy)

Author keywords

2 arachidonoylglycerol; agonists; anandamide; anandamide transporter; antagonists; cannabinoids; fatty acid amide hydrolase; inhibitors; receptors; vanilloid

Indexed keywords

EID: 0001501784     PISSN: 14728222     EISSN: 17447631     Source Type: Journal    
DOI: 10.1517/14728222.5.2.241     Document Type: Review

References (140)

1. MECHOULAM R: The pharmacohistory of Cannabis sativa. In: Cannabinoids as Therapeutic Agents. R Mechoulam (Ed.), Boca Raton: CRS Press (1986) pp. 1-19.
2. GAONI Y AND MECHOULAM R: Isolation, structure and partial synthesis of an active constituent of hashish. J. Am. Chem. Soc. (1964) 86:1646-1647.
3. MATSUDA LA, LOLAIT SJ, BROWNSTEIN MJ, YOUNG AC, BONNER TI: Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature (1990) 346:561-564.
4. MUNRO S, THOMAS KL, ABU-SHAAR M: Molecular characterization of a peripheral receptor for cannabinoids. Nature (1993) 365, 61-65.
5. MARMOR JB: Medical marijuana. West J. Med. (1998) 168:540-543.
6. DI MARZO V, BISOGNO T AND DE PETROCELLIS L: Endocannabinoids: new targets for drug development. Curr. Pharm. Des. (2000) 6:1361-1380.
7. PERTWEE RG: Cannabinoid receptor ligands: clinical and neuropharmacological considerations, relevant to future drug discovery and development. Expert Opin. Investig. Drugs (2000) 9:1553-1571.
8. MECHOULAM R: Recent advantages in cannabinoid research. ForschKomplementarmed (1999) 6:16-20.
9. PAROLARO D: Presence and functional regulation of cannabinoid receptors in immune cells. Life Sci. (1999) 65:637-644.
10. KLEIN TW, LANE B, NEWTON CA, FRIEDMAN H: The cannabinoid system and cytokine network. Proc. Soc. Exp. Biol. Med. (2000) 225:1-8.
11. DEVANE WA, HANUS L, BREUER A et al: Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science (1992) 258:1946-1949.
12. MECHOULAM R, BEN-SHABAT S, HANUS L et al.: Identifi cation of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors. Biochem. Pharmacol. (1995) 50:83-90.
13. SUGIURA T, KONDO S, SUKAGAWA A et al.: 2-Arachidonoylglycerol: a possible endogenous cannabinoid receptor ligand in brain. Biochem. Biophys. Res. Commun. (1995) 215:89-97.
14. DI MARZO V, FONTANA A: Anandamide, an endoge nous cannabimimetic eicosanoid: 'killing two birds with a stone'. Prostaglandins Leukot. Essent. Fatty Acids (1995) 53:1-11.
15. SCHMID HHO, SCHMID PC, NATARAJAN V: N-acylated glycerophospholipids and their derivatives. Prog. Lipid Res. (1990) 29:1-43.
16. CRAVATT BF, PROSPERO-GARCIA O, SIUZDAK G et al: Chemical characterization of a family of brain lipids that induce sleep. Science (1995) 268:1506-1509.
17. LAMBERT DM, DI MARZO V: The palmitoylethanola-mide and oleamide enigmas: are these two fatty acid amides cannabimimetic? Curr. Med. Chem. (1999) 6:757-773.
18. SHESKIN T, HANUS L, SLAGER J, VOGEL Z, MECHOULAM R: Structural requirements for binding of anandamide-type compounds to the brain cannabinoid receptor. J. Med. Chem. (1997) 40:659-667.
19. HANUS L, ABU-LAFI S, FRIDE E et al: 2-Arachidonoyl Glyceryl Ether, a novel endogenous agonist of the CB1 cannabinoid receptor. Proc. Natl. Acad. Sci. USA (2001) in press.
20. PERTWEE RG: Pharmacology of cannabinoid CB1 and CB2 receptors. Pharmacol. Ther. (1997) 74:129-180.
21. HERKENHAM M, LYNN AB, LITTLE MD et al: Cannabinoid receptor localization in brain. Proc. Natl. Acad. Sci. USA (1990) 87:1932-1936.
22. FARQUHAR-SMITH WP, EGERTOVA M, BRADBURY EJ, MCMAHON SB, RICE AS, ELPHICK MR: Cannabinoid CB(1) receptor expression in rat spinal cord. Mol. Cell Neurosci. (2000) 15:510-521.
23. WAGNER JA, VARGA K, KUNOS G: Cardiovascular actions of cannabinoids and their generation during shock. J. Mol. Med. (1998) 76:824-836.
24. PERTWEE RG: Evidence for the presence of CB1 cannabinoid receptors on peripheral neurones and for the existence of neuronal non-CB1 cannabinoid receptors. Life Sci. (1999) 65:597-605.
25. PARIA BC, DEY SK: Ligand-receptor signaling with endocannabinoids in preimplantation embryo development and implantation. Chem. Phys. Lipids (2000) 108:211-220.
26. HILLARD CJ: Endocannabinoids and vascular function. J. Pharmacol Exp. Ther. (2000) 294:27-32.
27. KAMINSKI NE: Regulation of the cAMP cascade, gene expression and immune function by cannabinoid receptors. J. Neuroimmunol. (1998) 83:124-132.
28. DEUTSCH DG, GOLIGORSKY MS, SCHMID PC et al: Production and physiological actions of anandamide in the vasculature of the rat kidney.J. Clin. Invest. (1997) 100:1538-1546.
29. CALIGNANO A, KATONA I, DESARNAUD F et al: Bidirectional control of airway responsiveness by endogenous cannabinoids. Nature (2000) 408:96-101.
30. PUFFENBARGER RA, BOOTHE AC, CABRAL GA: Cannabinoids inhibit LPS-inducible cytokine mRNA expression in rat microglial cells. Glia (2000) 29:58-69.
31. LEDENT C, VALVERDE O, COSSU G etal: Unresponsive ness to cannabinoids and reduced addictive effects of opiates in CB1 receptor knockout mice. Science (1999) 283:401-404.
32. ZIMMER A, ZIMMER AM, HOHMANN AG, HERKENHAM M, BONNER TI: Increased mortality, hypoactivity and hypoalgesia in cannabinoid CB1 receptor knockout mice. Proc. Natl. Acad. Sci. USA (1999) 96:5780-5785.
33. BUCKLEYNE, MCCOYKL, MEZEYE etal: Immunomodu-lation by cannabinoids is absent in mice deficient for the cannabinoid CB(2) receptor. Eur. J. Pharmacol. (2000) 396:141-149.
34. DI MARZO V, BREIVOGEL CS, TAO Q et al.: Levels, metabolism and pharmacological activity of anandamide in CB(1) cannabinoid receptor knockout mice: evidence for non-CB(1),non-CB(2) receptor-mediated actions of anandamide in mouse brain. J. Neurochem. (2000) 75:2434-2444.
35. DI MARZO V: 'Endocannabinoids' and other fatty acid derivatives with cannabimimetic properties: biochemistry and possible physiopathological relevance. Biochim. Biophys. Acta (1998) 1392:153-175.
36. SAGAN S, VENANCE L, TORRENS Y, CORDIER J, GLOWINSKI J, GIAUME C: Anandamide and WIN 55212-2 inhibit cyclic AMP formation through G-protein-coupled receptors distinct from CB1 cannabinoid receptors in cultured astrocytes. Eur. J. Neurosci. (1999) 11:691-699.
37. BREIVOGEL CS, GRIFFIN G, DI MARZO V, MARTIN BR: Evidence for a new G-protein-coupled cannabinoid receptor in mouse brain. Submitted.
38. JARAI Z, WAGNER JA, VARGA K et al.: Cannabinoid-induced mesenteric vasodilation through an endothelial site distinct from CB1 or CB2 receptors. Proc. Natl. Acad. Sci. USA (1999) 96:14136-14141.
39. ZYGMUNT PM, PETERSSON J, ANDERSSON DA et al.: Vanilloid receptors on sensory nerves mediate the vasodilator action of anandamide. Nature (1999) 400:452-457.
40. SZALLASI A, BLUMBERG PM: Vanilloid (Capsaicin) receptors and mechanisms. Pharmacol. Rev. (1999) 51:159-212.
41. MEZEY E, TOTH ZE, CORTRIGHT DN et al: Distribution of mRNA for vanilloid receptor subtype 1 (VR1) and VR1-like immunoreactivity, in the central nervous system of the rat and human. Proc. Natl. Acad. Sci. USA (2000) 97:3655-3660.
42. SMART D, GUNTHORPE MJ, JERMANJC etal: The endoge nous lipid anandamide is a full agonist at the human vanilloid receptor (hVR1). Br J. Pharmacol (2000) 129:227-230.
43. ROSS RA, GIBSON TM, BROCKIE HC et al: Structure-activity relationship for the endogenous cannabinoid, anandamide and certain of its analogues at vanilloid receptors in transfected cells and vas deferens. Br J. Pharmacol (2001) 132:631-640
44. MACCARRONE M, LORENZON T, BARI M, MELINO G AND FINAZZI-AGRÒ A: Anandamide induces apoptosis in human cells via vanilloid receptors. Evidence for a protective role of cannabinoid receptors.J. Biol. Chem. (2000) 275:31938-31945.
45. TOGNETTO M, AMADESI S, HARRISON S et al.: Anandamide excites central terminals of dorsal root ganglion neurons via vanilloid receptor-1 (VR-1) activation. J. Neurosci. (2001) 21:1104-1109.
46. MELCK D, BISOGNO T, DE PETROCELLIS L etal: Unsatu rated long-chain N-acyl-vanillyl-amides (N-AVAMs): vanilloid receptor ligands that inhibit anandamide-facilitated transport and bind to CB1 cannabinoid receptors. Biochem. Biophys. Res. Commun. (1999) 262:275-284.
47. DI MARZO V, BREIVOGEL C, BISOGNO T etal: Neurobe-havioral activity in mice of N-vanillyl-arachidonyl-amide. Eur.J. Pharmacol. (2000) 406:363-374.
48. SZOLCSANYI J: Anandamide and the question of its functional role for activation of capsaicin receptors. Trends Pharmacol Sci. (2000) 21:203-204.
49. PREMKUMAR LS, AHERN GP: Induction of vanilloid receptor channel activity by protein kinase C. Nature (2000) 408:985-990.
50. DE PETROCELLIS L, BISOGNO T, MACCARRONE M, DAVIS JB, FINAZZI-AGRÒ A, DI MARZO V: The activity of anandamide at vanilloid VR1 receptors requires facilitated transport across the cell membrane and is limited by intracellular metabolism. J. Biol. Chem. (2001) in press.
51. HOWLETT AC: Pharmacology of cannabinoid receptors. Ann. Rev. Pharmacol. Toxicol. (1995) 35:607-634.
52. HOWLETT AC AND MUKHOPADHYAY S: Cellular signal transduction by anandamide and 2-arachidonoylglycerol. Chem. Phys. Lipids (2000) 108:53-70.
53. MELCK D, RUEDA D, GALVE-ROPERH I, DE PETROCELLIS L, GUZMAN M, DI MARZO V: Involvement of the cAMP/protein kinase A pathway and of mitogen-activated protein kinase in the anti-proliferative effects of anandamide in human breast cancer cells. FEBS Lett. (1999) 463:235-240.
54. BOUABOULA M, POINOT-CHAZEL C, BOURRIE B et al: Activation of mitogen-activated protein kinases by stimulation of the central cannabinoid receptor CB1. Biochem. J. (1995) 312:637-641.
55. GALVE-ROPERH I, SANCHEZ C, CORTES ML, DEL PULGAR TG, IZQUIERDO M, GUZMAN M: Anti-tumoral action of cannabinoids: involvement of sustained ceramide accumulation and extracellular signal-regulated kinase activation. Nature Med. (2000) 6:313-319.
56. RUEDA D, GALVE-ROPERH I, HARO A, GUZMAN M: The CB(1) cannabinoid receptor is coupled to the activation of c-Jun N-terminal kinase. Mol. Pharmacol. (2000) 58:814-820.
57. SUGIURA T, KONDO S, KISHIMOTO S et al: 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. (2000) 275:605-612.
58. SUGIURA T, KODAKA T, NAKANE S et al.: 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. (1999) 274:2794-2801.
59. NETZEBAND JG, CONROY SM, PARSONS KL, GRUOL DL: Cannabinoids enhance NMDA-elicited Ca2+signals in cerebellar granule neurons in culture. J. Neurosci. (1999) 19:8765-8777.
60. HENRY DJ, CHAVKIN C: Activation of inwardly rectifying potassium channels (GIRK1) by co-expressed rat brain cannabinoid receptors in Xenopus oocytes. Neurosci. Lett. (1995) 186:91-94.
61. GLASS M, FELDER CC: Concurrent stimulation of cannabinoid CB1 and dopamine D2 receptors augments cAMP accumulation in striatal neurons: evidence for a Gs linkage to the CB1 receptor. J.Neurosci. (1997) 17:5327-5333.
62. TWITCHELL W, BROWNS AND MACKIEK: Cannabinoids inhibit N-and P/Q-type calcium channels in cultured rat hippocampal neurons. J. Neurophysiol. (1997) 78:43-50.
63. SUGIURA T, KODAKA T, KONDO S et al: Inhibition by 2-arachidonoylglycerol, a novel type of possible neuromodulator, of the depolarization-induced increase in intracellular free calcium in neuroblastoma x glioma hybrid NG108-15 cells. Biochem. Biophys. Res. Commun. (1997) 233:207-210.
64. GEBREMEDHIN D, LANGE AR, CAMPBELL WB, HILLARD CJ, HARDER DR: Cannabinoid CB1 receptor of cat cerebral arterial muscle functions to inhibit L-type Ca2+ channel current. Am. J. Physiol. (1999) 276H2085-2093.
65. FIMIANI C, MATTOCKS D, CAVANI F et al: Morphine and anandamide stimulate intracellular calcium transients in human arterial endothelial cells: coupling to nitric oxide release. Cell Signal. (1999) 11:189-193.
66. HILLARD CJ, MUTHIAN S, KEARN CS: Effects of CB(1) cannabinoid receptor activation on cerebellar granule cell nitric oxide synthase activity. FEBS Lett. (1999) 459:277-281.
67. JOHNSON DE, HEALD SL, DALLY RD, JANIS RA: Isolation, identification and synthesis of an endogenous arachi-donic amide that inhibits calcium channel antagonist 1,4-dihydropyridine binding. Prostaglandins Leukot. Essent. Fatty Acids (1993) 48:429-437.
68. LIU J, GAO B, MIRSHAHI F et al: Functional CB1 cannabi noid receptors in human vascular endothelial cells. Biochem. J. (2000) 346:835-840.
69. POLING JS, ROGAWSKI MA, SALEM N JR., VICINI S: Anandamide, an endogenous cannabinoid, inhibits Shaker-related voltage-gated K+ channels. Neuropharmacology (1996) 35:983-991.
70. KISS Z: Anandamide stimulates phospholipase D activity in PC12 cells but not in NIH 3T3 fibroblasts. FEBS Lett. (1999) 447:209-212.
71. DE PETROCELLIS L, ORLANDO P, DI MARZO V: Anandamide, an endogenous cannabinomimetic substance, modulates rat brain protein kinase C in vitro. Biochem. Mol. Biol. Int. (1995) 36:1127-1133.
72. VENANCE L, PIOMELLI D, GLOWINSKI J, GIAUME C: Inhibition by anandamide of gap junctions and intercellular calcium signalling in striatal astrocytes. Nature (1995) 376:590-594.
73. BOGER DL, PATTERSON JE, GUAN X, CRAVATT BF, LERNER RA, GILULA NB: Chemical requirements for inhibition of gap junction communication by the biologically active lipid oleamide. Proc. Natl. Acad. Sci. USA (1998) 95:4810-4815.
74. SCHMID HH, SCHMID PC, NATARAJAN V: The N-acylation-phosphodiesterase pathway and cell signalling. Chem. Phys. Lipids (1996) 80:133-142.
75. HANSEN HS, LAURITZEN L, MOESGAARD B, STRAND AM, HANSEN HH: Formation of N-acyl-phosphatidylethanolamines and N-acetylethanolamines: proposed role in neurotoxicity. Biochem. Pharmacol. (1998) 55:719-725.
76. DI MARZO V: Biosynthesis and inactivation of endocannabinoids: relevance to their proposed role as neuromodulators. Life Sci. (1999) 65:645-655.
77. DI MARZO V, FONTANA A, CADAS H et al.Formation and inactivation of endogenous cannabinoid anandamide in central neurons. Nature (1994) 372:686-691.
78. BISOGNO T, SEPE N, MELCK D, MAURELLI S, DE PETROCELLIS L, DI MARZO V: Biosynthesis, release and degradation of the novel endogenous cannabimimetic metabolite 2-arachidonoylglycerol in mouse neuroblastoma cells. Biochem. J. (1997) 322:671-677.
79. SUGIURA T, KONDO S, SUKAGAWA A et al.: Transacylase-mediated and phosphodiesterase-mediated synthesis of N-arachidonoyl-ethanolamine, an endogenous cannabinoid-receptor ligand, in rat brain microsomes. Comparison with synthesis from free arachidonic acid and ethanolamine. Eur. J. Biochem. (1996) 240:53-62.
80. CADAS H, DI TOMASO E, PIOMELLI D: Occurrence and biosynthesis of endogenous cannabinoid precursor, N-arachidonoyl phosphatidylethanolamine, in rat brain. J. Neurosci. (1997) 17:1226-1242.
81. STELLA N, SCHWEITZER P, PIOMELLI D: A second endogenous cannabinoid that modulates long-term potentiation. Nature (1997) 388:773-778.
82. BISOGNO T, MELCK D, DE PETROCELLIS L, DI MARZO V: Phosphatidic acid as the biosynthetic precursor of the endocannabinoid 2-arachidonoylglycerol in intact mouse neuroblastoma cells stimulated with ionomycin. J. Neurochem. (1999) 72:2113-2119.
83. SCHMID HH: Pathways and mechanisms of N-acylethanolamine biosynthesis: can anandamide be generated selectively? Chem. Phys. Lipids (2000) 108:71-87.
84. HILLARD CJ, JARRAHIAN A: The movement of N-arachidonoyl-ethanolamine (anandamide) across cellular membranes. Chem. Phys. Lipids (2000) 108:123-134.
85. DEUTSCHDG, GLASERST, HOWELL JM etal:The cellular uptake of anandamide is coupled to its breakdown by fatty acid amide hydrolase (FAAH). J. Biol. Chem. (2001) in press.
86. DI MARZO V, BISOGNO T, SUGIURA T, MELCK D AND DE PETROCELLIS L: The novel endogenous cannabinoid 2-arachidonoylglycerol is inactivated by neuronal-and basophil-like cells: connections with anandamide. Biochem. J. (1998) 331:15-19.
87. CRAVATT BF, GIANG DK, MAYFIELD SP, BOGER DL, LERNER RA, GILULA NB: Molecular characterization of an enzyme that degrades neuromodulatory fatty-acid amides. Nature (1996) 384:83-87.
88. UEDA N, KURAHASHI Y, YAMAMOTO S, TOKUNAGA T: Partial purification and characterization of the porcine brain enzyme hydrolyzing and synthesizing anandamide. J. Biol. Chem. (1995) 270:23823-23827.
89. DI MARZO V, BISOGNO T, DE PETROCELLIS L et al.: Biosynthesis and inactivation of the endocannabinoid 2-arachidonoylglycerol in circulating and tumoral macrophages. Eur. J. Biochem. (1999) 264:258-267.
90. BELTRAMO M, STELLA N, CALIGNANO A et al: Functional role of high-affinity anandamide transport, as revealed by selective inhibition. Science (1997) 277:1094-1097.
91. MACCARRONE M, BARI M, LORENZON T, BISOGNO T, DI MARZO V, FINAZZI-AGRO' A: Anandamide uptake by human endothelial cells and its regulation by nitric oxide. J. Biol. Chem. (2000) 275:13484-13492.
92. GIFFORD AN, BRUNEUS M, LIN S et al: Potentiation of the action of anandamide on hippocampal slices by the fatty acid amide hydrolase inhibitor, palmityl-sulphonyl fluoride (AM 374). Eur. J. Pharmacol. (1999) 383:9-14.
93. MARTIN BR, BELETSKAYA I, PATRICK G et al: Cannabi-noidproperties of methylfluorophosphonate analogs. J. Pharmacol Exp. Ther. (2000) 294:1209-1218.
94. BELTRAMO M, PIOMELLI D: Carrier-mediated transport and enzymatic hydrolysis of the endogenous cannabinoid 2-arachidonylglycerol. Neuroreport (2000) 11:1231-1235.
95. BISOGNO T, MACCARRONE M, DE PETROCELLIS L et al: On the uptake by cells of 2-arachidonoylglycerol, an endogenous agonist of cannabinoid receptors. (2001) Eur. J. Biochem. In press.
96. MACCARRONE M, VAN DER STELT M, ROSSI A, VELDINK GA, VLIEGENTHART JF, FINAZZI-AGRO' A: Anandamide hydrolysis by human cells in culture and brain. J. Biol Chem. (1998) 273:32332-32339.
97. UEDA N, PUFFENBARGER RA, YAMAMOTO S, DEUTSCH DG: The fatty acid amide hydrolase. Chem. Phys. Lipids (2000) 108:107-121.
98. ARREAZA G, DEUTSCH DG: Deletion of a proline-rich region and a transmembrane domain in fatty acid amide hydrolase. FEBS Lett. (1999) 454:57-60.
99. PATRICELLI MP, CRAVATT BF: Clarifying the catalytic roles of conserved residues in the amidase signature family. J. Biol. Chem. (2000) 275:19177-19184.
100. DINH TP, LESLIE F, ZHOU QY, PIOMELLI D: Molecular characterization of a rat brain monoacylglycerol lipase that participates in the hydrolysis of the endocannabinoid 2-arachidonoylglycerol. Soc. Neurosci. (2000) 26:2164, 813.8.
101. KOZAK KR, ROWLINSON SW, MARNETT LJ: Oxygenation of the endocannabinoid, 2-arachidonylglycerol, to glyceryl prostaglandins by cyclooxygenase-2. J. Biol. Chem. (2000) 275:33744-33749.
102. YU M, IVES D, RAMESHA CS: Synthesis of prostaglandin E2 ethanolamide from anandamide by cyclooxygenase-2.J.Biol. Chem. (1997) 272:21181-21186.
103. EDGEMOND WS, HILLARD CJ, FALCK JR, KEARN CS, CAMPBELL WB: Human platelets and polymorphonuclear leukocytes synthesize oxygenated derivatives of arachidonylethanolamide (anandamide): their affinities for cannabinoid receptors and pathways of inacti-vation. Mol. Pharmacol. (1998) 54:180-188.
104. UEDA N, YAMANAKA K, TERASAWA Y, YAMAMOTO S: An acid amidase hydrolyzing anandamide as an endogenous ligand for cannabinoid receptors. FEBS Lett. (1999) 454:267-270.
105. MACCARRONE M, DI MARZO V, BARI M etal: Lipopoly-saccharide down-regulates fatty acid amide hydrolase expression and increases anandamide levels in human peripheral lymphocytes. Submitted.
106. ADAMS IB, RYAN W, SINGER M et al: Evaluation of cannabinoid receptor binding and in vivoactivities for anandamide analogs. J. Pharmacol. Exp. Ther. (1995) 273:1172-1181.
107. HILLARD CJ, MANNA S, GREENBERG MJ et al: Synthesis and characterization of potent and selective agonists of the neuronal cannabinoid receptor (CB1). J. Pharmacol. Exp. Ther. (1999) 289:1427-1433.
108. BISOGNO T, MELCK D, BOBROV MY et al: N-acyl-dopamines: novel synthetic CB1 cannabinoid-receptor ligands and inhibitors of anandamide inactivation with cannabimimetic activity in vitro and in vivo. Biochem. J. (2000) 351:817-824.
109. KHANOLKAR AD, MAKRIYANNIS A: Structure-activity relationships of anandamide, an endogenous cannabinoid ligand. Life Sci. (1999) 65:607-616.
110. MARTIN BR, MECHOULAM R, RAZDAN RK: Discovery and characterization of endogenous cannabinoids. Life Sci. (1999) 65:573-595.
111. DE PETROCELLIS L, BISOGNO T, DAVIS JB, PERTWEE RG, DI MARZO V: 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. (2000) 483:52-56.
112. DI MARZO V, BISOGNO T, DE PETROCELLIS L et al: Highly selective CB1 cannabinoid receptor ligands and novel CB1/VR1 vanilloid receptor 'hybrid' ligands. Biochem. Biophys. Res. Commun. (2001) 281:444-451.
113. ROSS RA, BROCKIE HC, STEVENSON LA etal: Agonist-inverse agonist characterization at CB1 and CB2 cannabinoid receptors of L759633, L759656 and AM630. Br. J. Pharmacol. (1999) 126:665-672.
114. HUFFMAN JW: The search for selective ligands for the CB2 receptor. Curr. Pharm. Des. (2000) 6:1323-1337.
115. TREMBLAY N, ROCHETTE C, SAWYER N etal: New class of potent ligands for the human peripheral cannabinoid receptor. Bioorg. Med. Chem. Lett. (1996) 6:2263-2268.
116. BAKER D, PRYCE G, CROXFORD JL et al: Cannabinoids control spasticity and tremor in a multiple sclerosis model. Nature (2000) 404:84-87.
117. HANUS L, BREUER A, TCHILIBON S et al: HU-308: a specific agonist for CB(2), a peripheral cannabinoid receptor. Proc. Natl Acad. Sci. USA (1999) 96:14228-14233.
118. BARTH F, RINALDI-CARMONA M: The development of cannabinoid antagonists. Curr. Med. Chem. (1999) 6:745-755.
119. RINALDI-CARMONA M, BARTH F, HEAULME M et al: SR141716A, a potent and selective antagonist of the brain cannabinoid receptor. FEBS Lett. (1994) 350:240-244.
120. GATLEY SJ, GIFFORD AN, VOLKOW ND, LAN R AND MAKRIYANNIS A: 123I-labeled AM251: a radioiodinated ligand which binds in vivo to mouse brain cannabinoid CB1 receptors. Eur. J. Pharmacol. (1996) 307, 331-338.
121. FELDER CC, JOYCE KE, BRILEY EM et al: LY320135, a novel cannabinoid CB1 receptor antagonist, unmasks coupling of the CB1 receptor to stimulation of cAMP accumulation. J. Pharmacol. Exp. Ther. (1998) 284:291-297.
122. CHAYTOR AT, MARTIN PE, EVANS WH, RANDALL MD, GRIFFITH TM: The endothelial component of cannabinoid-induced relaxation in rabbit mesenteric artery depends on gap junctional communication. J. Physiol. (1999) 520:539-550.
123. RINALDI-CARMONA M, BARTH F, MILLAN J et al: SR 144528, the first potent and selective antagonist of the CB2 cannabinoid receptor. J. Pharmacol. Exp. Ther (1998) 284:644-650.
124. BAKER D, PRYCE G, CROXFORD JL etal: Endocannabi-noids control spasticity in a multiple sclerosis model. FASEBJ. (2001) 15:300-302
125. JARRAHIAN A, MANNA S, EDGEMOND WS, CAMPBELL WB, HILLARD CJ: Structure-activity relationships among N-arachidonylethanolamine (Anandamide) head group analogues for the anandamide transporter. J. Neurochem. (2000) 74:2597-2606.
126. DI MARZO V, BISOGNO T, MELCK D etal: Interactions between synthetic vanilloids and the endogenous cannabinoid system. FEBSLett. (1998) 436:449-454.
127. ZYGMUNT PM, CHUANG H, MOVAHED P, JULIUS D AND HOGESTATT ED: The anandamide transport inhibitor AM404 activates vanilloid receptors. Eur. J. Pharmacol. (2000) 396:39-42.
128. SMART D, JERMAN JC: Anandamide: an endogenous activator of the vanilloid receptor. Trends Pharmacol. Sci. (2000) 21:134.
129. KOUTEK B, PRESTWICH GD, HOWLETT AC etal: Inhibitors of arachidonoyl ethanolamide hydrolysis. J. Biol. Chem. (1994) 269:22937-22940.
130. DE PETROCELLIS L, MELCK D, UEDA N et al: Novel inhibitors of brain, neuronal and basophilic anandamide amidohydrolase. Biochem. Biophys. Res. Commun. (1997) 231:82-88.
131. DEUTSCH DG, OMEIR R, ARREAZA G et al: Methyl arachidonyl fluorophosphonate: a potent irreversible inhibitor of anandamide amidase. Biochem. Pharmacol (1997) 53:255-260.
132. EDGEMOND WS, GREENBERG MJ, MCGINLEY PJ, MUTHIAN S, CAMPBELL WB, HILLARD CJ: Synthesis and characterization of diazomethylarachidonyl ketone: an irreversible inhibitor of N-arachidonylethanolamine amidohydrolase. J. Pharmacol Exp. Ther. (1998) 286:184-190.
133. DE PETROCELLIS L, MELCK D, UEDA N et al: Brain and peripheral anandamide amidohydrolase and its inhibition by synthetic arachidonate analogues. Adv. Exp. Med. Biol. (1997) 433:259-263.
134. BISOGNO T, MELCK D, DE PETROCELLIS L et al: Arachi-donoylserotonin and other novel inhibitors of fatty acid amide hydrolase. Biochem. Biophys. Res. Commun. (1998) 248:515-522.
135. DEUTSCH DG, LIN S, HILL WA et al: Fatty acid sulfonyl fluorides inhibit anandamide metabolism and bind to the cannabinoid receptor. Biochem. Biophys. Res. Commun. (1997) 231:217-221.
136. BEN-SHABAT S, FRIDE E, SHESKIN T etal: An entourage effect: inactive endogenous fatty acid glycerol esters enhance 2-arachidonoyl-glycerol cannabinoid activity. Eur. J. Pharmacol (1998) 353:23-31.
137. MALFAIT AM, GALLILY R, SUMARIWALLA PF et al: The nonpsychoactive cannabis constituent cannabidiol is an oral anti-arthritic therapeutic in murine collagen-induced arthritis. Proc. Natl. Acad. Sci. USA (2000) 97:9561-9566.
138. RAKHSHAN F, DAY TA, BLAKELY RD, BARKER EL: Carrier-mediated uptake of the endogenous cannabinoid anandamide in RBL-2H3 cells. J. Pharmacol Exp. Ther (2000) 292:960-967.
139. BURSTEIN SH: The cannabinoid acids: nonpsychoactive derivatives with therapeutic potential. Pharmacol Ther (1999) 82:87-96.
140. DI MARZO V, HILL MP, BISOGNO T, CROSSMAN AR, BROTCHIE JM: Enhanced levels of endogenous cannabinoids in the globus pallidus are associated with a reduction in movement in an animal model of Parkinson's disease. FASEBJ. (2000) 14:1432-1438.