Recent development of CB2 selective and peripheral CB1/CB2 cannabinoid receptor ligands

Current Medicinal Chemistry

Volumn 21, Issue 2, 2014, Pages 187-203

  Nevalainen, Tapio ^a  

^a UNIVERSITY OF EASTERN FINLAND   (Finland)

Author keywords

Agonist; Anti proliferative; Antipruritics; Cannabinoid; CB1; CB2; Inverse agonist; Pain; Partial agonists; Peripheral ligands

Indexed keywords

1 (2,3 DICHLOROBENZOYL) 5 METHOXY 2 METHYL 3 (2 MORPHOLINOETHYL)INDOLE; 1 DEOXY 3 (1,1 DIMETHYLBUTYL) DELTA8 TETRAHYDROCANNABINOL; 1,4 DIAZEPANE CARBOXAMIDE DERIVATIVE; 1,8 NAPHTHYRIDINONE DERIVATIVE; 2 METHYL 3 (1 NAPHTHOYL) 1 PROPYLINDOLE; 2,3 DIHYDRO 5 METHYL 3 (MORPHOLINOMETHYL) 6 (1 NAPHTHOYL)PYRROLO[1,2,3 DE][1,4]BENZOXAZINE; 3 (2 IODO 5 NITROBENZOYL) 1 (1 METHYL 2 PIPERIDINYLMETHYL)INDOLE; 3 CARBAMOYL 2 PYRIDONE DERIVATIVE; 4 [4 (1,1 DIMETHYLHEPTYL) 2,6 DIMETHOXYPHENYL] 6,6 DIMETHYLBICYCLO[3.1.1]HEPT 2 EN 2 YLMETHANOL; A 836339; AM 1710; AZ 11713908; BENZIMIDAZOLE DERIVATIVE; CANNABINOID RECEPTOR AGONIST; CANNABINOR; CB 13; COR 167; COR 170; DIHYDROQUINOLINE 3 CARBOXAMIDE DERIVATIVE; GAMMA CARBOLINE DERIVATIVE; GSK 554418A; GW 833972A; GW 842166; HU 910; IMIDAZOLE DERIVATIVE; NESS 400; PRS 211375; PURINE DERIVATIVE; PYRIDINE DERIVATIVE; S 444823; UNCLASSIFIED DRUG; UNINDEXED DRUG; CANNABINOID 1 RECEPTOR; CANNABINOID 2 RECEPTOR; LIGAND;

ALLODYNIA; ANALGESIA; ANTINEOPLASTIC ACTIVITY; ANTINOCICEPTION; ARTICLE; AUTOIMMUNE DISEASE; BONE PAIN; CANCER PAIN; CLINICAL TRIAL (TOPIC); COLITIS; DRUG SCREENING; DRUG STRUCTURE; HUMAN; INFLAMMATION; INFLAMMATORY PAIN; LIVER INJURY; NEUROPATHIC PAIN; NONHUMAN; OSTEOARTHRITIS; PAIN; TOOTH PAIN; AGONISTS; ANIMAL; CHEMICAL STRUCTURE;

ANIMALS; HUMANS; LIGANDS; MOLECULAR STRUCTURE; RECEPTOR, CANNABINOID, CB1; RECEPTOR, CANNABINOID, CB2;

EID: 84893338885     PISSN: 09298673     EISSN: 1875533X     Source Type: Journal    
DOI: 10.2174/09298673113206660296     Document Type: Article

References (123)

1. Matsuda, L. A.; Lolait, S. J.; Brownstein, M. J.; Young, A. C.; Bonner, T. I. Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature, 1990, 346, 561-564.
2. Munro, S.; Thomas, K. L.; Abu-Shaar, M. Molecular characterization of a peripheral receptor for cannabinoids. Nature, 1993, 365, 61-65.
3. Van Sickle, M. D.; Duncan, M.; Kingsley, P. J.; Mouihate, A.; Urbani, P.; Mackie, K.; Stella, N.; Makriyannis, A.; Piomelli, D.; Davison, J. S.; Marnett, L. J.; Di Marzo, V.; Pittman, Q. J.; Patel, K. D.; Sharkey, K. A. Identification and functional characterization of brainstem cannabinoid CB2 receptors. Science, 2005, 310, 329-332.
4. Nevalainen, T.; Irving, A. J. GPR55, a lysophosphatidylinositol receptor with cannabinoid sensitivity? Curr. Top. Med. Chem., 2010, 10, 799-813.
5. Thakur, G. A.; Tichkule, R.; Bajaj, S.; Makriyannis, A. Latest advances in cannabinoid receptor agonists. Expert Opin. Ther. Pat., 2009, 19, 1647-1673.
6. Worm, K.; Dolle, R. E. Simultaneous Optimization of Potency, Selectivity and Physicochemical Properties for Cannabinoid CB2 Ligands. Curr. Pharm. Des., 2009, 15, 3345-3366.
7. Han, S.; Thatte, J.; Jones, R. M. Chapter 11 Recent Advances in the Discovery of CB2 Selective Agonists. In Annual Reports in Medicinal Chemistry; Academic Press: Vol. Volume 44, pp 227-246.
8. Leleu-Chavain, N.; Body-Malapel, M.; Spencer, J.; Chavatte, P.; Desreumaux, P.; Millet, R. Recent Advances in the Development of Selective CB2 Agonists as Promising Anti-Inflammatory Agents. Curr. Med. Chem., 2012, 19, 3457-3474.
9. Riether, D. Selective cannabinoid receptor 2 modulators: a patent review 2009 - present. Expert Opin. Ther. Pat., 2012, 22, 495-510.
10. Murineddu, G.; Asproni, B.; Pinna, G. A. A survey of recent patents on CB2 agonists in the management of pain. Recent. Pat. CNS Drug Discov., 2012, 7, 4-24.
11. Sanchez, C.; de Ceballos, M. L.; Gomez del Pulgar, T.; Rueda, D.; Corbacho, C.; Velasco, G.; Galve-Roperh, I.; Huffman, J. W.; Ramon y Cajal, S.; Guzman, M. Inhibition of glioma growth in vivo by selective activation of the CB(2) cannabinoid receptor. Cancer Res., 2001, 61, 5784-5789.
12. Hanuš, L.; Breuer, A.; Tchilibon, S.; Shiloah, S.; Goldenberg, D.; Horowitz, M.; Pertwee, R. G.; Ross, R. A.; Mechoulam, R.; Fride, E. HU-308: A specific agonist for CB2, a peripheral cannabinoid receptor. Proc. Natl. Acad. Sci. U.S.A., 1999, 96, 14228-14233.
13. Malan Jr., T. P.; 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.
14. Giblin, G. M. P.; O'Shaughnessy, C. T.; Naylor, A.; Mitchell, W. L.; Eatherton, A. J.; Slingsby, B. P.; Rawlings, D. A.; Goldsmith, P.; Brown, A. J.; Haslam, C. P.; Clayton, N. M.; Wilson, A. W.; Chessell, I. P.; Wittington, A. R.; Green, R. Discovery of 2-[(2,4- Dichlorophenyl)amino]-N-[(tetrahydro- 2H-pyran-4-yl)methyl]-4- (trifluoromethyl)- 5-pyrimidinecarboxamide, a Selective CB2 Receptor Agonist for the Treatment of Inflammatory Pain. J. Med. Chem., 2007, 50, 2597-2600.
15. Belvisi, M. G.; Patel, H. J.; Freund-Michel, V.; Hele, D. J.; Crispino, N.; Birrell, M. A. Inhibitory activity of the novel CB2 receptor agonist, GW833972A, on guinea-pig and human sensory nerve function in the airways. Br. J. Pharmacol., 2008, 155, 547-557.
16. Giblin, G. M. P.; Billinton, A.; Briggs, M.; Brown, A. J.; Chessell, I. P.; Clayton, N. M.; Eatherton, A. J.; Goldsmith, P.; Haslam, C.; Johnson, M. R.; Mitchell, W. L.; Naylor, A.; Perboni, A.; Slingsby, B. P.; Wilson, A. W. Discovery of 1-[4-(3-Chlorophenylamino)-1- methyl-1H-pyrrolo[3,2-c]pyridin-7-yl] -1-morpholin-4-ylmethanone (GSK554418A), a Brain Penetrant 5-Azaindole CB2 Agonist for the Treatment of Chronic Pain. J. Med. Chem., 2009, 52, 5785-5788.
17. Guindon, J.; Hohmann, A. G. Cannabinoid CB2 receptors: a therapeutic target for the treatment of inflammatory and neuropathic pain. Br. J. Pharmacol., 2008, 153, 319-334.
18. Benito, C.; Tolón, R. M.; Pazos, M. R.; Núñez, E.; Castillo, A. I.; Romero, J. Cannabinoid CB2 receptors in human brain inflammation. Br. J. Pharmacol., 2008, 153, 277-285.
19. Patel, K. D.; Davison, J. S.; Pittman, Q. J.; Sharkey, K. A. Cannabinoid CB(2) Receptors in Health and Disease. Curr. Med. Chem., 2010, 17, 1393-1410.
20. Bab, I.; Zimmer, A. Cannabinoid receptors and the regulation of bone mass. Br. J. Pharmacol., 2008, 153, 182-188.
21. Hermanson, D. J.; Marnett, L. J. Cannabinoids, endocannabinoids, and cancer. Cancer Metastasis Rev., 2011, 30, 599-612.
22. Murineddu, G.; Lazzari, P.; Ruiu, S.; Sanna, A.; Loriga, G.; Manca, I.; Falzoi, M.; Dessi, C.; Curzu, M. M.; Chelucci, G.; Pani, L.; Pinna, G. A. Tricyclic Pyrazoles. 4. Synthesis and Biological Evaluation of Analogues of the Robust and Selective CB2 Cannabinoid Ligand 1-(2',4'-Dichlorophenyl)-6-methyl-N- piperidin-1- yl- 1,4-dihydroindeno[1,2-c]pyrazole-3-carboxamide. J. Med. Chem., 2006, 49, 7502-7512.
23. Luongo, L.; Palazzo, E.; Tambaro, S.; Giordano, C.; Gatta, L.; Scafuro, M. A.; Rossi, F. s.; Lazzari, P.; Pani, L.; de Novellis, V.; Malcangio, M.; Maione, S. 1-(2-,4 - dichlorophenyl)-6-methyl-Ncyclohexylamine- 1,4-dihydroindeno[1,2-c]pyrazole-3-carboxamide, a novel CB2 agonist, alleviates neuropathic pain through functional microglial changes in mice. Neurobiol. Dis., 2010, 37, 177-185.
24. Zindell, R.; Riether, D.; Bosanac, T.; Berry, A.; Gemkow, M. J.; Ebneth, A.; Löbbe, S.; Raymond, E. L.; Thome, D.; Shih, D.; Thomson, D. Morpholine containing CB2 selective agonists. Bioorg. Med. Chem. Lett., 2009, 19, 1604-1609.
25. McGaraughty, S.; Chu, K. L.; Dart, M. J.; Yao, B. B.; Meyer, M. D. A CB2 receptor agonist, A-836339, modulates wide dynamic range neuronal activity in neuropathic rats: Contributions of spinal and peripheral CB2 receptors. Neuroscience, 2009, 158, 1652-1661.
26. Hsieh, G. C.; Pai, M.; Chandran, P.; Hooker, B. A.; Zhu, C. Z.; Salyers, A. K.; Wensink, E. J.; Zhan, C.; Carroll, W. A.; Dart, M. J.; Yao, B. B.; Honore, P.; Meyer, M. D. Central and peripheral sites of action for CB2 receptor mediated analgesic activity in chronic inflammatory and neuropathic pain models in rats. Br. J. Pharmacol., 2011, 162, 428-440.
27. Chu, G.; Saeui, C. T.; Worm, K.; Weaver, D. G.; Goodman, A. J.; Broadrup, R. L.; Cassel, J. A.; DeHaven, R. N.; LaBuda, C. J.; Koblish, M.; Brogdon, B.; Smith, S.; Bourdonnec, B. L.; Dolle, R. E. Novel pyridine derivatives as potent and selective CB2 cannabinoid receptor agonists. Bioorg. Med. Chem. Lett., 2009, 19, 5931-5935.
28. Huffman, J. W.; Yu, S.; Showalter, V.; Abood, M. E.; Wiley, J. L.; Compton, D. R.; Martin, B. R.; Bramblett, R. D.; Reggio, P. H. Synthesis and Pharmacology of a Very Potent Cannabinoid Lacking a Phenolic Hydroxyl with High Affinity for the CB2 Receptor. J. Med. Chem., 1996, 39, 3875-3877.
29. Elmes, S. J. R.; Jhaveri, M. D.; Smart, D.; Kendall, D. A.; Chapman, V. Cannabinoid CB2 receptor activation inhibits mechanically evoked responses of wide dynamic range dorsal horn neurons in naïve rats and in rat models of inflammatory and neuropathic pain. Eur. J. Neurosci., 2004, 20, 2311-2320.
30. Elmes, S. J. R.; Winyard, L. A.; Medhurst, S. J.; Clayton, N. M.; Wilson, A. W.; Kendall, D. A.; Chapman, V. Activation of CB1 and CB2 receptors attenuates the induction and maintenance of inflammatory pain in the rat. Pain, 2005, 118, 327-335.
31. Xu, H.; Cheng, C. L.; Chen, M.; Manivannan, A.; Cabay, L.; Pertwee, R. G.; Coutts, A.; Forrester, J. V. Anti-inflammatory property of the cannabinoid receptor-2-selective agonist JWH-133 in a rodent model of autoimmune uveoretinitis. J. Leukoc. Biol., 2007, 82, 532-541.
32. Kimball, E. S.; Schneider, C. R.; Wallace, N. H.; Hornby, P. J. Agonists of cannabinoid receptor 1 and 2 inhibit experimental colitis induced by oil of mustard and by dextran sulfate sodium. Am. J. Physiol. Gastrointest. Liver Physiol., 2006, 291, G364-G371.
33. Bátkai, S.; Osei-Hyiaman, D.; Pan, H.; El-Assal, O.; Rajesh, M.; Mukhopadhyay, P.; Hong, F.; Harvey-White, J.; Jafri, A.; Haskó, G.; Huffman, J. W.; Gao, B.; Kunos, G.; Pacher, P. Cannabinoid-2 receptor mediates protection against hepatic ischemia/reperfusion injury. FASEB J., 2007, 21, 1788-1800.
34. Brownjohn, P. W.; Ashton, J. C. Spinal cannabinoid CB2 receptors as a target for neuropathic pain: an investigation using chronic constriction injury. Neuroscience, 2012, 203, 180-193.
35. Xi, Z.; Peng, X.; Li, X.; Song, R.; Zhang, H.; Liu, Q.; Yang, H.; Bi, G.; Li, J.; Gardner, E. L. Brain cannabinoid CB2 receptors modulate cocaine's actions in mice. Nat. Neurosci., 2011, 14, 1160-1166.
36. Vidinsky, B.; Gal, P.; Pilatova, M.; Vidova, Z.; Solar, P.; Varinska, L.; Ivanova, L.; Mojzis, J. Anti-proliferative and anti-angiogenic effects of CB2R agonist (JWH-133) in non-small lung cancer cells (A549) and human umbilical vein endothelial cells: an in vitro investigation. Folia Biol. (Praha), 2012, 58, 75-80.
37. Gratzke, C.; Streng, T.; Stief, C. G.; Downs, T. R.; Alroy, I.; Rosenbaum, J. S.; Andersson, K.; Hedlund, P. Effects of Cannabinor, a Novel Selective Cannabinoid 2 Receptor Agonist, on Bladder Function in Normal Rats. Eur. Urol., 2010, 57, 1093-1100.
38. Gratzke, C.; Streng, T.; Stief, C. G.; Alroy, I.; Limberg, B. J.; Downs, T. R.; Rosenbaum, J. S.; Hedlund, P.; Andersson, K. Cannabinor, a Selective Cannabinoid-2 Receptor Agonist, Improves Bladder Emptying in Rats With Partial Urethral Obstruction. J. Urol., 2011, 185, 731-736.
39. Horváth, B.; Magid, L.; Mukhopadhyay, P.; Bátkai, S.; Rajesh, M.; Park, O.; Tanchian, G.; Gao, R. Y.; Goodfellow, C. E.; Glass, M.; Mechoulam, R.; Pacher, P. A new cannabinoid CB2 receptor agonist HU-910 attenuates oxidative stress, inflammation and cell death associated with hepatic ischaemia/reperfusion injury. Br. J. Pharmacol., 2012, 165, 2462-2478.
40. Rahn, E. J.; Thakur, G. A.; Wood, J. A. T.; Zvonok, A. M.; Makriyannis, A.; Hohmann, A. G. Pharmacological characterization of AM1710, a putative cannabinoid CB2 agonist from the cannabilactone class: Antinociception without central nervous system sideeffects. Pharmacol. Biochem. Behav., 2011, 98, 493-502.
41. Rempel, V.; Volz, N.; Hinz, S.; Karcz, T.; Melicani, I.; Nieger, M.; Wenzel, W.; Bräse, S.; Müller, C.,E. 7-Alkyl-3-benzylcoumarins: a versatile scaffold for the development of potent and selective cannabinoid receptor agonists and antagonists. J. Med. Chem., 2012, 55, 7967-7977.
42. Stern, E.; Muccioli, G. G.; Bosier, B.; Hamtiaux, L.; Millet, R.; Poupaert, J. H.; Henichart, J.; Depreux, P.; Goossens, J.; Lambert, D. M. Pharmacomodulations around the 4-Oxo-1,4- dihydroquinoline-3-carboxamides, a Class of Potent CB2-Selective Cannabinoid Receptor Ligands: Consequences in Receptor Affinity and Functionality. J. Med. Chem., 2007, 50, 5471-5484.
43. Stern, E.; Muccioli, G. G.; Millet, R.; Goossens, J.; Farce, A.; Chavatte, P.; Poupaert, J. H.; Lambert, D. M.; Depreux, P.; Henichart, J. Novel 4-Oxo-1,4-dihydroquinoline-3-carboxamide Derivatives as New CB2 Cannabinoid Receptors Agonists: Synthesis, Pharmacological Properties and Molecular Modeling. J. Med. Chem., 2006, 49, 70-79.
44. Manera, C.; Saccomanni, G.; Adinolfi, B.; Benetti, V.; Ligresti, A.; Cascio, M. G.; Tuccinardi, T.; Lucchesi, V.; Martinelli, A.; Nieri, P.; Masini, E.; Di Marzo, V.; Ferrarini, P. L. Rational design, synthesis, and pharmacological properties of new 1,8-naphthyridin- 2(1H)-on-3-carboxamide derivatives as highly selective cannabinoid- 2 receptor agonists. J. Med. Chem., 2009, 52, 3644-3651.
45. Manera, C.; Cascio, M. G.; Benetti, V.; Allarà, M.; Tuccinardi, T.; Martinelli, A.; Saccomanni, G.; Vivoli, E.; Ghelardini, C.; Di Marzo, V.; Ferrarini, P. L. New 1,8-naphthyridine and quinoline derivatives as CB2 selective agonists. Bioorg. Med. Chem. Lett., 2007, 17, 6505-6510.
46. Manera, C.; Benetti, V.; Castelli, M. P.; Cavallini, T.; Lazzarotti, S.; Pibiri, F.; Saccomanni, G.; Tuccinardi, T.; Vannacci, A.; Martinelli, A.; Ferrarini, P. L. Design, synthesis, and biological evaluation of new 1,8-naphthyridin-4(1H)-on-3-carboxamide and quinolin- 4(1H)-on-3-carboxamide derivatives as CB2 selective agonists. J. Med. Chem., 2006, 49, 5947-5957.
47. Ferrarini, P. L.; Calderone, V.; Cavallini, T.; Manera, C.; Saccomanni, G.; Pani, L.; Ruiu, S.; Gessa, G. L. Synthesis and biological evaluation of 1,8-naphthyridin-4(1H)-on-3-carboxamide derivatives as new ligands of cannabinoid receptors. Bioorg. Med. Chem., 2004, 12, 1921-1933.
48. Pasquini, S.; Botta, L.; Semeraro, T.; Mugnaini, C.; Ligresti, A.; Palazzo, E.; Maione, S.; Di Marzo, V.; Corelli, F. Investigations on the 4-Quinolone-3-carboxylic Acid Motif. 2. Synthesis and Structure-Activity Relationship of Potent and Selective Cannabinoid-2 Receptor Agonists Endowed with Analgesic Activity in Vivo. J. Med. Chem., 2008, 51, 5075-5084.
49. Cianchi, F.; Papucci, L.; Schiavone, N.; Lulli, M.; Magnelli, L.; Vinci, M. C.; Messerini, L.; Manera, C.; Ronconi, E.; Romagnani, P.; Donnini, M.; Perigli, G.; Trallori, G.; Tanganelli, E.; Capaccioli, S.; Masini, E. Cannabinoid Receptor Activation Induces Apoptosis through Tumor Necrosis Factor - Mediated Ceramide De novo Synthesis in Colon Cancer Cells. Clin. Cancer Res., 2008, 14, 7691-7700.
50. Contartese, A.; Valoti, M.; Corelli, F.; Pasquini, S.; Mugnaini, C.; Pessina, F.; Aldinucci, C.; Sgaragli, G.; Frosini, M. A novel CB2 agonist, COR167, potently protects rat brain cortical slices against OGD and reperfusion injury. Pharmacol. Res., 2012, 66, 555-563.
51. Cascio, M. G.; Bolognini, D.; Pertwee, R. G.; Palazzo, E.; Corelli, F.; Pasquini, S.; Di Marzo, V.; Maione, S. In vitro and in vivo pharmacological characterization of two novel selective cannabinoid CB2 receptor inverse agonists. Pharmacol. Res., 2010, 61, 349-354.
52. Pasquini, S.; Ligresti, A.; Mugnaini, C.; Semeraro, T.; Cicione, L.; De Rosa, M.; Guida, F.; Luongo, L.; De Chiaro, M.; Cascio, M. G.; Bolognini, D.; Marini, P.; Pertwee, R.; Maione, S.; Marzo, V. D.; Corelli, F. Investigations on the 4-Quinolone-3-carboxylic Acid Motif. 3. Synthesis, Structureâ 'Affinity Relationships, and Pharmacological Characterization of 6-Substituted 4-Quinolone-3- carboxamides as Highly Selective Cannabinoid-2 Receptor Ligands. J. Med. Chem., 2010, 53, 5915-5928.
53. El Bakali, J.; Muccioli, G. G.; Renault, N.; Pradal, D.; Body-Malapel, M.; Djouina, M.; Hamtiaux, L.; Andrzejak, V.; Desreumaux, P.; Chavatte, P.; Lambert, D. M.; Millet, R. 4-Oxo-1,4- dihydropyridines as Selective CB2 Cannabinoid Receptor Ligands: Structural Insights into the Design of a Novel Inverse Agonist Series. J. Med. Chem., 2010, 53, 7918-7931.
54. Dixon, S.; Smondyrev, A.; Knoll, E.; Rao, S.; Shaw, D.; Friesner, R. PHASE: a new engine for pharmacophore perception, 3D QSAR model development, and 3D database screening: 1. Methodology and preliminary results. J. Comput. Aided Mol. Des., 2006, 20, 647-671.
55. Brogi, S.; Corelli, F.; Di Marzo, V.; Ligresti, A.; Mugnaini, C.; Pasquini, S.; Tafi, A. Three-dimensional quantitative structure- selectivity relationships analysis guided rational design of a highly selective ligand for the cannabinoid receptor 2. Eur. J. Med. Chem., 2011, 46, 547-555.
56. Pasquini, S.; De Rosa, M.; Pedani, V.; Mugnaini, C.; Guida, F.; Luongo, L.; De Chiaro, M.; Maione, S.; Dragoni, S.; Frosini, M.; Ligresti, A.; Di Marzo, V.; Corelli, F. Investigations on the 4- Quinolone-3-carboxylic Acid Motif. 4. Identification of New Potent and Selective Ligands for the Cannabinoid Type 2 Receptor with Diverse Substitution Patterns and Antihyperalgesic Effects in Mice. J. Med. Chem., 2011, 54, 5444-5453.
57. Mugnaini, C.; Nocerino, S.; Pedani, V.; Pasquini, S.; Tafi, A.; De Chiaro, M.; Bellucci, L.; Valoti, M.; Guida, F.; Luongo, L.; Dragoni, S.; Ligresti, A.; Rosenberg, A.; Bolognini, D.; Cascio, M. G.; Pertwee, R. G.; Moaddel, R.; Maione, S.; Di Marzo, V.; Corelli, F. Investigations on the 4-Quinolone-3-Carboxylic Acid Motif Part 5: Modulation of the Physicochemical Profile of a Set of Potent and Selective Cannabinoid-2 Receptor Ligands through a Bioisosteric Approach. ChemMedChem, 2012, 7, 920-934.
58. Pasquini, S.; De Rosa, M.; Ligresti, A.; Mugnaini, C.; Brizzi, A.; Caradonna, N. P.; Cascio, M. G.; Bolognini, D.; Pertwee, R. G.; Di Marzo, V.; Corelli, F. Investigations on the 4-quinolone-3- carboxylic acid motif. 6. Synthesis and pharmacological evaluation of 7-substituted quinolone-3- carboxamide derivatives as high affinity ligands for cannabinoid receptors. Eur. J. Med. Chem., 2012, 58, 30-43.
59. Manera, C.; Saccomanni, G.; Malfitano, A. M.; Bertini, S.; Castelli, F.; Laezza, C.; Ligresti, A.; Lucchesi, V.; Tuccinardi, T.; Rizzolio, F.; Bifulco, M.; Di Marzo, V.; Giordano, A.; Macchia, M.; Martinelli, A. Rational design, synthesis and anti-proliferative properties of new CB2 selective cannabinoid receptor ligands: An investigation of the 1,8-naphthyridin-2(1H)-one scaffold. Eur. J. Med. Chem., 2012, 52, 284-294.
60. Baraldi, P. G.; Saponaro, G.; Moorman, A. R.; Romagnoli, R.; Preti, D.; Baraldi, S.; Ruggiero, E.; Varani, K.; Targa, M.; Vincenzi, F.; Borea, P. A.; Aghazadeh Tabrizi, M. 7-Oxo-[1,4] oxazino[ 2,3,4-ij]quinoline-6-carboxamides as Selective CB2 Cannabinoid Receptor Ligands: Structural Investigations around a Novel Class of Full Agonists. J. Med. Chem., 2012, 55, 6608-6623.
61. Aghazadeh Tabrizi, M.; Baraldi, P. G.; Saponaro, G.; Moorman, A. R.; Romagnoli, R.; Preti, D.; Baraldi, S.; Corciulo, C.; Vincenzi, F.; Borea, P. A.; Varani, K. Design, Synthesis, and Pharmacological Properties of New Heteroarylpyridine/Heteroarylpyrimidine Derivatives as CB2 Cannabinoid Receptor Partial Agonists. J. Med. Chem., 2013, 56, 1098-1112.
62. Huffman, J. W.; Padgett, L. W. Recent developments in the medicinal chemistry of cannabimimetic indoles, pyrroles and indenes. Curr. Med. Chem., 2005, 12, 1395-1411.
63. D'Ambra, T. E.; Estep, K. G.; Bell, M. R.; Eissenstat, M. A.; Josef, K. A.; Ward, S. J.; Haycock, D. A.; Baizman, E. R.; Casiano, F. M.; Beglin, N. C. Conformationally restrained analogues of pravadoline: nanomolar potent, enantioselective, (aminoalkyl)indole agonists of the cannabinoid receptor. J. Med. Chem., 1992, 35, 124-135.
64. Huffman, J. W.; Dai, D.; Martin, B. R.; Compton, D. R. Design, Synthesis and Pharmacology of Cannabimimetic Indoles. Bioorg. Med. Chem. Lett., 1994, 4, 563-566.
65. 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. U. S. A., 2003, 100, 10529-10533.
66. Lozano-Ondoua, A. N.; Wright, C.; Vardanyan, A.; King, T.; Largent-Milnes, T. M.; Nelson, M.; Jimenez-Andrade, J. M.; Mantyh, P. W.; Vanderah, T. W. A cannabinoid 2 receptor agonist attenuates bone cancer-induced pain and bone loss. Life Sci., 2010, 86, 646-653.
67. Wilkerson, J. L.; Gentry, K. R.; Dengler, E. C.; Wallace, J. A.; Kerwin, A. A.; Kuhn, M. N.; Zvonok, A. M.; Thakur, G. A.; Makriyannis, A.; Milligan, E. D. Immunofluorescent spectral analysis reveals the intrathecal cannabinoid agonist, AM1241, produces spinal anti-inflammatory cytokine responses in neuropathic rats exhibiting relief from allodynia. Brain Behav., 2012, 2, 155-177.
68. Paszcuk, A. F.; Dutra, R. C.; da Silva, Kathryn A. B. S.; Quintão, N. L. M.; Campos, M. M.; Calixto, J. B. Cannabinoid Agonists Inhibit Neuropathic Pain Induced by Brachial Plexus Avulsion in Mice by Affecting Glial Cells and MAP Kinases. PLoS ONE, 2011, 6, e24034.
69. Gu, X.; Mei, F.; Liu, Y.; Zhang, R.; Zhang, J.; Ma, Z. Intrathecal Administration of the Cannabinoid 2 Receptor Agonist JWH015 Can Attenuate Cancer Pain and Decrease mRNA Expression of the 2B Subunit of N-Methyl-d-Aspartic Acid. Anesth. Analg. (Hagerstown, MD, U. S. A.), 2011, 113, 405-411.
70. Valenzano, K. J.; Tafesse, L.; Lee, G.; Harrison, J. E.; Boulet, J. M.; Gottshall, S. L.; Mark, L.; Pearson, M. S.; Miller, W.; Shan, S.; Rabadi, L.; Rotshteyn, Y.; Chaffer, S. M.; Turchin, P. I.; Elsemore, D. A.; Toth, M.; Koetzner, L.; Whiteside, G. T. Pharmacological and pharmacokinetic characterization of the cannabinoid receptor 2 agonist, GW405833, utilizing rodent models of acute and chronic pain, anxiety, ataxia and catalepsy. Neuropharmacology, 2005, 48, 658-672.
71. Trotter, B. W.; Nanda, K. K.; Burgey, C. S.; Potteiger, C. M.; Deng, J. Z.; Green, A. I.; Hartnett, J. C.; Kett, N. R.; Wu, Z.; Henze, D. A.; Penna, K. D.; Desai, R.; Leitl, M. D.; Lemaire, W.; White, R. B.; Yeh, S.; Urban, M. O.; Kane, S. A.; Hartman, G. D.; Bilodeau, M. T. Imidazopyridine CB2 agonists: Optimization of CB2/CB1 selectivity and implications for in vivo analgesic efficacy. Bioorg. Med. Chem. Lett., 2011, 21, 2354-2358.
72. Yao, B. B.; Hsieh, G. C.; Frost, J. M.; Fan, Y.; Garrison, T. R.; Daza, A. V.; Grayson, G. K.; Zhu, C. Z.; Pai, M.; Chandran, P.; Salyers, A. K.; Wensink, E. J.; Honore, P.; Sullivan, J. P.; Dart, M. J.; Meyer, M. D. In vitro and in vivo characterization of A-796260: a selective cannabinoid CB2 receptor agonist exhibiting analgesic activity in rodent pain models. Br. J. Pharmacol., 2008, 153, 390-401.
73. Frost, J. M.; Dart, M. J.; Tietje, K. R.; Garrison, T. R.; Grayson, G. K.; Daza, A. V.; El-Kouhen, O.; Yao, B. B.; Hsieh, G. C.; Pai, M.; Zhu, C. Z.; Chandran, P.; Meyer, M. D. Indol-3-ylcycloalkyl Ketones: Effects of N1 Substituted Indole Side Chain Variations on CB2 Cannabinoid Receptor Activity. J. Med. Chem., 2010, 53, 295-315.
74. Diaz, P.; Xu, J.; Astruc-Diaz, F.; Pan, H.; Brown, D. L.; Naguib, M. Design and Synthesis of a Novel Series of N-Alkyl Isatin Acylhydrazone Derivatives that Act as Selective Cannabinoid Receptor 2 Agonists for the Treatment of Neuropathic Pain. J. Med. Chem., 2008, 51, 4932-4947.
75. Xu, J. J.; Diaz, P.; Astruc-Diaz, F.; Craig, S.; Munoz, E.; Naguib, M. Pharmacological Characterization of a Novel Cannabinoid Ligand, MDA19, for Treatment of Neuropathic Pain. Anesth. Analg. (Hagerstown, MD, U. S.A.), 2010, 111, 99-109.
76. Pasquini, S.; Mugnaini, C.; Ligresti, A.; Tafi, A.; Brogi, S.; Falciani, C.; Pedani, V.; Pesco, N.; Guida, F.; Luongo, L.; Varani, K.; Borea, P. A.; Maione, S.; Di Marzo, V.; Corelli, F. Design, Synthesis, and Pharmacological Characterization of Indole-3-ylacetamides, -oxoacetamides, and -carboxamides: Potent and Selective CB2 Cannabinoid Receptor Inverse Agonists. J. Med. Chem., 2012, 55, 5391-5402.
77. Odan, M.; Ishizuka, N.; Hiramatsu, Y.; Inagaki, M.; Hashizume, H.; Fujii, Y.; Mitsumori, S.; Morioka, Y.; Soga, M.; Deguchi, M.; Yasui, K.; Arimura, A. CB 1/2 dual agonists with 3-carbamoyl 2- pyridone derivatives as antipruritics: Reduction of CNS side effects by introducing polar functional groups. Bioorg. Med. Chem. Lett., 2012, 22, 2894-2897.
78. Odan, M.; Ishizuka, N.; Hiramatsu, Y.; Inagaki, M.; Hashizume, H.; Fujii, Y.; Mitsumori, S.; Morioka, Y.; Soga, M.; Deguchi, M.; Yasui, K.; Arimura, A. Discovery of S-777469: An orally available CB2 agonist as an antipruritic agent. Bioorg. Med. Chem. Lett., 2012, 22, 2803-2806.
79. Odan, M.; Ishizuka, N.; Hiramatsu, Y.; Inagaki, M.; Hashizume, H.; Fujii, Y.; Mitsumori, S.; Morioka, Y.; Soga, M.; Deguchi, M.; Yasui, K.; Arimura, A. Discovery of S-444823, a potent CB1/CB2 dual agonist as an antipruritic agent. Bioorg. Med. Chem. Lett., 2012, 22, 2898-2901.
80. Kusakabe, K.; Tada, Y.; Iso, Y.; Sakagami, M.; Morioka, Y.; Chomei, N.; Shinonome, S.; Kawamoto, K.; Takenaka, H.; Yasui, K.; Hamana, H.; Hanasaki, K. Design, synthesis, and binding mode prediction of 2-pyridone-based selective CB2 receptor agonists. Bioorg. Med. Chem., 2013, 21, 2045-2055.
81. Verbist, B. M. P.; De Cleyn, M. A. J.; Surkyn, M.; Fraiponts, E.; Aerssens, J.; Nijsen, M. J. M. A.; Gijsen, H. J. M. 5-Sulfonylbenzimidazoles as selective CB2 agonists. Bioorg. Med. Chem. Lett., 2008, 18, 2574-2579.
82. Gijsen, H. J. M.; De Cleyn, M. A. J.; Surkyn, M.; Van Lommen, G. R. E.; Verbist, B. M. P.; Nijsen, M. J. M. A.; Meert, T.; Wauwe, J. V.; Aerssens, J. 5-Sulfonyl-benzimidazoles as selective CB2 agonists- Part 2. Bioorg. Med. Chem. Lett., 2012, 22, 547-552.
83. Yu, X. H.; Cao, C. Q.; Martino, G.; Puma, C.; Morinville, A.; St-Onge, S.; Lessard, É.; Perkins, M. N.; Laird, J. M. A. A peripherally restricted cannabinoid receptor agonist produces robust antinociceptive effects in rodent models of inflammatory and neuropathic pain. Pain, 2010, 151, 337-344.
84. Watson, C.; Owen, D. R.; Harding, D.; Kon-I, K.; Lewis, M. L.; Mason, H. J.; Matsumizu, M.; Mukaiyama, T.; Rodriguez-Lens, M.; Shima, A.; Takeuchi, M.; Tran, I.; Young, T. Optimisation of a novel series of selective CNS penetrant CB2 agonists. Bioorg. Med. Chem. Lett., 2011, 21, 4284-4287.
85. Cheng, Y.; Pourashraf, M.; Luo, X.; Srivastava, S.; Walpole, C.; Salois, D.; St-Onge, S.; Payza, K.; Lessard, E.; Yu, X. H.; Tomaszewski, M. J. - Carbolines: A novel class of cannabinoid agonists with high aqueous solubility and restricted CNS penetration. Bioorg. Med. Chem. Lett., 2012, 22, 1619-1624.
86. Pagé, D.; Balaux, E.; Boisvert, L.; Liu, Z.; Milburn, C.; Tremblay, M.; Wei, Z.; Woo, S.; Luo, X.; Cheng, Y.; Yang, H.; Srivastava, S.; Zhou, F.; Brown, W.; Tomaszewski, M.; Walpole, C.; Hodzic, L.; St-Onge, S.; Godbout, C.; Salois, D.; Payza, K. Novel benzimidazole derivatives as selective CB2 agonists. Bioorg. Med. Chem. Lett., 2008, 18, 3695-3700.
87. Wei, Z.; Yang, H.; Liu, Z.; Tremblay, M.; Johnstone, S.; Béha, S.; Yue, S. Y.; Srivastava, S.; Tomaszewski, M. J.; Brown, W.; Walpole, C.; St-Onge, S.; Lessard, E.; Archambault, A.; Groblewski, T.; Pagé, D. N-Methyl-3-(tetrahydro-2H-pyran-4-yl)-2,3,4,9- tetrahydro-1H-carbazole-6- carboxamides as a novel class of cannabinoid receptors agonists with low CNS penetration. Bioorg. Med. Chem. Lett., 2012, 22, 3884-3889.
88. Yang, S.; Smotryski, J.; Matasi, J.; Ho, G.; Tulshian, D.; Greenlee, W. J.; Brusa, R.; Beltramo, M.; Cox, K. Structure-activity relationships of 2,4-diphenyl-1H-imidazole analogs as CB2 receptor agonists for the treatment of chronic pain. Bioorg. Med. Chem. Lett., 2011, 21, 182-185.
89. Gleave, R. J.; Beswick, P. J.; Brown, A. J.; Giblin, G. M. P.; Haslam, C. P.; Livermore, D.; Moses, A.; Nicholson, N. H.; Page, L. W.; Slingsby, B.; Swarbrick, M. E. 2-Amino-5-aryl-pyridines as selective CB2 agonists: Synthesis and investigation of structure- activity relationships. Bioorg. Med. Chem. Lett., 2009, 19, 6578-6581.
90. Gleave, R. J.; Beswick, P. J.; Brown, A. J.; Giblin, G. M. P.; Goldsmith, P.; Haslam, C. P.; Mitchell, W. L.; Nicholson, N. H.; Page, L. W.; Patel, S.; Roomans, S.; Slingsby, B. P.; Swarbrick, M. E. Synthesis and evaluation of 3-amino-6-aryl-pyridazines as selective CB2 agonists for the treatment of inflammatory pain. Bioorg. Med. Chem. Lett., 2010, 20, 465-468.
91. van, d. S.; Cals, J.; Broeders-Josten, S.; Cottney, J.; van, d. D.; Hermkens, M.; de Kimpe, V.; King, A.; Klomp, J.; Oosterom, J.; Pols-de Rooij, I.; de Roos, J.; van Tilborg, M.; Boyce, S.; Baker, J. Discovery and Optimization of 1-(4-(Pyridin-2- yl)benzyl)imidazolidine-2,4-dione Derivatives As a Novel Class of Selective Cannabinoid CB2 Receptor Agonists. J. Med. Chem., 2011, 54, 7350-7362.
92. Hollinshead, S. P.; Astles, P. C.; Chambers, M. G.; Johnson, M. P.; Palmer, J.; Tidwell, M. W. Discovery and optimization of novel purines as potent and selective CB2 agonists. Bioorg. Med. Chem. Lett., 2012, 22, 4962-4966.
93. Worm, K.; Zhou, Q. J.; Saeui, C. T.; Green, R. C.; Cassel, J. A.; Stabley, G. J.; DeHaven, R. N.; Conway-James, N.; LaBuda, C. J.; Koblish, M.; Little, P. J.; Dolle, R. E. Sulfamoyl benzamides as novel CB2 cannabinoid receptor ligands. Bioorg. Med. Chem. Lett., 2008, 18, 2830-2835.
94. Goodman, A. J.; Ajello, C. W.; Worm, K.; Bourdonnec, B. L.; Savolainen, M. A.; O'Hare, H.; Cassel, J. A.; Stabley, G. J.; De-Haven, R. N.; LaBuda, C. J.; Koblish, M.; Little, P. J.; Brogdon, B. L.; Smith, S. A.; Dolle, R. E. CB2 selective sulfamoyl benzamides: Optimization of the amide functionality. Bioorg. Med. Chem. Lett., 2009, 19, 309-313.
95. Sellitto, I.; Bourdonnec, B. L.; Worm, K.; Goodman, A.; Savolainen, M. A.; Chu, G.; Ajello, C. W.; Saeui, C. T.; Leister, L. K.; Cassel, J. A.; DeHaven, R. N.; LaBuda, C. J.; Koblish, M.; Little, P. J.; Brogdon, B. L.; Smith, S. A.; Dolle, R. E. Novel sulfamoyl benzamides as selective CB2 agonists with improved in vitro metabolic stability. Bioorg. Med. Chem. Lett., 2010, 20, 387-391.
96. Nelson, D. W.; Frost, J. M.; Tietje, K. R.; Florjancic, A. S.; Ryther, K.; Carroll, W. A.; Dart, M. J.; Daza, A. V.; Hooker, B. A.; Grayson, G. K.; Fan, Y.; Garrison, T. R.; El-Kouhen, O. F.; Yao, B.; Pai, M.; Chandran, P.; Zhu, C.; Hsieh, G. C.; Meyer, M. D. Synthesis and evaluation of 2-amido-3- carboxamide thiophene CB2 receptor agonists for pain management. Bioorg. Med. Chem. Lett., 2012, 22, 2604-2608.
97. Thur, Y.; Bhalerao, A.; Munshi, Z.; Pansare, N.; Mann, K.; Hanauer, G.; Kley, H.; Nappe, S.; Weiss-Haljiti, C.; Ostermann, C.; Zitt, C.; Schaefer, M.; Mondal, D.; Ali Siddiki, A.; Armugam, V.; Gudaghe, V.; Gupta, M.; Rayudu, P.; Dautzenberg, F. M.; Das Sarma, K. Structure-activity relationships of 2-arylamido-5,7- dihydro-4H-thieno[2,3-c]pyran-3-carboxamide derivatives as cannabinoid receptor agonists and their analgesic action. Bioorg. Med. Chem. Lett., 2012, 22, 7314-7321.
98. Riether, D.; Wu, L.; Cirillo, P. F.; Berry, A.; Walker, E. R.; Ermann, M.; Noya-Marino, B.; Jenkins, J. E.; Albaugh, D.; Albrecht, C.; Fisher, M.; Gemkow, M. J.; Grbic, H.; Löbbe, S.; Möller, C.; O'Shea, K.; Sauer, A.; Shih, D.; Thomson, D. S. 1,4-Diazepane compounds as potent and selective CB2 agonists: Optimization of metabolic stability. Bioorg. Med. Chem. Lett., 2011, 21, 2011-2016.
99. Zindell, R.; Walker, E. R.; Scott, J.; Amouzegh, P.; Wu, L.; Ermann, M.; Thomson, D.; Fisher, M. B.; Fullenwider, C. L.; Grbic, H.; Kaplita, P.; Linehan, B.; Patel, M.; Patel, M.; Löbbe, S.; Block, S.; Albrecht, C.; Gemkow, M. J.; Shih, D.; Riether, D. Aryl 1,4- diazepane compounds as potent and selective CB2 agonists: Optimization of drug-like properties and target independent parameters. Bioorg. Med. Chem. Lett., 2011, 21, 4276-4280.
100. Manley, P. J.; Zartman, A.; Paone, D. V.; Burgey, C. S.; Henze, D. A.; Penna, K. D.; Desai, R.; Leitl, M. D.; Lemaire, W.; White, R. B.; Yeh, S.; Urban, M. O.; Kane, S. A.; Hartman, G. D.; Bilodeau, M. T.; Trotter, B. W. Decahydroquinoline amides as highly selective CB2 agonists: Role of selectivity on in vivo efficacy in a rodent model of analgesia. Bioorg. Med. Chem. Lett., 2011, 21, 2359-2364.
101. Chianese, G.; Fattorusso, E.; Taglialatela-Scafati, O.; Bavestrello, G.; Calcinai, B.; Dien, H. A.; Ligresti, A.; Di Marzo, V. Desulfohaplosamate, a new phosphate-containing steroid from Dasychalina sp., is a selective cannabinoid CB2 receptor ligand. Steroids, 2011, 76, 998-1002.
102. Murineddu, G.; Asproni, B.; Ruiu, S.; Deligia, F.; Falzoi, M.; Pau, A.; Thomas, B. F.; Zhang, Y.; Pinna, G. A.; Pani, L.; Lazzari, P. Tricyclic Pyrazoles. Part 5. Novel 1,4-Dihydroindeno[1,2- c]pyrazole CB2 Ligands Using Molecular Hybridization Based on Scaffold Hopping. Open Med. Chem. J., 2012, 6, 1-14.
103. Reux, B.; Nevalainen, T.; Raitio, K. H.; Koskinen, A. M. P. Synthesis of quinolinyl and isoquinolinyl phenyl ketones as novel agonists for the cannabinoid CB2 receptor. Bioorg. Med. Chem., 2009, 17, 4441-4447.
104. Saari, R.; Törmä, J.; Nevalainen, T. Microwave-assisted synthesis of quinoline, isoquinoline, quinoxaline and quinazoline derivatives as CB2 receptor agonists. Bioorg. Med. Chem., 2011, 19, 939-950.
105. Yrjölä, S.; Kalliokoski, T.; Laitinen, T.; Poso, A.; Parkkari, T.; Nevalainen, T. Discovery of novel cannabinoid receptor ligands by a virtual screening approach: Further development of 2,4,6- trisubstituted 1,3,5-triazines as CB2 agonists. Eur. J. Pharm. Sci., 2013, 48, 9-20.
106. Yang, P.; Myint, K.; Tong, Q.; Feng, R.; Cao, H.; Almehizia, A. A.; Alqarni, M. H.; Wang, L.; Bartlow, P.; Gao, Y.; Gertsch, J.; Teramachi, J.; Kurihara, N.; Roodman, G. D.; Cheng, T.; Xie, X. Lead Discovery, Chemistry Optimization, and Biological Evaluation Studies of Novel Biamide Derivatives as CB2 Receptor Inverse Agonists and Osteoclast Inhibitors. J. Med. Chem., 2012, 55, 9973-9987.
107. Nettekoven, M.; Fingerle, J.; Grether, U.; Grüner, S.; Kimbara, A.; Püllmann, B.; Rogers-Evans, M.; Röver, S.; Schuler, F.; Schulz-Gasch, T.; Ullmer, C. Highly potent and selective cannabinoid receptor 2 agonists: Initial hit optimization of an adamantyl hit series identified from high-through-put screening. Bioorg. Med. Chem. Lett., 2013, 23, 1177-1181.
108. Pharmos. Pharmos Corporation Reports 2007 First Quarter Results. http://investors.pharmoscorp.com/releasedetail.cfm?ReleaseID=24 2146 (accessed March 4, 2013).
109. Pharmos. Pharmos Announces Clinical Data from Phase 2a Trial of Cannabinor for Nociceptive Pain in Third Molar Dental Extraction Model. http://investors.pharmoscorp.com/releasedetail.cfm? ReleaseID= 239149 (accessed March 4, 2013).
110. EvaluatePharma. Pharmos Announces Clinical Data from Phase 2a Trial of Cannabinor for Capsaicin-induced Painhttp://www.evaluate pharma.com/Universal/ View.aspx?type=Story&id=126649 (accessed March 4, 2013).
111. ClinicalTrials. Dental Pain 3rd Molar Tooth Extraction GW842166. http://clinicaltrials.gov/ct2/show/NCT00444769 (accessed March 4, 2013).
112. Ostenfeld, T. F.; Price, J. F.; Albanese, M. F.; Bullman, J. F.; Guillard, F. F.; Meyer, I. F.; Leeson, R. F.; Costantin, C. F.; Ziviani, L. F.; FAU, N. P.; Milleri, S. A randomized, controlled study to investigate the analgesic efficacy of single doses of the cannabinoid receptor- 2 agonist GW842166, ibuprofen or placebo in patients with acute pain following third molar tooth extraction. Clin. J. Pain, 2011, 27, 668-676.
113. Muthuppalaniappan, M.; Balasubramanian, G.; Gullapalli, S.; Joshi, N. K.; Narayanan, S. Carboxamide derivatives as novel cannabinoid receptor ligands, pharmaceutical compositions containing them, and process for their preparation. WO2006129178A1, 2006.
114. EvaluatePharma. Glenmark's Molecule for Neuropathic Pain, Osteoarthritis - GRC 10693, Successfully Completes Phase I Trials. http://www.evaluatepharma. com/Universal/View.aspx?type=Story &id=183092 (accessed March 4, 2013).
115. Media.corporate-ir.net. Advancing Abbott s Long-term Strategy http://media.corporate-ir.net/media-files/irol/94/94004/presentations/ Abbott-Investor-Day-2011r.pdf (accessed March 4, 2013).
116. Kyowa Hakko Kirin Co., Ltd. Annual Reports 2011, Development summary. http://www.kyowa-kirin.com/investors/annual-report/ pdf/annual2011e-07.pdf (accessed March 4, 2013).
117. ClinicalTrials. A Study of LY2828360 in Patients With Osteoarthritic Knee Pain. http://clinicaltrials.gov/ct2/show/ NCT0131 9929 (accessed March 4, 2013).
118. Mauler, F.; Horváth, E.; De Vry, J.; Jäger, R.; Schwarz, T.; Sandmann, S.; Weinz, C.; Heinig, R.; Böttcher, M. BAY 38-7271: A Novel Highly Selective and Highly Potent Cannabinoid Receptor Agonist for the Treatment of Traumatic Brain Injury. CNS Drug Rev., 2003, 9, 343-358.
119. Drugs.com. KeyNeurotek Pharmaceuticals Reports Positive Phase I Data of Its Cannabinoid Receptor-Agonist. http://www.drugs.com/ clinical-trials/ keyneurotek-pharmaceuticals-reports-positivephase- data-cannabinoid-receptor- agonist-4212.html (accessed March 4, 2013).
120. Drugs.com. KeyNeurotek Pharmaceuticals Reports Positive Phase I Data of Its Cannabinoid Receptor-Agonist. http://www.drugs.com/ clinical-trials/ keyneurotek-pharmaceuticals-reports-positivephase- data-cannabinoid-receptor- agonist-4212.html (accessed March 4, 2013).
121. Firsching, R.; Piek, J.; Skalej, M.; Rohde, V.; Schmidt, U.; Striggow, F.; the KN38-7271, S. G. Early Survival of Comatose Patients after Severe Traumatic Brain Injury with the Dual Cannabinoid CB1/CB2 Receptor Agonist KN38-7271: A Randomized, Double-Blind, Placebo-Controlled Phase II Trial. J. Neurol. Surg. A. Cent. Eur. Neurosurg., 2012, 73, 204-216.
122. ClinicalTrials. A Randomized, Double-Blind Study to Evaluate the Safety and Efficacy of 2 Doses of S-777469 in Patients With Atopic Dermatitis. http://clinicaltrials.gov/show/NCT00703573 (accessed March 4, 2013).
123. Mugnaini, C.; Pasquini, S.; Corelli, F. The bioisosteric concept applied to cannabinoid ligands. Curr. Med. Chem., 2012, 19(28), 4794-4815.