New Natural Noncannabinoid Ligands for Cannabinoid Type-2 (CB₂) Receptors

REFERENCES

• Devane W A, Dysarz F A, Johnson M R, Melvin L S, Howlett A C. Determination and characterization of a cannabinoid receptor in rat brain. Mol Pharmacol 1988; 34: 605–613
   PubMed Web of Science ®Google Scholar
• Howlett A C, Bidaut-Russell M, Devane W A, Melvin L S, Johnson M R, Herkenham M. The cannabinoid receptor: Biochemical, anatomical and behavioral characterization. Trends Neurosci 1990; 13: 420–423
   PubMed Web of Science ®Google Scholar
• Herkenham M, Lynn A B, Little M D, Johnson M R, Melvin L S, de Costa B R, Rice K C. Cannabinoid receptor localization in brain. Proc Natl Acad Sci USA 1990; 87: 1932–1936
   PubMed Web of Science ®Google Scholar
• Herkenham M, Lynn A B, Johnson M R, Melvin L S, de Costa B R, Rice K C. Characterization and localization of cannabinoid receptors in rat brain: A quantitative in vitro autoradiographic study. J Neurosci 1991; 11: 563–583
   PubMed Web of Science ®Google Scholar
• Mailleux P, Vanderhaeghen J J. Localization of cannabinoid receptor in the human developing and adult basal ganglia. Higher levels in the striatonigral neurons. Neurosci Lett 1992; 148: 173–176
   PubMed Web of Science ®Google Scholar
• Munro S, Thomas K L, Abu-Shaar M. Molecular characterization of a peripheral receptor for cannabinoids. Nature 1993; 365: 61–65
   PubMed Web of Science ®Google Scholar
• Cabral G A, Marciano-Cabral F. Cannabinoid receptors in microglia of the central nervous system: immune functional relevance. J Leukoc Biol 2005; 78: 1192–1197
   PubMed Web of Science ®Google Scholar
• Mackie K. Distribution of cannabinoid receptors in the central and peripheral nervous system. Handb Exp Pharmacol 2005; 168: 299–325
   PubMedGoogle Scholar
• Gong J P, Onaivi E S, Ishiguro H, Liu Q R, Tagliaferro P A, Brusco A, Uhl G R. Cannabinoid CB2 receptors: Immunohistochemical localization in rat brain. Brain Res 2006; 1071: 10–23
   PubMed Web of Science ®Google Scholar
• Howlett A C, Barth F, Bonner T I, Cabral G, Casellas P, Devane W A, Felder C C, Herkenham M, Mackie K, Martin B R, Mechoulam R, Pertwee R G. International Union of Pharmacology, XXVII. Classification of cannabinoid receptors. Pharmacol Rev 2002; 54: 161–202
   PubMed Web of Science ®Google Scholar
• Howlett A C. Cannabinoid receptor signalling. Handb Exp Pharmacol 2005; 168: 53–79
   PubMedGoogle Scholar
• Devane W A, Hanus L, Breuer A, Pertwee R G, Stevenson L A, Griffin G, Gibson D, Mandelbaum A, Etinger A, Mechoulam R. Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science 1992; 258: 1946–1949
   PubMed Web of Science ®Google Scholar
• Di Marzo V, Fontana A, Cadas H, Schinelli S, Cimino G, Schwartz J C, Piomelli D. Formation and inactivation of endogenous cannabinoid anandamide in central neurons. Nature 1994; 372: 686–691
   PubMed Web of Science ®Google Scholar
• Thomas B F, Adams I B, Mascarella S W, Martin B R, Razdan R K. Structure-activity analysis of anandamide analogs: Relationship to a cannabinoid pharmacophore. J Med Chem 1996; 39: 471–479
   PubMed Web of Science ®Google Scholar
• Ligresti A, Cascio M G, Di Marzo V. Endocannabinoid metabolic pathways and enzymes. Curr Drug Targets CNS Neurol Disord 2005; 4: 615–623
   PubMedGoogle Scholar
• Mechoulam R, Fride E, Di Marzo V. Endocannabinoids. Eur J Pharmacol 1998; 359: 1–18
   PubMed Web of Science ®Google Scholar
• Klein T W, Newton C, Larsen K, Lu L, Perkins I, Nong L, Friedman H. The cannabinoid system and immune modulation. J Leukoc Biol 2003; 74: 486–496
   PubMed Web of Science ®Google Scholar
• Kogan N M, Mechoulam R. The chemistry of endocannabinoids. J Endocrinol Invest 2006; 29: 3–14
   PubMedGoogle Scholar
• Appendino G, Minassi A, Berton L, Moriello A S, Cascio M G, De Petrocellis L, Di Marzo V. Oxyhomologues of anandamide and related endolipids: chemoselective synthesis and biological activity. J Med Chem 2006; 49: 2333–2338
   PubMed Web of Science ®Google Scholar
• Appendino G, Cascio M G, Bacchiega S, Moriello A S, Minassi A, Thomas A, Ross R, Pertwee R, De Petrocellis L, Di Marzo V. First “hybrid” ligands of vanilloid TRPV1 and cannabinoid CB2 receptors and non-polyunsaturated fatty acid-derived CB2-selective ligands. FEBS Lett 2006; 580: 568–574
   PubMed Web of Science ®Google Scholar
• Mahadevan A, Razdan R K. Further advances in the synthesis of endocannabinoid-related ligands. AAPS J 2005; 7: E496–502
   Web of Science ®Google Scholar
• Lambert D M, Fowler C J. The endocannabinoid system: drug targets, lead compounds, and potential therapeutic applications. J Med Chem 2005; 48: 5059–5087
   PubMed Web of Science ®Google Scholar
• Mackie K. Cannabinoid receptors as therapeutic targets. Annu Rev Pharmacol Toxicol 2006; 46: 101–122
   PubMed Web of Science ®Google Scholar
• Di Marzo V, Bifulco M, De Petrocellis L. The endocannabinoid system and its therapeutic exploitation. Nat Rev Drug Discov 2004; 3: 771–784
   PubMed Web of Science ®Google Scholar
• Alberich Jorda M, Rayman N, Tas M, Verbakel S E, Battista N, van Lom K, Lowenberg B, Maccarrone M, Delwel R. The peripheral cannabinoid receptor CB2, frequently expressed on AML blasts, either induces a neutrophilic differentiation block or confers abnormal migration properties in a ligand-dependent manner. Blood 2004; 104: 526–534
   PubMed Web of Science ®Google Scholar
• Sarfaraz S, Afaq F, Adhami V M, Mukhtar H. Cannabinoid receptor as a novel target for the treatment of prostate cancer. Cancer Res 2005; 65: 1635–1641
   PubMed Web of Science ®Google Scholar
• McKallip R J, Lombard C, Fisher M, Martin B R, Ryu S, Grant S, Nagarkatti P S, Nagarkatti M. Targeting CB2 cannabinoid receptors as a novel therapy to treat malignant lymphoblastic disease. Blood 2002; 100: 627–634
   PubMed Web of Science ®Google Scholar
• http://www.pharmoscorp.com/development/cannabinor.htmlCB-2 Selective Program: Cannabinor. Pharmos Web Site. Available at, Accessed June 23, 2006
   Google Scholar
• Lavon I, Sheinin T, Meilin S, Biton E, Weksler A, Efroni G, Bar-Joseph A, Fink G, Avraham A. A novel synthetic cannabinoid derivative inhibits inflammatory liver damage via negative cytokine regulation. Mol Pharmacol 2003; 64: 1334–1341
   PubMed Web of Science ®Google Scholar
• Reggio P H. Cannabinoid receptors and their ligands: ligand-ligand and ligand-receptor modeling approaches. Handb Exp Pharmacol 2005; 168: 247–281
   Google Scholar
• Hohmann A G, Suplita R L, Bolton N M, Neely M H, Fegley D, Mangieri R, Krey J F, Walker J M, Holmes P V, Crystal J D, Duranti A, Tontini A, Mor M, Tarzia G, Piomelli D. An endocannabinoid mechanism for stress-induced analgesia. Nature 2005; 435: 1108–1112
   PubMed Web of Science ®Google Scholar
• Hohmann A G, Farthing J N, Zvonok A M, Makriyannis A. Selective activation of cannabinoid CB2 receptors suppresses hyperalgesia evoked by intradermal capsaicin. J Pharmacol Exp Ther 2004; 308: 446–453
   PubMed Web of Science ®Google Scholar
• Ibrahim M M, Deng H, Zvonok A, Cockayne D A, Kwan J, Mata H P, Vanderah T W, Lai J, Porreca F, Makriyannis A, Malan T P, Jr. Activation of CB2 cannabinoid receptors by AM1241 inhibits experimental neuropathic pain: pain inhibition by receptors not present in the CNS. Proc Natl Acad Sci USA 2003; 100: 10529–10533
   PubMed Web of Science ®Google Scholar
• Ibrahim M M, Rude M L, Stagg N J, Mata H P, Lai J, Vanderah T W, Porreca F, Buckley N E, Makriyannis A, Malan T P, Jr. CB2 cannabinoid receptor mediation of antinociception. Pain 2006; 122: 36–42
   PubMed Web of Science ®Google Scholar
• Malan T P, Jr., Ibrahim M M, Deng H, Liu Q, Mata H P, Vanderah T, Porreca F, Makriyannis A. CB2 cannabinoid receptor-mediated peripheral antinociception. Pain 2001; 93: 239–245
   PubMed Web of Science ®Google Scholar
• Ibrahim M M, Porreca F, Lai J, Albrecht P J, Rice F L, Khodorova A, Davar G, Makriyannis A, Vanderah T W, Mata H P, Malan T P, Jr. CB2 cannabinoid receptor activation produces antinociception by stimulating peripheral release of endogenous opioids. Proc Natl Acad Sci USA 2005; 102: 3093–3098
   PubMed Web of Science ®Google Scholar
• Wotherspoon G, Fox A, McIntyre P, Colley S, Bevan S, Winter J. Peripheral nerve injury induces cannabinoid receptor 2 protein expression in rat sensory neurons. Neuroscience 2005; 135: 235–245
   PubMed Web of Science ®Google Scholar
• Ofek O, Karsak M, Leclerc N, Fogel M, Frenkel B, Wright K, Tam J, Attar-Namdar M, Kram V, Shohami E, Mechoulam R, Zimmer A, Bab I. Peripheral cannabinoid receptor, CB2, regulates bone mass. Proc Natl Acad Sci USA 2006; 103: 696–701
   PubMed Web of Science ®Google Scholar
• Karsak M, Cohen-Solal M, Freudenberg J, Ostertag A, Morieux C, Kornak U, Essig J, Erxlebe E, Bab I, Kubisch C, de Vernejoul M C, Zimmer A. Cannabinoid receptor type 2 gene is associated with human osteoporosis. Hum Mol Genet 2005; 14: 3389–3396
   PubMed Web of Science ®Google Scholar
• Idris A I, van't Hof R J, Greig I R, Ridge S A, Baker D, Ross R A, Ralston S H. Regulation of bone mass, bone loss and osteoclast activity by cannabinoid receptors. Nat Med 2005; 11: 774–779
   PubMed Web of Science ®Google Scholar
• Steffens S, Veillard N R, Arnaud C, Pelli G, Burger F, Staub C, Karsak M, Zimmer A, Frossard J L, Mach F. Low dose oral cannabinoid therapy reduces progression of atherosclerosis in mice. Nature 2005; 434: 782–786
   PubMed Web of Science ®Google Scholar
• Ramirez B G, Blazquez C, Gomez del Pulgar T, Guzman M, de Ceballos M L. Prevention of Alzheimer's disease pathology by cannabinoids: neuroprotection mediated by blockade of microglial activation. J Neurosci 2005; 25: 1904–1913
   PubMed Web of Science ®Google Scholar
• Benito C, Kim W K, Chavarria I, Hillard C J, Mackie K, Tolon R M, Williams K, Romero J. A glial endogenous cannabinoid system is upregulated in the brains of macaques with simian immunodeficiency virus-induced encephalitis. J Neurosci 2005; 25: 2530–2536
   PubMed Web of Science ®Google Scholar
• Adam J, Cowley P M, Kiyoi T, Morrison A J, Mort C JW. Recent progress in cannabinoid research. Progr Med Chem 2006; 44: 208–313
   Google Scholar
• Griffin G, Wray E J, Tao Q, McAllister S D, Rorrer W K, Aung M M, Martin B R, Abood M E. Evaluation of the cannabinoid CB2 receptor-selective antagonist, SR144528: further evidence for cannabinoid CB2 receptor absence in the rat central nervous system. Eur J Pharmacol 1999; 377: 117–125
   PubMed Web of Science ®Google Scholar
• Pertwee R, Griffin G, Fernando S, Li X, Hill A, Makriyannis A. AM630, a competitive cannabinoid receptor antagonist. Life Sci 1995; 56: 1949–1955
   PubMed Web of Science ®Google Scholar
• Huffman J W. CB2 receptor ligands. Mini Rev Med Chem 2005; 5: 641–649
   PubMed Web of Science ®Google Scholar
• Rhee M H, Kim S K. SR144528 as inverse agonist of CB2 cannabinoid receptor. J Vet Sci 2002; 3: 179–184
   PubMedGoogle Scholar
• Raduner S, Majewska A, Chen J Z, Xie X Q, Hamon J, Faller B, Altmann K H, Gertsch J. Alkylamides from Echinacea are a new class of cannabinomimetics. Cannabinoid type 2 receptor-dependent and-independent immunomodulatory effects. J Biol Chem 2006; 281: 14192–14206
   PubMed Web of Science ®Google Scholar
• Iwamura H, Suzuki H, Ueda Y, Kaya T, Inaba T. In vitro and in vivo pharmacological characterization of JTE-907, a novel selective ligand for cannabinoid CB2 receptor. J Pharmacol Exp Ther 2001; 296: 420–425
   PubMed Web of Science ®Google Scholar
• Ueda Y, Miyagawa N, Matsui T, Kaya T, Iwamura H. Involvement of cannabinoid CB2 receptor-mediated response and efficacy of cannabinoid CB2 receptor inverse agonist, JTE-907, in cutaneous inflammation in mice. Eur J Pharmacol 2005; 520: 164–171
   PubMed Web of Science ®Google Scholar
• Pertwee R, Griffin G, Fernando S, Li X, Hill A, Makriyannis A. AM630, a competitive cannabinoid receptor antagonist. Life Sci 1995; 56: 1949–1955
   PubMed Web of Science ®Google Scholar
• Chapman K D. Occurrence, metabolism, and prospective functions of N-acylethanolamines in plants. Prog Lipid Res 2004; 43: 302–327
   PubMed Web of Science ®Google Scholar
• Ramirez-Chavez E, Lopez-Bucio J, Herrera-Estrella L, Molina-Torres J. Alkamides isolated from plants promote growth and alter root development in Arabidopsis. Plant Physiol 2004; 134: 1058–1068
   PubMed Web of Science ®Google Scholar
• Molina-Torres J, Salazar-Cabrera C J, Armenta-Salinas C, Ramirez-Chavez E. Fungistatic and bacteriostatic activities of alkamides from Heliopsis longipes roots: affinin and reduced amides. J Agric Food Chem 2004; 52: 4700–4704
   PubMed Web of Science ®Google Scholar
• Lait C G, Alborn H T, Teal P E, Tumlinson J H. 3rd. Rapid biosynthesis of N-linolenoyl-L-glutamine, an elicitor of plant volatiles, by membrane-associated enzyme(s) in Manduca sexta. Proc Natl Acad Sci USA 2003; 100: 7027–7032
   PubMed Web of Science ®Google Scholar
• Chapman K D, Venables B, Markovic R, Blair R W, Jr., Bettinger C. N-Acylethanolamines in seeds. Quantification of molecular species and their degradation upon imbibition. Plant Physiol 1999; 120: 1157–1164
   PubMed Web of Science ®Google Scholar
• Di Marzo V, Sepe N, De Petrocellis L, Berger A, Crozier G, Fride E, Mechoulam R. Trick or treat from food endocannabinoids?. Nature 1998; 396: 636–637
   PubMed Web of Science ®Google Scholar
• Cravatt B F, Lichtman A H. Fatty acid amide hydrolase: an emerging therapeutic target in the endocannabinoid system. Curr Opin Chem Biol 2003; 7: 469–475
   PubMed Web of Science ®Google Scholar
• Gertsch J, Schoop R, Kuenzle U, Suter A. Echinacea alkylamides modulate TNF-alpha gene expression via cannabinoid receptor CB2 and multiple signal transduction pathways. FEBS Lett 2004; 577: 563–569
   PubMed Web of Science ®Google Scholar
• Woelkart K, Xu W, Pei Y, Makriyannis A, Picone R P, Bauer R. The endocannabinoid system as a target for alkamides from Echinacea angustifolia roots. Planta Med 2005; 71: 701–705
   PubMed Web of Science ®Google Scholar
• Muller-Jakic B, Breu W, Probstle A, Redl K, Greger H, Bauer R. In vitro inhibition of cyclooxygenase and 5-lipoxygenase by alkamides from Echinacea and Achillea species. Planta Med 1994; 60: 37–40
   PubMed Web of Science ®Google Scholar
• Greger H. Comparative Phytochemistry of Alkamides. Elsevier, New York 1988
   Google Scholar
• Bryant B P, Mezine I. Alkylamides that produce tingling paresthesia activate tactile and thermal trigeminal neurons. Brain Res 1999; 842: 452–460
   PubMed Web of Science ®Google Scholar
• Lin S, Khanolkar A D, Fan P, Goutopoulos A, Qin C, Papahadjis D, Makriyannis A. Novel analogues of arachidonylethanolamide (anandamide): Affinities for the CB1 and CB2 cannabinoid receptors and metabolic stability. J Med Chem 1998; 41: 5353–5361
   PubMed Web of Science ®Google Scholar
• Woelkart K, Koidl C, Grisold A, Gangemi J D, Turner R B, Marth E, Bauer R. Bioavailability and pharmacokinetics of alkamides from the roots of Echinacea angustifolia in humans. J Clin Pharmacol 2005; 45: 683–689
   PubMed Web of Science ®Google Scholar
• Matthias A, Addison R S, Penman K G, Dickinson R G, Bone K M, Lehmann R P. Echinacea alkamide disposition and pharmacokinetics in humans after tablet ingestion. Life Sci 2005; 77: 2018–2029
   PubMed Web of Science ®Google Scholar
• Lipinski C A, Lombardo F, Dominy B W, Feeney P J. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev 2001; 46: 3–26
   PubMed Web of Science ®Google Scholar
• Sugiura T, Kondo S, Kishimoto S, Miyashita T, Nakane S, Kodaka T, Suhara Y, Takayama H, Waku K. 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
   PubMed Web of Science ®Google Scholar
• Zoratti C, Kipmen-Korgun D, Osibow K, Malli R, Graier W F. Anandamide initiates Ca2+ signaling via CB2 receptor linked to phospholipase C in calf pulmonary endothelial cells. Br J Pharmacol 2003; 140: 1351–1362
   PubMed Web of Science ®Google Scholar
• Rao G K, Zhang W, Kaminski N E. Cannabinoid receptor-mediated regulation of intracellular calcium by delta9-tetrahydrocannabinol in resting T cells. J Leukoc Biol 2004; 75: 884–892
   PubMed Web of Science ®Google Scholar
• Rao G K, Kaminski N E. Cannabinoid-mediated elevation of intracellular calcium: a structure-activity relationship. J Pharmacol Exp Ther 2006; 317: 820–829
   PubMed Web of Science ®Google Scholar
• Chen Y, Fu T, Tao T, Yang J, Chang Y, Wang M, Kim L, Qu L, Cassady J, Scalzo R, Wang X. Macrophage activating effects of new alkamides from the roots of Echinacea species. J Nat Prod 2005; 68: 773–776
   PubMed Web of Science ®Google Scholar
• Baldwin G C, Tashkin D P, Buckley D M, Park A N, Dubinett S M, Roth M D. Marijuana and cocaine impair alveolar macrophage function and cytokine production. Am J Respir Crit Care Med 1997; 156: 1606–1613
   PubMed Web of Science ®Google Scholar
• Klein T W. Cannabinoid-based drugs as anti-inflammatory therapeutics. Nat Rev Immunol 2005; 5: 400–411
   PubMed Web of Science ®Google Scholar
• Klein T W, Newton C, Widen R, Friedman H. Delta 9-tetrahydrocannabinol injection induces cytokine-mediated mortality of mice infected with Legionella pneumophila. J Pharmacol Exp Ther 1993; 267: 635–640
   PubMed Web of Science ®Google Scholar
• Kishimoto S, Kobayashi Y, Oka S, Gokoh M, Waku K, Sugiura T. 2-Arachidonoylglycerol, an endogenous cannabinoid receptor ligand, induces accelerated production of chemokines in HL-60 cells. J Biochem 2004; 135: 517–524
   PubMed Web of Science ®Google Scholar
• Sasagawa M, Cech N B, Gray D E, Elmer G W, Wenner C A. Echinacea alkylamides inhibit interleukin-2 production by Jurkat T cells. Int Immunopharmacol 2006; 6: 1214–1221
   PubMed Web of Science ®Google Scholar