Innovative Therapeutic Potential of Cannabinoid Receptors as  Targets in Alzheimer’s Disease and Less Well-Known Diseases

Juan    A.    Páez; Nuria    E.    Campillo
doi:10.2174/0929867325666180226095132
Abstract

The discovery of cannabinoid receptors at the beginning of the 1990s, CB1 cloned in 1990 and CB2 cloned in 1993, and the availability of selective and potent cannabimimetics could only be justified by the existence of endogenous ligands that are capable of binding to them. Thus, the characterisation and cloning of the first cannabinoid receptor (CB1) led to the isolation and characterisation of the first endocannabinoid, arachidonoylethanolamide (AEA), two years later and the subsequent identification of a family of lipid transmitters known as the fatty acid ester 2-arachidonoylglycerol (2-AG).
The endogenous cannabinoid system is a complex signalling system that comprises transmembrane endocannabinoid receptors, their endogenous ligands (the endocannabinoids), the specific uptake mechanisms and the enzymatic systems related to their biosynthesis and degradation.
The endocannabinoid system has been implicated in a wide diversity of biological processes, in both the central and peripheral nervous systems, including memory, learning, neuronal development, stress and emotions, food intake, energy regulation, peripheral metabolism, and the regulation of hormonal balance through the endocrine system.
In this context, this article will review the current knowledge of the therapeutic potential of cannabinoid receptor as a target in Alzheimer’s disease and other less well-known diseases that include, among others, multiple sclerosis, bone metabolism, and Fragile X syndrome.
The therapeutic applications will be addressed through the study of cannabinoid agonists acting as single drugs and multi-target drugs highlighting the CB2 receptor agonist.
Keywords: Alzheimer's disease, CB2 agonist, endocannabinoid system (eCS), bone disorders, autism disorders, cardiovascular diseases.
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[1] 
Li, H.L. The origin and use of Cannabis in eastern Asia linguistic-cultural implications. Econ. Bot.,  1974, (28), 293-301.
[http://dx.doi.org/10.1007/BF02861426] 
[2] 
Li, H.L.; Lin, H. An archaeological and historical account of Cannabis in China. Econ. Bot.,  1974, 28(4), 437-448.
[3] 
Touw, M. The religious and medicinal uses of Cannabis in China, India and Tibet. J. Psychoactive Drugs,  1981, 13(1), 23-34.
[http://dx.doi.org/10.1080/02791072.1981.10471447] [PMID:  7024492] 
[4] 
Jiang, H.E.; Li, X.; Zhao, Y.X.; Ferguson, D.K.; Hueber, F.; Bera, S.; Wang, Y.F.; Zhao, L.C.; Liu, C.J.; Li, C.S. A new insight into Cannabis sativa (Cannabaceae) utilization from 2500-year-old Yanghai Tombs, Xinjiang, China. J. Ethnopharmacol.,  2006, 108(3), 414-422.
[http://dx.doi.org/10.1016/j.jep.2006.05.034] [PMID:  16879937] 
[5] 
Lozano, I. The therapeutic use of cannabis sativa (L.) in arabic medicine. J. Cannabis Ther.,  2001, 1, 63-70.
[http://dx.doi.org/10.1300/J175v01n01_05] 
[6] 
Russo, E.B. History of cannabis and its preparations in saga, science, and sobriquet. Chem. Biodivers.,  2007, 4(8), 1614-1648.
[http://dx.doi.org/10.1002/cbdv.200790144] [PMID:  17712811] 
[7] 
Fasinu, P.S.; Phillips, S.; ElSohly, M.A.; Walker, L.A. Current status and prospects for cannabidiol preparations as new therapeutic agents. Pharmacotherapy,  2016, 36(7), 781-796.
[http://dx.doi.org/10.1002/phar.1780] [PMID:  27285147] 
[8] 
O’Shaughnessy, W.B. The Bengal Dispensatory and Pharmacopoeia. The Bengal Dispensatory and Pharmacopoeia; Bishop's College Press, 1841. 
[9] 
Mechoulam, R.; Shvo, Y.; Hashish, I. The structure of cannabidiol. Tetrahedron,  1963, 19(12), 2073-2078.
[http://dx.doi.org/10.1016/0040-4020(63)85022-X] [PMID:  5879214] 
[10] 
Gaoni, Y.; Mechoulam, R. The isolation and structure of A′-tetrahydrocannabinol and other neutral cannabinoids from hashish J. Am. Chem. Soc.,  1964, 86, 1646-1647.
[http://dx.doi.org/10.1021/ja01062a046] 
[11] 
Mechoulam, R.; Hanuš, L.O.; Pertwee, R.; Howlett, A.C. Early phytocannabinoid chemistry to endocannabinoids and beyond. Nat. Rev. Neurosci.,  2014, 15(11), 757-764.
[http://dx.doi.org/10.1038/nrn3811] [PMID:  25315390] 
[12] 
Devane, W.A.; Dysarz, F.A., III; Johnson, M.R.; Melvin, L.S.; Howlett, A.C. Determination and characterization of a cannabinoid receptor in rat brain. Mol. Pharmacol.,  1988, 34(5), 605-613.
[PMID:  2848184] 
[13] 
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(5), 1932-1936.
[http://dx.doi.org/10.1073/pnas.87.5.1932] [PMID:  2308954] 
[14] 
Howlett, A.C. Inhibition of neuroblastoma adenylate cyclase by cannabinoid and nantradol compounds. Life Sci.,  1984, 35(17), 1803-1810.
[http://dx.doi.org/10.1016/0024-3205(84)90278-9] [PMID:  6090851] 
[15] 
Howlett, A.C.; Fleming, R.M. Cannabinoid inhibition of adenylate cyclase. Pharmacology of the response in neuroblastoma cell membranes. Mol. Pharmacol.,  1984, 26(3), 532-538.
[PMID:  6092901] 
[16] 
Howlett, A.C. Cannabinoid inhibition of adenylate cyclase. Biochemistry of the response in neuroblastoma cell membranes. Mol. Pharmacol.,  1985, 27(4), 429-436.
[PMID:  2984538] 
[17] 
Howlett, A.C.; Qualy, J.M.; Khachatrian, L.L. Involvement of Gi in the inhibition of adenylate cyclase by cannabimimetic drugs. Mol. Pharmacol.,  1986, 29(3), 307-313.
[PMID:  2869405] 
[18] 
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(6284), 561-564.
[http://dx.doi.org/10.1038/346561a0] [PMID:  2165569] 
[19] 
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(5090), 1946-1949.
[http://dx.doi.org/10.1126/science.1470919] [PMID:  1470919] 
[20] 
Munro, S.; Thomas, K.L.; Abu-Shaar, M. Molecular characterization of a peripheral receptor for cannabinoids. Nature,  1993, 365(6441), 61-65.
[http://dx.doi.org/10.1038/365061a0] [PMID:  7689702] 
[21] 
Di Marzo, V.; Fontana, A. Anandamide, an endogenous cannabinomimetic eicosanoid: ‘killing two birds with one stone’. Prostaglandins Leukot. Essent. Fatty Acids,  1995, 53(1), 1-11.
[http://dx.doi.org/10.1016/0952-3278(95)90077-2] [PMID:  7675818] 
[22] 
Maccarrone, M.; Bab, I.; Bíró, T.; Cabral, G.A.; Dey, S.K.; Di Marzo, V.; Konje, J.C.; Kunos, G.; Mechoulam, R.; Pacher, P.; Sharkey, K.A.; Zimmer, A. Endocannabinoid signaling at the periphery: 50 years after THC. Trends Pharmacol. Sci.,  2015, 36(5), 277-296.
[http://dx.doi.org/10.1016/j.tips.2015.02.008] [PMID:  25796370] 
[23] 
Aizpurua-Olaizola, O.; Elezgarai, I.; Rico-Barrio, I.; Zarandona, I.; Etxebarria, N.; Usobiaga, A. Targeting the endocannabinoid system: future therapeutic strategies. Drug Discov. Today,  2017, 22(1), 105-110.
[http://dx.doi.org/10.1016/j.drudis.2016.08.005] [PMID:  27554802] 
[24] 
Gonzalez, A.; Duran, L.S.; Araya-Secchi, R.; Garate, J.A.; Pessoa-Mahana, C.D.; Lagos, C.F.; Perez-Acle, T. Computational modeling study of functional microdomains in cannabinoid receptor type 1. Bioorg. Med. Chem.,  2008, 16(8), 4378-4389.
[http://dx.doi.org/10.1016/j.bmc.2008.02.070] [PMID:  18342519] 
[25] 
McPartland, J.; Di Marzo, V.; De Petrocellis, L.; Mercer, A.; Glass, M. Cannabinoid receptors are absent in insects. J. Comp. Neurol.,  2001, 436(4), 423-429.
[http://dx.doi.org/10.1002/cne.1078] [PMID:  11447587] 
[26] 
Campillo, N.E.; Páez, J.A. Cannabinoid system in neurodegeneration: New perspectives in Alzheimer’s disease. Mini Rev. Med. Chem.,  2009, 9(5), 539-559.
[http://dx.doi.org/10.2174/138955709788167628] [PMID:  19456285] 
[27] 
Svízenská, I.; Dubový, P.; Sulcová, A. Cannabinoid receptors 1 and 2 (CB1 and CB2), their distribution, ligands and functional involvement in nervous system structures--a short review. Pharmacol. Biochem. Behav.,  2008, 90(4), 501-511.
[http://dx.doi.org/10.1016/j.pbb.2008.05.010] [PMID:  18584858] 
[28] 
Herkenham, M.; Groen, B.G.; Lynn, A.B.; De Costa, B.R.; Richfield, E.K. Neuronal localization of cannabinoid receptors and second messengers in mutant mouse cerebellum. Brain Res.,  1991, 552(2), 301-310.
[http://dx.doi.org/10.1016/0006-8993(91)90096-E] [PMID:  1913192] 
[29] 
Pertwee, R.G. Cannabinoid receptors and pain. Prog. Neurobiol.,  2001, 63(5), 569-611.
[http://dx.doi.org/10.1016/S0301-0082(00)00031-9] [PMID:  11164622] 
[30] 
Szabo, B.; Nordheim, U.; Niederhoffer, N. Effects of cannabinoids on sympathetic and parasympathetic neuroeffector transmission in the rabbit heart. J. Pharmacol. Exp. Ther.,  2001, 297(2), 819-826.
[PMID:  11303075] 
[31] 
Wagner, J.A.; Járai, Z.; Bátkai, S.; Kunos, G. Hemodynamic effects of cannabinoids: Coronary and cerebral vasodilation mediated by cannabinoid CB(1) receptors. Eur. J. Pharmacol.,  2001, 423(2-3), 203-210.
[http://dx.doi.org/10.1016/S0014-2999(01)01112-8] [PMID:  11448486] 
[32] 
Pertwee, R.G. Pharmacology of cannabinoid CB1 and CB2 receptors. Pharmacol. Ther.,  1997, 74(2), 129-180.
[http://dx.doi.org/10.1016/S0163-7258(97)82001-3] [PMID:  9336020] 
[33] 
Croci, T.; Manara, L.; Aureggi, G.; Guagnini, F.; Rinaldi-Carmona, M.; Maffrand, J.P.; Le Fur, G.; Mukenge, S.; Ferla, G. In vitro functional evidence of neuronal cannabinoid CB1 receptors in human ileum. Br. J. Pharmacol.,  1998, 125(7), 1393-1395.
[http://dx.doi.org/10.1038/sj.bjp.0702190] [PMID:  9884065] 
[34] 
Spoto, B.; Fezza, F.; Parlongo, G.; Battista, N.; Sgro’, E.; Gasperi, V.; Zoccali, C.; Maccarrone, M. Human adipose tissue binds and metabolizes the endocannabinoids anandamide and 2-arachidonoylglycerol. Biochimie,  2006, 88(12), 1889-1897.
[http://dx.doi.org/10.1016/j.biochi.2006.07.019] [PMID:  16949718] 
[35] 
Silvestri, C.; Di Marzo, V. The endocannabinoid system in energy homeostasis and the etiopathology of metabolic disorders. Cell Metab.,  2013, 17(4), 475-490.
[http://dx.doi.org/10.1016/j.cmet.2013.03.001] [PMID:  23562074] 
[36] 
Centonze, D.; Battistini, L.; Maccarrone, M. The endocannabinoid system in peripheral lymphocytes as a mirror of neuroinflammatory diseases. Curr. Pharm. Des.,  2008, 14(23), 2370-42.
[http://dx.doi.org/10.2174/138161208785740018] [PMID:  18781987] 
[37] 
Ashton, J.C.; Glass, M. The cannabinoid CB2 receptor as a target for inflammation-dependent neurodegeneration. Curr. Neuropharmacol.,  2007, 5(2), 73-80.
[http://dx.doi.org/10.2174/157015907780866884] [PMID:  18615177] 
[38] 
Miller, A.M.; Stella, N. CB2 receptor-mediated migration of immune cells: It can go either way. Br. J. Pharmacol.,  2008, 153(2), 299-308.
[http://dx.doi.org/10.1038/sj.bjp.0707523] [PMID:  17982478] 
[39] 
Basu, S.; Dittel, B.N. Unraveling the complexities of cannabinoid receptor 2 (CB2) immune regulation in health and disease. Immunol. Res.,  2011, 51(1), 26-38.
[http://dx.doi.org/10.1007/s12026-011-8210-5] [PMID:  21626285] 
[40] 
Cabral, G.A.; Griffin-Thomas, L. Emerging role of the cannabinoid receptor CB2 in immune regulation: therapeutic prospects for neuroinflammation.  Expert Rev. Mol. Med,  2009, 11e3.
[http://dx.doi.org/10.1017/S1462399409000957] [PMID: 19152719] 
[41] 
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(5746), 329-332.
[http://dx.doi.org/10.1126/science.1115740] [PMID:  16224028] 
[42] 
Fernández-Ruiz, J.; Romero, J.; Velasco, G.; Tolón, R.M.; Ramos, J.A.; Guzmán, M. Cannabinoid CB2 receptor: a new target for controlling neural cell survival? Trends Pharmacol. Sci.,  2007, 28(1), 39-45.
[http://dx.doi.org/10.1016/j.tips.2006.11.001] [PMID:  17141334] 
[43] 
Callén, L.; Moreno, E.; Barroso-Chinea, P.; Moreno-Delgado, D.; Cortés, A.; Mallol, J.; Casadó, V.; Lanciego, J.L.; Franco, R.; Lluis, C.; Canela, E.I.; McCormick, P.J. Cannabinoid receptors CB1 and CB2 form functional heteromers in brain. J. Biol. Chem.,  2012, 287(25), 20851-20865.
[http://dx.doi.org/10.1074/jbc.M111.335273] [PMID:  22532560] 
[44] 
Khurana, L.; Mackie, K.; Piomelli, D.; Kendall, D.A. Modulation of CB1 cannabinoid receptor by allosteric ligands: Pharmacology and therapeutic opportunities. Neuropharmacology,  2017, 124, 3-12.
[http://dx.doi.org/10.1016/j.neuropharm.2017.05.018] [PMID:  28527758] 
[45] 
Viñals, X.; Moreno, E.; Lanfumey, L.; Cordomí, A.; Pastor, A.; de La Torre, R.; Gasperini, P.; Navarro, G.; Howell, L.A.; Pardo, L.; Lluís, C.; Canela, E.I.; McCormick, P.J.; Maldonado, R.; Robledo, P. Cognitive impairment induced by delta9-tetrahydrocannabinol occurs through heteromers between cannabinoid CB1 and serotonin 5-HT2A receptors. PLoS Biol.,  2015, 13(7), e1002194.
[http://dx.doi.org/10.1371/journal.pbio.1002194] [PMID:  26158621] 
[46] 
Moreno, E.; Chiarlone, A.; Medrano, M.; Puigdellivol, M.; Bibic, L.; Howell, L.A.; Resel, E.; Puente, N.; Casarejos, M.J.; Perucho, J.; Botta, J.; Suelves, N.; Ciruela, F.; Gines, S.; Galve-Roperh, I.; Casado, V.; Grandes, P.; Lutz, B.; Monory, K.; Canela, E.I.; Lluis, C.; McCormick, P.J.; Guzman, M. Singular location and signaling profile of adenosine A2A-cannabinoid CB1 receptor heteromers in the dorsal striatum. Neuropsychopharmacology,  2018, 43(5), 964-977.
[47] 
Ross, R.A. The enigmatic pharmacology of GPR55. Trends Pharmacol. Sci.,  2009, 30(3), 156-163.
[http://dx.doi.org/10.1016/j.tips.2008.12.004] [PMID:  19233486] 
[48] 
Pertwee, R.G. Receptors and channels targeted by synthetic cannabinoid receptor agonists and antagonists. Curr. Med. Chem.,  2010, 17(14), 1360-1381.
[http://dx.doi.org/10.2174/092986710790980050] [PMID:  20166927] 
[49] 
Ibsen, M.S.; Connor, M.; Glass, M. Cannabinoid CB1 and CB2 receptor signaling and bias. Cannabis Cannabinoid Res.,  2017, 2(1), 48-60.
[http://dx.doi.org/10.1089/can.2016.0037] [PMID:  28861504] 
[50] 
Pistis, M.; Melis, M. From surface to nuclear receptors: The endocannabinoid family extends its assets. Curr. Med. Chem.,  2010, 17(14), 1450-1467.
[http://dx.doi.org/10.2174/092986710790980014] [PMID:  20166922] 
[51] 
O’Sullivan, S.E. An update on PPAR activation by cannabinoids. Br. J. Pharmacol.,  2016, 173(12), 1899-1910.
[http://dx.doi.org/10.1111/bph.13497] [PMID:  27077495] 
[52] 
Alexander, S.P.; Kendall, D.A. The complications of promiscuity: endocannabinoid action and metabolism. Br. J. Pharmacol.,  2007, 152(5), 602-623.
[http://dx.doi.org/10.1038/sj.bjp.0707456] [PMID:  17876303] 
[53] 
Di Marzo, V.; De Petrocellis, L. Endocannabinoids as regulators of transient receptor potential (TRP) channels: A further opportunity to develop new endocannabinoid-based therapeutic drugs. Curr. Med. Chem.,  2010, 17(14), 1430-1449.
[http://dx.doi.org/10.2174/092986710790980078] [PMID:  20166923] 
[54] 
(a)Greenshaw, A.J. Behavioural pharmacology of 5-HT3 receptor antagonists: A critical update on therapeutic potential. Trends Pharmacol. Sci.,  1993, 14(7), 265-270.
[http://dx.doi.org/10.1016/0165-6147(93)90128-7] [PMID: PMID: 8105596] 
bPertwee, R.G. Endocannabinoids and their pharmacological actions. Handb. Exp. Pharmacol.,  2015, 231, 1-37.
[http://dx.doi.org/10.1007/978-3-319-20825-1_1] [PMID: PMID: 26408156] 
cRodríguez-Muñoz, M.; Sánchez-Blázquez, P.; Merlos, M.; Garzón-Niño, J. Endocannabinoid control of glutamate NMDA receptors: The therapeutic potential and consequences of dysfunction. Oncotarget,  2016, 7(34), 55840-55862.
[http://dx.doi.org/10.18632/oncotarget.10095] [PMID:  27323834] 
[55] 
Solinas, M.; Goldberg, S.R.; Piomelli, D. The endocannabinoid system in brain reward processes. Br. J. Pharmacol.,  2008, 154(2), 369-383.
[http://dx.doi.org/10.1038/bjp.2008.130] [PMID:  18414385] 
[56] 
Chiu, C.Q.; Puente, N.; Grandes, P.; Castillo, P.E. Dopaminergic modulation of endocannabinoid-mediated plasticity at GABAergic synapses in the prefrontal cortex. J. Neurosci.,  2010, 30(21), 7236-7248.
[http://dx.doi.org/10.1523/JNEUROSCI.0736-10.2010] [PMID:  20505090] 
[57] 
Franklin, J.M.; Carrasco, G.A. Cannabinoid receptor agonists upregulate and enhance serotonin 2A (5-HT(2A)) receptor activity via ERK1/2 signaling. Synapse,  2013, 67(3), 145-159.
[http://dx.doi.org/10.1002/syn.21626] [PMID:  23151877] 
[58] 
Nasehi, M.; Farrahizadeh, M.; Ebrahimi-Ghiri, M.; Zarrindast, M.R. Modulation of cannabinoid signaling by hippocampal 5-HT4 serotonergic system in fear conditioning. J. Psychopharmacol. (Oxford),  2016, 30(9), 936-944.
[http://dx.doi.org/10.1177/0269881116652584] [PMID:  27296273] 
[59] 
Hu, B.; Bai, F.; Xiong, L.; Wang, Q. The endocannabinoid system, a novel and key participant in acupuncture’s multiple beneficial effects. Neurosci. Biobehav. Rev.,  2017, 77, 340-357.
[http://dx.doi.org/10.1016/j.neubiorev.2017.04.006] [PMID:  28412017] 
[60] 
Glass, M.; Northup, J.K. Agonist selective regulation of G proteins by cannabinoid CB(1) and CB(2) receptors. Mol. Pharmacol.,  1999, 56(6), 1362-1369.
[http://dx.doi.org/10.1124/mol.56.6.1362] [PMID:  10570066] 
[61] 
Felder, C.C.; Joyce, K.E.; Briley, E.M.; Mansouri, J.; Mackie, K.; Blond, O.; Lai, Y.; Ma, A.L.; Mitchell, R.L. Comparison of the pharmacology and signal transduction of the human cannabinoid CB1 and CB2 receptors. Mol. Pharmacol.,  1995, 48(3), 443-450.
[PMID:  7565624] 
[62] 
Mechoulam, R.; Ben-Shabat, S.; Hanus, L.; Ligumsky, M.; Kaminski, N.E.; Schatz, A.R.; Gopher, A.; Almog, S.; Martin, B.R.; Compton, D.R. Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors. Biochem. Pharmacol.,  1995, 50(1), 83-90.
[http://dx.doi.org/10.1016/0006-2952(95)00109-D] [PMID:  7605349] 
[63] 
Sugiura, T.; Kondo, S.; Sukagawa, A.; Nakane, S.; Shinoda, A.; Itoh, K.; Yamashita, A.; Waku, K. 2-Arachidonoylglycerol: A possible endogenous cannabinoid receptor ligand in brain. Biochem. Biophys. Res. Commun.,  1995, 215(1), 89-97.
[http://dx.doi.org/10.1006/bbrc.1995.2437] [PMID:  7575630] 
[64] 
Sugiura, T.; Waku, K. 2-Arachidonoylglycerol and the cannabinoid receptors. Chem. Phys. Lipids,  2000, 108(1-2), 89-106.
[http://dx.doi.org/10.1016/S0009-3084(00)00189-4] [PMID:  11106784] 
[65] 
Childers, S.R.; Breivogel, C.S. Cannabis and endogenous cannabinoid systems. Drug Alcohol Depend.,  1998, 51(1-2), 173-187.
[http://dx.doi.org/10.1016/S0376-8716(98)00075-1] [PMID:  9716939] 
[66] 
Hanus, L.; Abu-Lafi, S.; Fride, E.; Breuer, A.; Vogel, Z.; Shalev, D.E.; Kustanovich, I.; Mechoulam, R. 2-arachidonyl glyceryl ether, an endogenous agonist of the cannabinoid CB1 receptor. Proc. Natl. Acad. Sci. USA,  2001, 98(7), 3662-3665.
[http://dx.doi.org/10.1073/pnas.061029898] [PMID:  11259648] 
[67] 
Porter, A.C.; Sauer, J.M.; Knierman, M.D.; Becker, G.W.; Berna, M.J.; Bao, J.; Nomikos, G.G.; Carter, P.; Bymaster, F.P.; Leese, A.B.; Felder, C.C. Characterization of a novel endocannabinoid, virodhamine, with antagonist activity at the CB1 receptor. J. Pharmacol. Exp. Ther.,  2002, 301(3), 1020-1024.
[http://dx.doi.org/10.1124/jpet.301.3.1020] [PMID:  12023533] 
[68] 
Grigorenko, E.; Kittler, J.; Clayton, C.; Wallace, D.; Zhuang, S.; Bridges, D.; Bundey, S.; Boon, A.; Pagget, C.; Hayashizaki, S.; Lowe, G.; Hampson, R.; Deadwyler, S. Assessment of cannabinoid induced gene changes: tolerance and neuroprotection. Chem. Phys. Lipids,  2002, 121(1-2), 257-266.
[http://dx.doi.org/10.1016/S0009-3084(02)00161-5] [PMID:  12505705] 
[69] 
Hillard, C.J.; Jarrahian, A. The movement of N-arachidonoylethanolamine (anandamide) across cellular membranes. Chem. Phys. Lipids,  2000, 108(1-2), 123-134.
[http://dx.doi.org/10.1016/S0009-3084(00)00191-2] [PMID:  11106786] 
[70] 
Maccarrone, M.; Dainese, E.; Oddi, S. Intracellular trafficking of anandamide: new concepts for signaling. Trends Biochem. Sci.,  2010, 35(11), 601-608.
[http://dx.doi.org/10.1016/j.tibs.2010.05.008] [PMID:  20570522] 
[71] 
Hillard, C.J. Biochemistry and pharmacology of the endocannabinoids arachidonylethanolamide and 2-arachidonylglycerol. Prostaglandins Other Lipid Mediat.,  2000, 61(1-2), 3-18.
[http://dx.doi.org/10.1016/S0090-6980(00)00051-4] [PMID:  10785538] 
[72] 
Vandevoorde, S. Overview of the chemical families of fatty acid amide hydrolase and monoacylglycerol lipase inhibitors. Curr. Top. Med. Chem.,  2008, 8(3), 247-267.
[http://dx.doi.org/10.2174/156802608783498005] [PMID:  18289091] 
[73] 
Di Marzo, V. Endocannabinoids: synthesis and degradation. Rev. Physiol. Biochem. Pharmacol.,  2008, 160, 1-24.
[PMID:  18481028] 
[74] 
Bari, M.; Battista, N.; Fezza, F.; Gasperi, V.; Maccarrone, M. New insights into endocannabinoid degradation and its therapeutic potential. Mini Rev. Med. Chem.,  2006, 6(3), 257-268.
[http://dx.doi.org/10.2174/138955706776073466] [PMID:  16515464] 
[75] 
Maccarrone, M. Fatty acid amide hydrolase: a potential target for next generation therapeutics. Curr. Pharm. Des.,  2006, 12(6), 759-772.
[http://dx.doi.org/10.2174/138161206775474279] [PMID:  16472164] 
[76] 
Makriyannis, A. 2012 Division of medicinal chemistry award address. Trekking the cannabinoid road: a personal perspective. J. Med. Chem.,  2014, 57(10), 3891-3911.
[http://dx.doi.org/10.1021/jm500220s] [PMID:  24707904] 
[77] 
Aghazadeh Tabrizi, M.; Baraldi, P.G.; Borea, P.A.; Varani, K. Medicinal chemistry, pharmacology, and potential therapeutic benefits of cannabinoid CB2 receptor agonists. Chem. Rev.,  2016, 116(2), 519-560.
[http://dx.doi.org/10.1021/acs.chemrev.5b00411] [PMID:  26741146] 
[78] 
Nimczick, M.; Decker, M. New approaches in the design and development of cannabinoid receptor ligands: Multifunctional and bivalent compounds. ChemMedChem,  2015, 10(5), 773-786.
[http://dx.doi.org/10.1002/cmdc.201500041] [PMID:  25820617] 
[79] 
Spinelli, F.; Capparelli, E.; Abate, C.; Colabufo, N.A.; Contino, M. Perspectives of Cannabinoid Type 2 Receptor (CB2R) ligands in neurodegenerative disorders: Structure-Affinity Relationship (SAfiR) and Structure-Activity Relationship (SAR) studies. J. Med. Chem.,  2017, 60(24), 9913-9931.
[http://dx.doi.org/10.1021/acs.jmedchem.7b00155] [PMID:  28608697] 
[80] 
ElSohly, M.A.; Radwan, M.M.; Gul, W.; Chandra, S.; Galal, A. Phytochemistry of Cannabis sativa L. Prog. Chem. Org. Nat. Prod.,  2017, 103, 1-36.
[http://dx.doi.org/10.1007/978-3-319-45541-9_1] [PMID:  28120229] 
[81] 
Shire, D.; Calandra, B.; Bouaboula, M.; Barth, F.; Rinaldi-Carmona, M.; Casellas, P.; Ferrara, P. Cannabinoid receptor interactions with the antagonists SR 141716A and SR 144528. Life Sci.,  1999, 65(6-7), 627-635.
[http://dx.doi.org/10.1016/S0024-3205(99)00285-4] [PMID:  10462063] 
[82] 
Barth, F.; Rinaldi-Carmona, M. The development of cannabinoid antagonists. Curr. Med. Chem.,  1999, 6(8), 745-755.
[PMID:  10469889] 
[83] 
Rinaldi-Carmona, M.; Barth, F.; Héaulme, M.; Shire, D.; Calandra, B.; Congy, C.; Martinez, S.; Maruani, J.; Néliat, G.; Caput, D. SR141716A, a potent and selective antagonist of the brain cannabinoid receptor. FEBS Lett.,  1994, 350(2-3), 240-244.
[http://dx.doi.org/10.1016/0014-5793(94)00773-X] [PMID:  8070571] 
[84] 
Bifulco, M.; Grimaldi, C.; Gazzerro, P.; Pisanti, S.; Santoro, A. Rimonabant: just an antiobesity drug? Current evidence on its pleiotropic effects. Mol. Pharmacol.,  2007, 71(6), 1445-1456.
[http://dx.doi.org/10.1124/mol.106.033118] [PMID:  17327463] 
[85] 
Pertwee, R.; Griffin, G.; Fernando, S.; Li, X.; Hill, A.; Makriyannis, A. AM630, a competitive cannabinoid receptor antagonist. Life Sci.,  1995, 56(23-24), 1949-1955.
[http://dx.doi.org/10.1016/0024-3205(95)00175-6] [PMID:  7776818] 
[86] 
Lunn, C.A.; Reich, E.P.; Fine, J.S.; Lavey, B.; Kozlowski, J.A.; Hipkin, R.W.; Lundell, D.J.; Bober, L. Biology and therapeutic potential of cannabinoid CB2 receptor inverse agonists. Br. J. Pharmacol.,  2008, 153(2), 226-239.
[http://dx.doi.org/10.1038/sj.bjp.0707480] [PMID:  17906679] 
[87] 
Manera, C.; Arena, C.; Chicca, A. Synthetic cannabinoid receptor agonists and antagonists: Implication in CNS disorders. Recent Patents CNS Drug Discov.,  2016, 10(2), 142-156.
[http://dx.doi.org/10.2174/1574889810666160519113853] [PMID:  27193072] 
[88] 
Fong, T.M.; Heymsfield, S.B. Cannabinoid-1 receptor inverse agonists: current understanding of mechanism of action and unanswered questions. Int. J. Obes.,  2009, 33(9), 947-955.
[http://dx.doi.org/10.1038/ijo.2009.132] [PMID:  19597516] 
[89] 
Morales, P.; Hernandez-Folgado, L.; Goya, P.; Jagerovic, N. Cannabinoid receptor 2 (CB2) agonists and antagonists: a patent update. Expert Opin. Ther. Pat.,  26(7), 843-856.
[90] 
Sharma, M.K.; Murumkar, P.R.; Kanhed, A.M.; Giridhar, R.; Yadav, M.R. Prospective therapeutic agents for obesity: molecular modification approaches of centrally and peripherally acting selective cannabinoid 1 receptor antagonists. Eur. J. Med. Chem.,  2014, 79, 298-339.
[http://dx.doi.org/10.1016/j.ejmech.2014.04.011] [PMID:  24747288] 
[91] 
Sharma, M.K.; Murumkar, P.R.; Barmade, M.A.; Giridhar, R.; Yadav, M.R. A comprehensive patents review on cannabinoid 1 receptor antagonists as antiobesity agents. Expert Opin. Ther. Pat.,  25(10), 1093-1116.2015. 
[http://dx.doi.org/10.1517/13543776.2015.1064898] 
[92] 
Elsohly, M.A.; Slade, D. Chemical constituents of marijuana: The complex mixture of natural cannabinoids. Life Sci.,  2005, 78(5), 539-548.
[http://dx.doi.org/10.1016/j.lfs.2005.09.011] [PMID:  16199061] 
[93] 
Hill, A.J.; Williams, C.M.; Whalley, B.J.; Stephens, G.J. Phytocannabinoids as novel therapeutic agents in CNS disorders. Pharmacol. Ther.,  2012, 133(1), 79-97.
[http://dx.doi.org/10.1016/j.pharmthera.2011.09.002] [PMID:  21924288] 
[94] 
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(2), 420-425.
[PMID:  11160626] 
[95] 
Thomas, A.; Stevenson, L.A.; Wease, K.N.; Price, M.R.; Baillie, G.; Ross, R.A.; Pertwee, R.G. Evidence that the plant cannabinoid Delta9-tetrahydrocannabivarin is a cannabinoid CB1 and CB2 receptor antagonist. Br. J. Pharmacol.,  2005, 146(7), 917-926.
[http://dx.doi.org/10.1038/sj.bjp.0706414] [PMID:  16205722] 
[96] 
Mechoulam, R.; Peters, M.; Murillo-Rodriguez, E.; Hanus, L.O. Cannabidiol--recent advances. Chem. Biodivers.,  2007, 4(8), 1678-1692.
[http://dx.doi.org/10.1002/cbdv.200790147] [PMID:  17712814] 
[97] 
Thomas, A.; Baillie, G.L.; Phillips, A.M.; Razdan, R.K.; Ross, R.A.; Pertwee, R.G. Cannabidiol displays unexpectedly high potency as an antagonist of CB1 and CB2 receptor agonists in vitro. Br. J. Pharmacol.,  2007, 150(5), 613-623.
[http://dx.doi.org/10.1038/sj.bjp.0707133] [PMID:  17245363] 
[98] 
Pertwee, R.G. The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: delta9-tetrahydrocannabinol, cannabidiol and delta9-tetrahydrocannabivarin. Br. J. Pharmacol.,  2008, 153(2), 199-215.
[http://dx.doi.org/10.1038/sj.bjp.0707442] [PMID:  17828291] 
[99] 
Gertsch, J.; Leonti, M.; Raduner, S.; Racz, I.; Chen, J.Z.; Xie, X.Q.; Altmann, K.H.; Karsak, M.; Zimmer, A. Beta-caryophyllene is a dietary cannabinoid. Proc. Natl. Acad. Sci. USA,  2008, 105(26), 9099-9104.
[http://dx.doi.org/10.1073/pnas.0803601105] [PMID:  18574142] 
[100] 
Weissman, A.; Milne, G.M.; Melvin, L.S. Jr Cannabimimetic activity from CP-47,497, a derivative of 3-phenylcyclohexanol. J. Pharmacol. Exp. Ther.,  1982, 223(2), 516-523.
[PMID:  6290642] 
[101] 
Little, P.J.; Compton, D.R.; Johnson, M.R.; Melvin, L.S.; Martin, B.R. Pharmacology and stereoselectivity of structurally novel cannabinoids in mice. J. Pharmacol. Exp. Ther.,  1988, 247(3), 1046-1051.
[PMID:  2849657] 
[102] 
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(2), 563-583.
[http://dx.doi.org/10.1523/JNEUROSCI.11-02-00563.1991] [PMID:  1992016] 
[103] 
Gareau, Y.; Dufresne, C.; Gallant, M.; Rochette, C.; Nicole, S.; Slipetz, D.M.; Tremblay, N.; Weech, P.K.; Metters, K.M.; Labelle, M. Structure activity relationships of tetrahydrocanabinol analogs on human cannabinoid receptors. Bioorg. Med. Chem. Lett.,  1996, 6(2), 189-194.
[http://dx.doi.org/10.1016/0960-894X(95)00573-C] 
[104] 
Little, P.J.; Compton, D.R.; Mechoulam, R.; Martin, B.R. Stereochemical effects of 11-OH-delta 8-THC-dimethylheptyl in mice and dogs. Pharmacol. Biochem. Behav.,  1989, 32(3), 661-666.
[http://dx.doi.org/10.1016/0091-3057(89)90014-2] [PMID:  2544901] 
[105] 
Järbe, T.U.; Hiltunen, A.J.; Mechoulam, R. Stereospecificity of the discriminative stimulus functions of the dimethylheptyl homologs of 11-hydroxy-delta 8-tetrahydrocannabinol in rats and pigeons. J. Pharmacol. Exp. Ther.,  1989, 250(3), 1000-1005.
[PMID:  2550611] 
[106] 
Govaerts, S.J.; Hermans, E.; Lambert, D.M. Comparison of cannabinoid ligands affinities and efficacies in murine tissues and in transfected cells expressing human recombinant cannabinoid receptors. Eur. J. Pharm. Sci.,  2004, 23(3), 233-243.
[http://dx.doi.org/10.1016/j.ejps.2004.07.013] [PMID:  15489124] 
[107] 
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(20), 3875-3877.
[http://dx.doi.org/10.1021/jm960394y] [PMID:  8831752] 
[108] 
Huffman, J.W.; Zengin, G.; Wu, M.J.; Lu, J.; Hynd, G.; Bushell, K.; Thompson, A.L.; Bushell, S.; Tartal, C.; Hurst, D.P.; Reggio, P.H.; Selley, D.E.; Cassidy, M.P.; Wiley, J.L.; Martin, B.R. Structure-activity relationships for 1-alkyl-3-(1-naphthoyl)indoles at the cannabinoid CB(1) and CB(2) receptors: steric and electronic effects of naphthoyl substituents. New highly selective CB(2) receptor agonists. Bioorg. Med. Chem.,  2005, 13(1), 89-112.
[http://dx.doi.org/10.1016/j.bmc.2004.09.050] [PMID:  15582455] 
[109] 
Hanus, 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 CB(2), a peripheral cannabinoid receptor. Proc. Natl. Acad. Sci. USA,  1999, 96(25), 14228-14233.
[http://dx.doi.org/10.1073/pnas.96.25.14228] [PMID:  10588688] 
[110] 
Khanolkar, A.D.; Lu, D.; Ibrahim, M.; Duclos, R.I., Jr; Thakur, G.A.; Malan, T.P., Jr; Porreca, F.; Veerappan, V.; Tian, X.; George, C.; Parrish, D.A.; Papahatjis, D.P.; Makriyannis, A. Cannabilactones: a novel class of CB2 selective agonists with peripheral analgesic activity. J. Med. Chem.,  2007, 50(26), 6493-6500.
[http://dx.doi.org/10.1021/jm070441u] [PMID:  18038967] 
[111] 
Wiley, J.L.; Beletskaya, I.D.; Ng, E.W.; Dai, Z.; Crocker, P.J.; Mahadevan, A.; Razdan, R.K.; Martin, B.R. Resorcinol derivatives: a novel template for the development of cannabinoid CB(1)/CB(2) and CB(2)-selective agonists. J. Pharmacol. Exp. Ther.,  2002, 301(2), 679-689.
[http://dx.doi.org/10.1124/jpet.301.2.679] [PMID:  11961073] 
[112] 
Worm, K.; Zhou, Q.J.; Stabley, G.J.; DeHaven, R.N.; Dolle, R.E. Biaryl cannabinoid mimetics--synthesis and structure-activity relationship. Bioorg. Med. Chem. Lett.,  2007, 17(13), 3652-3656.
[http://dx.doi.org/10.1016/j.bmcl.2007.04.059] [PMID:  17507224] 
[113] 
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(8), 2462-2478.
[http://dx.doi.org/10.1111/j.1476-5381.2011.01381.x] [PMID:  21449982] 
[114] 
Smoum, R.; Baraghithy, S.; Chourasia, M.; Breuer, A.; Mussai, N.; Attar-Namdar, M.; Kogan, N.M.; Raphael, B.; Bolognini, D.; Cascio, M.G.; Marini, P.; Pertwee, R.G.; Shurki, A.; Mechoulam, R.; Bab, I. CB2 cannabinoid receptor agonist enantiomers HU-433 and HU-308: An inverse relationship between binding affinity and biological potency. Proc. Natl. Acad. Sci. USA,  2015, 112(28), 8774-8779.
[http://dx.doi.org/10.1073/pnas.1503395112] [PMID:  26124120] 
[115] 
Ohta, H.; Ishizaka, T.; Tatsuzuki, M.; Yoshinaga, M.; Iida, I.; Yamaguchi, T.; Tomishima, Y.; Futaki, N.; Toda, Y.; Saito, S. Imine derivatives as new potent and selective CB2 cannabinoid receptor agonists with an analgesic action. Bioorg. Med. Chem.,  2008, 16(3), 1111-1124.
[http://dx.doi.org/10.1016/j.bmc.2007.10.087] [PMID:  18006322] 
[116] 
Yang, S.W.; 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(1), 182-185.
[http://dx.doi.org/10.1016/j.bmcl.2010.11.044] [PMID:  21115245] 
[117] 
Tourteau, A.; Andrzejak, V.; Body-Malapel, M.; Lemaire, L.; Lemoine, A.; Mansouri, R.; Djouina, M.; Renault, N.; El Bakali, J.; Desreumaux, P.; Muccioli, G.G.; Lambert, D.M.; Chavatte, P.; Rigo, B.; Leleu-Chavain, N.; Millet, R. 3-Carboxamido-5-aryl-isoxazoles as new CB2 agonists for the treatment of colitis. Bioorg. Med. Chem.,  2013, 21(17), 5383-5394.
[http://dx.doi.org/10.1016/j.bmc.2013.06.010] [PMID:  23849204] 
[118] 
Ohta, H.; Ishizaka, T.; Yoshinaga, M.; Morita, A.; Tomishima, Y.; Toda, Y.; Saito, S. Sulfonamide derivatives as new potent and selective CB2 cannabinoid receptor agonists. Bioorg. Med. Chem. Lett.,  2007, 17(18), 5133-5135.
[http://dx.doi.org/10.1016/j.bmcl.2007.07.005] [PMID:  17643986] 
[119] 
Ohta, H.; Ishizaka, T.; Tatsuzuki, M.; Yoshinaga, M.; Iida, I.; Tomishima, Y.; Toda, Y.; Saito, S. N-Alkylidenearylcarboxamides as new potent and selective CB(2) cannabinoid receptor agonists with good oral bioavailability. Bioorg. Med. Chem. Lett.,  2007, 17(22), 6299-6304.
[http://dx.doi.org/10.1016/j.bmcl.2007.09.004] [PMID:  17884496] 
[120] 
Cheng, Y.; Albrecht, B.K.; Brown, J.; Buchanan, J.L.; Buckner, W.H.; DiMauro, E.F.; Emkey, R.; Fremeau, R.T., Jr; Harmange, J.C.; Hoffman, B.J.; Huang, L.; Huang, M.; Lee, J.H.; Lin, F.F.; Martin, M.W.; Nguyen, H.Q.; Patel, V.F.; Tomlinson, S.A.; White, R.D.; Xia, X.; Hitchcock, S.A. Discovery and optimization of a novel series of N-arylamide oxadiazoles as potent, highly selective and orally bioavailable cannabinoid receptor 2 (CB2) agonists. J. Med. Chem.,  2008, 51(16), 5019-5034.
[http://dx.doi.org/10.1021/jm800463f] [PMID:  18680277] 
[121] 
DiMauro, E.F.; Buchanan, J.L.; Cheng, A.; Emkey, R.; Hitchcock, S.A.; Huang, L.; Huang, M.Y.; Janosky, B.; Lee, J.H.; Li, X.; Martin, M.W.; Tomlinson, S.A.; White, R.D.; Zheng, X.M.; Patel, V.F.; Fremeau, R.T., Jr Structural modifications of N-arylamide oxadiazoles: Identification of N-arylpiperidine oxadiazoles as potent and selective agonists of CB2. Bioorg. Med. Chem. Lett.,  2008, 18(15), 4267-4274.
[http://dx.doi.org/10.1016/j.bmcl.2008.06.096] [PMID:  18640038] 
[122] 
Han, S.; Thoresen, L.; Zhu, X.; Narayanan, S.; Jung, J.K.; Strah-Pleynet, S.; Decaire, M.; Choi, K.; Xiong, Y.; Yue, D.; Semple, G.; Thatte, J.; Solomon, M.; Fu, L.; Whelan, K.; Al-Shamma, H.; Gatlin, J.; Chen, R.; Dang, H.; Pride, C.; Gaidarov, I.; Unett, D.J.; Behan, D.P.; Sadeque, A.; Usmani, K.A.; Chen, C.; Edwards, J.; Morgan, M.; Jones, R.M. Discovery of 1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalen-4-carboxamides as potent and selective CB2 receptor agonists. Bioorg. Med. Chem. Lett.,  2015, 25(2), 322-326.
[http://dx.doi.org/10.1016/j.bmcl.2014.11.040] [PMID:  25488844] 
[123] 
Eatherton, A.J.; Giblin, G.M.P.; Green, R.H.; Mitchell, W.L.; Naylor, A.; Rawlings, D.A.; Slingsby, B.P.; Brian, P.; Whittington, A.R. Preparation of aminopyrimidinecarboxamides and their use as CB2-type cannabinoid receptor modulators. PCT Int. Appl. WO,  2004, 2004018433, A1.
[124] 
Giblin, G.M.; 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(11), 2597-2600.
[http://dx.doi.org/10.1021/jm061195+] [PMID:  17477516] 
[125] 
Mitchell, W.L.; Giblin, G.M.; Naylor, A.; Eatherton, A.J.; Slingsby, B.P.; Rawlings, A.D.; Jandu, K.S.; Haslam, C.P.; Brown, A.J.; Goldsmith, P.; Clayton, N.M.; Wilson, A.W.; Chessell, I.P.; Green, R.H.; Whittington, A.R.; Wall, I.D. Pyridine-3-carboxamides as novel CB(2) agonists for analgesia. Bioorg. Med. Chem. Lett.,  2009, 19(1), 259-263.
[http://dx.doi.org/10.1016/j.bmcl.2008.10.118] [PMID:  19010671] 
[126] 
Zindell, R.; Riether, D.; Bosanac, T.; Berry, A.; Gemkow, M.J.; Ebneth, A.; Löbbe, S.; Raymond, E.L.; Thome, D.; Shih, D.T.; Thomson, D. Morpholine containing CB2 selective agonists. Bioorg. Med. Chem. Lett.,  2009, 19(6), 1604-1609.
[http://dx.doi.org/10.1016/j.bmcl.2009.02.033] [PMID:  19243942] 
[127] 
Mukhopadhyay, P.; Baggelaar, M.; Erdelyi, K.; Cao, Z.; Cinar, R.; Fezza, F.; Ignatowska-Janlowska, B.; Wilkerson, J.; van Gils, N.; Hansen, T.; Ruben, M.; Soethoudt, M.; Heitman, L.; Kunos, G.; Maccarrone, M.; Lichtman, A.; Pacher, P.; Van der Stelt, M. The novel, orally available and peripherally restricted selective cannabinoid CB2 receptor agonist LEI-101 prevents cisplatin-induced nephrotoxicity. Br. J. Pharmacol.,  2016, 173(3), 446-458.
[http://dx.doi.org/10.1111/bph.13338] [PMID:  26398481] 
[128] 
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(8), 2898-2901.
[http://dx.doi.org/10.1016/j.bmcl.2012.02.050] [PMID:  22421019] 
[129] 
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(22), 7918-7931.
[http://dx.doi.org/10.1021/jm100286k] [PMID:  20979417] 
[130] 
Gleave, R.J.; Beswick, P.J.; Brown, A.J.; Giblin, G.M.; 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(23), 6578-6581.
[http://dx.doi.org/10.1016/j.bmcl.2009.10.041] [PMID:  19864133] 
[131] 
Gleave, R.J.; Beswick, P.J.; Brown, A.J.; Giblin, G.M.; 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 CB(2) agonists for the treatment of inflammatory pain. Bioorg. Med. Chem. Lett.,  2010, 20(2), 465-468.
[http://dx.doi.org/10.1016/j.bmcl.2009.11.117] [PMID:  20005703] 
[132] 
Qian, H.Y.; Wang, Z.L.; Xie, X.Y.; Pan, Y.L.; Li, G.J.; Xie, X.; Chen, J.Z. Developing pyridazine-3-carboxamides to be CB2 agonists: The design, synthesis, structure-activity relationships and docking studies. Eur. J. Med. Chem.,  2017, 137, 598-611.
[http://dx.doi.org/10.1016/j.ejmech.2017.05.060] [PMID:  28651225] 
[133] 
Kai, H.; Morioka, Y.; Murashi, T.; Morita, K.; Shinonome, S.; Nakazato, H.; Kawamoto, K.; Hanasaki, K.; Takahashi, F.; Mihara, S.; Arai, T.; Abe, K.; Okabe, H.; Baba, T.; Yoshikawa, T.; Takenaka, H. 2-Arylimino-5,6-dihydro-4H-1,3-thiazines as a new class of cannabinoid receptor agonists. Part 1: discovery of CB2 receptor selective compounds. Bioorg. Med. Chem. Lett.,  2007, 17(14), 4030-4034.
[http://dx.doi.org/10.1016/j.bmcl.2007.04.093] [PMID:  17521907] 
[134] 
Kai, H.; Morioka, Y.; Tomida, M.; Takahashi, T.; Hattori, M.; Hanasaki, K.; Koike, K.; Chiba, H.; Shinohara, S.; Kanemasa, T.; Iwamoto, Y.; Takahashi, K.; Yamaguchi, Y.; Baba, T.; Yoshikawa, T.; Takenaka, H. 2-Arylimino-5,6-dihydro-4H-1,3-thiazines as a new class of cannabinoid receptor agonists. Part 2: orally bioavailable compounds. Bioorg. Med. Chem. Lett.,  2007, 17(14), 3925-3929.
[http://dx.doi.org/10.1016/j.bmcl.2007.04.099] [PMID:  17531479] 
[135] 
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(1-2), 9-20.
[http://dx.doi.org/10.1016/j.ejps.2012.10.020] [PMID:  23131798] 
[136] 
Yrjölä, S.; Sarparanta, M.; Airaksinen, A.J.; Hytti, M.; Kauppinen, A.; Pasonen-Seppänen, S.; Adinolfi, B.; Nieri, P.; Manera, C.; Keinänen, O.; Poso, A.; Nevalainen, T.J.; Parkkari, T. Synthesis, in vitro and in vivo evaluation of 1,3,5-triazines as cannabinoid CB2 receptor agonists. Eur. J. Pharm. Sci.,  2015, 67, 85-96.
[http://dx.doi.org/10.1016/j.ejps.2014.11.003] [PMID:  25447744] 
[137] 
Bell, M.R.; D’Ambra, T.E.; Kumar, V.; Eissenstat, M.A.; Herrmann, J.L., Jr; Wetzel, J.R.; Rosi, D.; Philion, R.E.; Daum, S.J.; Hlasta, D.J. Antinociceptive (aminoalkyl)indoles. J. Med. Chem.,  1991, 34(3), 1099-1110.
[http://dx.doi.org/10.1021/jm00107a034] [PMID:  1900533] 
[138] 
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(1), 124-135.
[http://dx.doi.org/10.1021/jm00079a016] [PMID:  1732519] 
[139] 
Marriott, K.S.; Huffman, J.W. Recent advances in the development of selective ligands for the cannabinoid CB(2) receptor. Curr. Top. Med. Chem.,  2008, 8(3), 187-204.
[http://dx.doi.org/10.2174/156802608783498014] [PMID:  18289088] 
[140] 
Manera, C.; Tuccinardi, T.; Martinelli, A. Indoles and related compounds as cannabinoid ligands. Mini Rev. Med. Chem.,  2008, 8(4), 370-387.
[http://dx.doi.org/10.2174/138955708783955935] [PMID:  18473928] 
[141] 
Huffman, J.W.; Padgett, L.W. Recent developments in the medicinal chemistry of cannabimimetic indoles, pyrroles and indenes. Curr. Med. Chem.,  2005, 12(12), 1395-1411.
[http://dx.doi.org/10.2174/0929867054020864] [PMID:  15974991] 
[142] 
Poso, A.; Huffman, J.W. Targeting the cannabinoid CB2 receptor: modelling and structural determinants of CB2 selective ligands. Br. J. Pharmacol.,  2008, 153(2), 335-346.
[http://dx.doi.org/10.1038/sj.bjp.0707567] [PMID:  17982473] 
[143] 
Showalter, V.M.; Compton, D.R.; Martin, B.R.; Abood, M.E. Evaluation of binding in a transfected cell line expressing a peripheral cannabinoid receptor (CB2): identification of cannabinoid receptor subtype selective ligands. J. Pharmacol. Exp. Ther.,  1996, 278(3), 989-999.
[PMID:  8819477] 
[144] 
Gallant, M.D.C.; Gareau, Y.; Guay, D.; Leblanc, Y.; Prasit, P.; Rochette, C.; Sawyer, N.; Slipetz, D.M. New class of potent ligands for the human peripheral cannabinoid receptor. Bioorg. Med. Chem. Lett.,  1996, 6(19), 2263-2268.
[http://dx.doi.org/10.1016/0960-894X(96)00426-X] 
[145] 
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(5), 658-672.
[http://dx.doi.org/10.1016/j.neuropharm.2004.12.008] [PMID:  15814101] 
[146] 
Bingham, B.; Jones, P.G.; Uveges, A.J.; Kotnis, S.; Lu, P.; Smith, V.A.; Sun, S.C.; Resnick, L.; Chlenov, M.; He, Y.; Strassle, B.W.; Cummons, T.A.; Piesla, M.J.; Harrison, J.E.; Whiteside, G.T.; Kennedy, J.D. Species-specific in vitro pharmacological effects of the cannabinoid receptor 2 (CB2) selective ligand AM1241 and its resolved enantiomers. Br. J. Pharmacol.,  2007, 151(7), 1061-1070.
[http://dx.doi.org/10.1038/sj.bjp.0707303] [PMID:  17549048] 
[147] 
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(3), 239-245.
[http://dx.doi.org/10.1016/S0304-3959(01)00321-9] [PMID:  11514083] 
[148] 
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(18), 10529-10533.
[http://dx.doi.org/10.1073/pnas.1834309100] [PMID:  12917492] 
[149] 
Hynes, J., Jr; Leftheris, K.; Wu, H.; Pandit, C.; Chen, P.; Norris, D.J.; Chen, B.C.; Zhao, R.; Kiener, P.A.; Chen, X.; Turk, L.A.; Patil-Koota, V.; Gillooly, K.M.; Shuster, D.J.; McIntyre, K.W. C-3 Amido-indole cannabinoid receptor modulators. Bioorg. Med. Chem. Lett.,  2002, 12(17), 2399-2402.
[http://dx.doi.org/10.1016/S0960-894X(02)00466-3] [PMID:  12161142] 
[150] 
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(2), 390-401.
[http://dx.doi.org/10.1038/sj.bjp.0707568] [PMID:  17994110] 
[151] 
Frost, J.M.; Dart, M.J.; Tietje, K.R.; Garrison, T.R.; Grayson, G.K.; Daza, A.V.; El-Kouhen, O.F.; Miller, L.N.; Li, L.; Yao, B.B.; Hsieh, G.C.; Pai, M.; Zhu, C.Z.; Chandran, P.; Meyer, M.D. Indol-3-yl-tetramethylcyclopropyl ketones: Effects of indole ring substitution on CB2 cannabinoid receptor activity. J. Med. Chem.,  2008, 51(6), 1904-1912.
[http://dx.doi.org/10.1021/jm7011613] [PMID:  18311894] 
[152] 
Verbist, B.M.; De Cleyn, M.A.; Surkyn, M.; Fraiponts, E.; Aerssens, J.; Nijsen, M.J.; Gijsen, H.J. 5-Sulfonyl-benzimidazoles as selective CB2 agonists. Bioorg. Med. Chem. Lett.,  2008, 18(8), 2574-2579.
[http://dx.doi.org/10.1016/j.bmcl.2008.03.048] [PMID:  18394887] 
[153] 
Pagé, D.; Balaux, E.; Boisvert, L.; Liu, Z.; Milburn, C.; Tremblay, M.; Wei, Z.; Woo, S.; Luo, X.; Cheng, Y.X.; 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(13), 3695-3700.
[http://dx.doi.org/10.1016/j.bmcl.2008.05.073] [PMID:  18522867] 
[154] 
Ryckmans, T.; Edwards, M.P.; Horne, V.A.; Correia, A.M.; Owen, D.R.; Thompson, L.R.; Tran, I.; Tutt, M.F.; Young, T. Rapid assessment of a novel series of selective CB(2) agonists using parallel synthesis protocols: A Lipophilic Efficiency (LipE) analysis. Bioorg. Med. Chem. Lett.,  2009, 19(15), 4406-4409.
[http://dx.doi.org/10.1016/j.bmcl.2009.05.062] [PMID:  19500981] 
[155] 
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 CB(2) agonists. Bioorg. Med. Chem. Lett.,  2011, 21(14), 4284-4287.
[http://dx.doi.org/10.1016/j.bmcl.2011.05.063] [PMID:  21669533] 
[156] 
Gijsen, H.J.; De Cleyn, M.A.; Surkyn, M.; Van Lommen, G.R.; Verbist, B.M.; Nijsen, M.J.; Meert, T.; Wauwe, J.V.; Aerssens, J. 5-sulfonyl-benzimidazoles as selective CB2 agonists-part 2. Bioorg. Med. Chem. Lett.,  2012, 22(1), 547-552.
[http://dx.doi.org/10.1016/j.bmcl.2011.10.091] [PMID:  22130134] 
[157] 
Nanda, K.K.; Henze, D.A.; Della Penna, K.; Desai, R.; Leitl, M.; Lemaire, W.; White, R.B.; Yeh, S.; Brouillette, J.N.; Hartman, G.D.; Bilodeau, M.T.; Trotter, B.W. Benzimidazole CB2 agonists: design, synthesis and SAR. Bioorg. Med. Chem. Lett.,  2014, 24(4), 1218-1221.
[http://dx.doi.org/10.1016/j.bmcl.2013.12.068] [PMID:  24461289] 
[158] 
Iwata, Y.; Ando, K.; Taniguchi, K.; Koba, N.; Sugiura, A.; Sudo, M. Identification of a highly potent and selective CB2 agonist, RQ-00202730, for the treatment of irritable bowel syndrome. Bioorg. Med. Chem. Lett.,  2015, 25(2), 236-240.
[http://dx.doi.org/10.1016/j.bmcl.2014.11.062] [PMID:  25499880] 
[159] 
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 CB(2) cannabinoid receptor partial agonists. J. Med. Chem.,  2013, 56(3), 1098-1112.
[http://dx.doi.org/10.1021/jm301527r] [PMID:  23350768] 
[160] 
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.; Della Penna, K.; 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(8), 2354-2358.
[http://dx.doi.org/10.1016/j.bmcl.2011.02.082] [PMID:  21420860] 
[161] 
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(15), 4962-4966.
[http://dx.doi.org/10.1016/j.bmcl.2012.06.035] [PMID:  22765893] 
[162] 
Hollinshead, S.P.; Tidwell, M.W.; Palmer, J.; Guidetti, R.; Sanderson, A.; Johnson, M.P.; Chambers, M.G.; Oskins, J.; Stratford, R.; Astles, P.C. Selective cannabinoid receptor type 2 (CB2) agonists: optimization of a series of purines leading to the identification of a clinical candidate for the treatment of osteoarthritic pain. J. Med. Chem.,  2013, 56(14), 5722-5733.
[http://dx.doi.org/10.1021/jm400305d] [PMID:  23795771] 
[163] 
Diaz, P.; Phatak, S.S.; Xu, J.; Fronczek, F.R.; Astruc-Diaz, F.; Thompson, C.M.; Cavasotto, C.N.; Naguib, M. 2,3-Dihydro-1-benzofuran derivatives as a series of potent selective cannabinoid receptor 2 agonists: design, synthesis, and binding mode prediction through ligand-steered modeling. ChemMedChem,  2009, 4(10), 1615-1629.
[http://dx.doi.org/10.1002/cmdc.200900226] [PMID:  19637157] 
[164] 
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(20), 5947-5957.
[http://dx.doi.org/10.1021/jm0603466] [PMID:  17004710] 
[165] 
Stern, E.; Muccioli, G.G.; Millet, R.; Goossens, J.F.; Farce, A.; Chavatte, P.; Poupaert, J.H.; Lambert, D.M.; Depreux, P.; Hénichart, J.P. 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(1), 70-79.
[http://dx.doi.org/10.1021/jm050467q] [PMID:  16392793] 
[166] 
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(16), 5075-5084.
[http://dx.doi.org/10.1021/jm800552f] [PMID:  18680276] 
[167] 
Manley, P.J.; Zartman, A.; Paone, D.V.; Burgey, C.S.; Henze, D.A.; Della Penna, K.; 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(8), 2359-2364.
[http://dx.doi.org/10.1016/j.bmcl.2011.02.078] [PMID:  21420857] 
[168] 
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(23), 6505-6510.
[http://dx.doi.org/10.1016/j.bmcl.2007.09.089] [PMID:  17942307] 
[169] 
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 alpha-mediated ceramide de novo synthesis in colon cancer cells. Clin. Cancer Res.,  2008, 14(23), 7691-7700.
[http://dx.doi.org/10.1158/1078-0432.CCR-08-0799] [PMID:  19047095] 
[170] 
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(12), 3644-3651.
[http://dx.doi.org/10.1021/jm801563d] [PMID:  19435366] 
[171] 
Lucchesi, V.; Hurst, D.P.; Shore, D.M.; Bertini, S.; Ehrmann, B.M.; Allarà, M.; Lawrence, L.; Ligresti, A.; Minutolo, F.; Saccomanni, G.; Sharir, H.; Macchia, M.; Di Marzo, V.; Abood, M.E.; Reggio, P.H.; Manera, C. CB2-selective cannabinoid receptor ligands: synthesis, pharmacological evaluation, and molecular modeling investigation of 1,8-Naphthyridin-2(1H)-one-3-carboxamides. J. Med. Chem.,  2014, 57(21), 8777-8791.
[http://dx.doi.org/10.1021/jm500807e] [PMID:  25272206] 
[172] 
Cheng, Y.X.; Pourashraf, M.; Luo, X.; Srivastava, S.; Walpole, C.; Salois, D.; St-Onge, S.; Payza, K.; Lessard, E.; Yu, X.H.; Tomaszewski, M.J. γ-Carbolines: a novel class of cannabinoid agonists with high aqueous solubility and restricted CNS penetration. Bioorg. Med. Chem. Lett.,  2012, 22(4), 1619-1624.
[http://dx.doi.org/10.1016/j.bmcl.2011.12.124] [PMID:  22284817] 
[173] 
El Bakali, J.; Muccioli, G.G.; Body-Malapel, M.; Djouina, M.; Klupsch, F.; Ghinet, A.; Barczyk, A.; Renault, N.; Chavatte, P.; Desreumaux, P.; Lambert, D.M.; Millet, R. Conformational restriction leading to a selective CB2 cannabinoid receptor agonist orally active against colitis. ACS Med. Chem. Lett.,  2014, 6(2), 198-203.
[http://dx.doi.org/10.1021/ml500439x] [PMID:  25699149] 
[174] 
Gonsiorek, W.; Lunn, C.A.; Fan, X.; Deno, G.; Kozlowski, J.; Hipkin, R.W. Sch35966 is a potent, selective agonist at the peripheral cannabinoid receptor (CB2) in rodents and primates. Br. J. Pharmacol.,  2007, 151(8), 1262-1271.
[http://dx.doi.org/10.1038/sj.bjp.0707336] [PMID:  17603556] 
[175] 
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 CB(2) cannabinoid receptor ligands: structural investigations around a novel class of full agonists. J. Med. Chem.,  2012, 55(14), 6608-6623.
[http://dx.doi.org/10.1021/jm300763w] [PMID:  22738271] 
[176] 
Vincenzi, F.; Targa, M.; Corciulo, C.; Tabrizi, M.A.; Merighi, S.; Gessi, S.; Saponaro, G.; Baraldi, P.G.; Borea, P.A.; Varani, K. Antinociceptive effects of the selective CB2 agonist MT178 in inflammatory and chronic rodent pain models. Pain,  2013, 154(6), 864-873.
[http://dx.doi.org/10.1016/j.pain.2013.02.007] [PMID:  23518609] 
[177] 
Marx, I.E.; DiMauro, E.F.; Cheng, A.; Emkey, R.; Hitchcock, S.A.; Huang, L.; Huang, M.Y.; Human, J.; Lee, J.H.; Li, X.; Martin, M.W.; White, R.D.; Fremeau, R.T., Jr; Patel, V.F. Discovery of alpha-amidosulfones as potent and selective agonists of CB2: synthesis, SAR, and pharmacokinetic properties. Bioorg. Med. Chem. Lett.,  2009, 19(1), 31-35.
[http://dx.doi.org/10.1016/j.bmcl.2008.11.026] [PMID:  19062274] 
[178] 
Ermann, M.; Riether, D.; Walker, E.R.; Mushi, I.F.; Jenkins, J.E.; Noya-Marino, B.; Brewer, M.L.; Taylor, M.G.; Amouzegh, P.; East, S.P.; Dymock, B.W.; Gemkow, M.J.; Kahrs, A.F.; Ebneth, A.; Löbbe, S.; O’Shea, K.; Shih, D.T.; Thomson, D. Arylsulfonamide CB2 receptor agonists: SAR and optimization of CB2 selectivity. Bioorg. Med. Chem. Lett.,  2008, 18(5), 1725-1729.
[http://dx.doi.org/10.1016/j.bmcl.2008.01.042] [PMID:  18255291] 
[179] 
Goodman, A.J.; Ajello, C.W.; Worm, K.; Le Bourdonnec, B.; Savolainen, M.A.; O’Hare, H.; Cassel, J.A.; Stabley, G.J.; Dehaven, 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(2), 309-313.
[http://dx.doi.org/10.1016/j.bmcl.2008.11.091] [PMID:  19091565] 
[180] 
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.T.; Thomson, D.S. 1,4-Diazepane compounds as potent and selective CB2 agonists: optimization of metabolic stability. Bioorg. Med. Chem. Lett.,  2011, 21(7), 2011-2016.
[http://dx.doi.org/10.1016/j.bmcl.2011.02.017] [PMID:  21354795] 
[181] 
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.T.; 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(14), 4276-4280.
[http://dx.doi.org/10.1016/j.bmcl.2011.05.068] [PMID:  21689933] 
[182] 
Guzior, N.; Wieckowska, A.; Panek, D.; Malawska, B. Recent development of multifunctional agents as potential drug candidates for the treatment of Alzheimer’s disease. Curr. Med. Chem.,  2015, 22(3), 373-404.
[http://dx.doi.org/10.2174/0929867321666141106122628] [PMID:  25386820] 
[183] 
Bajda, M.; Guzior, N.; Ignasik, M.; Malawska, B. Multi-target-directed ligands in Alzheimer’s disease treatment. Curr. Med. Chem.,  2011, 18(32), 4949-4975.
[http://dx.doi.org/10.2174/092986711797535245] [PMID:  22050745] 
[184] 
Pérez, D.I.; Martínez, A.; Gil, C.; Campillo, N.E. From bitopic inhibitors to multitarget drugs for the future treatment of Alzheimer’s disease. Curr. Med. Chem.,  2015, 22(33), 3789-3806.
[http://dx.doi.org/10.2174/0929867322666150812145825] [PMID:  26264921] 
[185] 
González-Naranjo, P.; Pérez-Macias, N.; Campillo, N.E.; Pérez, C.; Arán, V.J.; Girón, R.; Sánchez-Robles, E.; Martín, M.I.; Gómez-Cañas, M.; García-Arencibia, M.; Fernández-Ruiz, J.; Páez, J.A. Cannabinoid agonists showing BuChE inhibition as potential therapeutic agents for Alzheimer’s disease. Eur. J. Med. Chem.,  2014, 73, 56-72.
[http://dx.doi.org/10.1016/j.ejmech.2013.11.026] [PMID:  24378710] 
[186] 
Páez, J. A.; Campillo, N. E.; González-Naranjo, P.; Pérez, C.; Pérez-Macias, N.; López de Ceballos, M.; Martín-Requero, A.; Alquezar, C.; Martin Fontelles, M. I.; Girón, R.; Sánchez, E. M.; Romero, J. PCT/ES2016/070906. New family of 1-Indazolyl carbonyl derivatives with cannabinoid and/or cholinergic properties and/or beta-amyloid peptide regulators. December 16,  2016.
[187] 
Dolles, D.; Nimczick, M.; Scheiner, M.; Ramler, J.; Stadtmüller, P.; Sawatzky, E.; Drakopoulos, A.; Sotriffer, C.; Wittmann, H.J.; Strasser, A.; Decker, M. Aminobenzimidazoles and structural isomers as templates for dual-acting butyrylcholinesterase inhibitors and hCB2 R ligands to combat neurodegenerative disorders. ChemMedChem,  2016, 11(12), 1270-1283.
[http://dx.doi.org/10.1002/cmdc.201500418] [PMID:  26548365] 
[188] 
 WHO. Global action plan on the public health response to dementia 2017-2025. 2016. Available from:
                    https://www.who.int/mental_health/neurology/dementia/action_plan_2017_2025/en/. 
[189] 
Claassen, J.A.; Jansen, R.W. Cholinergically mediated augmentation of cerebral perfusion in Alzheimer’s disease and related cognitive disorders: the cholinergic-vascular hypothesis. J. Gerontol. A Biol. Sci. Med. Sci.,  2006, 61(3), 267-271.
[http://dx.doi.org/10.1093/gerona/61.3.267] [PMID:  16567376] 
[190] 
Coulthard, E.; Singh-Curry, V.; Husain, M. Treatment of attention deficits in neurological disorders. Curr. Opin. Neurol.,  2006, 19(6), 613-618.
[http://dx.doi.org/10.1097/01.wco.0000247605.57567.9a] [PMID:  17102702] 
[191] 
Villarroya, M.; García, A.G.; Marco-Contelles, J.; López, M.G. An update on the pharmacology of galantamine. Expert Opin. Investig. Drugs,  2007, 16(12), 1987-1998.
[http://dx.doi.org/10.1517/13543784.16.12.1987] [PMID:  18042006] 
[192] 
Klafki, H.W.; Staufenbiel, M.; Kornhuber, J.; Wiltfang, J. Therapeutic approaches to Alzheimer’s disease. Brain,  2006, 129(Pt 11), 2840-2855.
[http://dx.doi.org/10.1093/brain/awl280] [PMID:  17018549] 
[193] 
Thomas, S.J.; Grossberg, G.T. Memantine: a review of studies into its safety and efficacy in treating Alzheimer’s disease and other dementias. Clin. Interv. Aging,  2009, 4, 367-377.
[PMID:  19851512] 
[194] 
Ferrer, I. Defining Alzheimer as a common age-related neurodegenerative process not inevitably leading to dementia. Prog. Neurobiol.,  2012, 97(1), 38-51.
[http://dx.doi.org/10.1016/j.pneurobio.2012.03.005] [PMID:  22459297] 
[195] 
Aso, E.; Ferrer, I. CB2 cannabinoid receptor as potential target against Alzheimer’s disease. Front. Neurosci.,  2016, 10, 243.
[http://dx.doi.org/10.3389/fnins.2016.00243] [PMID:  27303261] 
[196] 
Di Marzo, V.; Stella, N.; Zimmer, A. Endocannabinoid signalling and the deteriorating brain. Nat. Rev. Neurosci.,  2015, 16(1), 30-42.
[http://dx.doi.org/10.1038/nrn3876] [PMID:  25524120] 
[197] 
Cassano, T.; Calcagnini, S.; Pace, L.; De Marco, F.; Romano, A.; Gaetani, S. Cannabinoid receptor 2 signaling in neurodegenerative disorders: From pathogenesis to a promising therapeutic target. Front. Neurosci.,  2017, 11, 30.
[http://dx.doi.org/10.3389/fnins.2017.00030] [PMID:  28210207] 
[198] 
Ahmed, A.; van der Marck, M.A.; van den Elsen, G.; Olde Rikkert, M. Cannabinoids in late-onset Alzheimer’s disease. Clin. Pharmacol. Ther.,  2015, 97(6), 597-606.
[http://dx.doi.org/10.1002/cpt.117] [PMID:  25788394] 
[199] 
Aso, E.; Ferrer, I. Cannabinoids for treatment of Alzheimer’s disease: Moving toward the clinic. Front. Pharmacol.,  2014, 5, 37.
[http://dx.doi.org/10.3389/fphar.2014.00037] [PMID:  24634659] 
[200] 
Koppel, J.; Davies, P. Targeting the endocannabinoid system in Alzheimer’s disease. J. Alzheimers Dis.,  2008, 15(3), 495-504.
[http://dx.doi.org/10.3233/JAD-2008-15315] [PMID:  18997302] 
[201] 
Ramírez, B.G.; Blázquez, C.; Gómez del Pulgar, T.; Guzmán, M.; de Ceballos, M.L. Prevention of Alzheimer’s disease pathology by cannabinoids: neuroprotection mediated by blockade of microglial activation. J. Neurosci.,  2005, 25(8), 1904-1913.
[http://dx.doi.org/10.1523/JNEUROSCI.4540-04.2005] [PMID:  15728830] 
[202] 
Solas, M.; Francis, P.T.; Franco, R.; Ramirez, M.J. CB2 receptor and amyloid pathology in frontal cortex of Alzheimer’s disease patients. Neurobiol. Aging,  2013, 34(3), 805-808.
[http://dx.doi.org/10.1016/j.neurobiolaging.2012.06.005] [PMID:  22763024] 
[203] 
Bedse, G.; Romano, A.; Cianci, S.; Lavecchia, A.M.; Lorenzo, P.; Elphick, M.R.; Laferla, F.M.; Vendemiale, G.; Grillo, C.; Altieri, F.; Cassano, T.; Gaetani, S. Altered expression of the CB1 cannabinoid receptor in the triple transgenic mouse model of Alzheimer’s disease. J. Alzheimers Dis.,  2014, 40(3), 701-712.
[http://dx.doi.org/10.3233/JAD-131910] [PMID:  24496074] 
[204] 
Pacher, P.; Mechoulam, R. Is lipid signaling through cannabinoid 2 receptors part of a protective system? Prog. Lipid Res.,  2011, 50(2), 193-211.
[http://dx.doi.org/10.1016/j.plipres.2011.01.001] [PMID:  21295074] 
[205] 
Bisogno, T.; Di Marzo, V. Cannabinoid receptors and endocannabinoids: role in neuroinflammatory and neurodegenerative disorders. CNS Neurol. Disord. Drug Targets,  2010, 9(5), 564-573.
[http://dx.doi.org/10.2174/187152710793361568] [PMID:  20632970] 
[206] 
Fernández-Ruiz, J.; Romero, J.; Ramos, J.A. Endocannabinoids and neurodegenerative disorders: Parkinson’s disease, Huntington’s Chorea, Alzheimer’s disease, and others. Handb. Exp. Pharmacol.,  2015, 231, 233-259.
[http://dx.doi.org/10.1007/978-3-319-20825-1_8] [PMID:  26408163] 
[207] 
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(2), 277-285.
[http://dx.doi.org/10.1038/sj.bjp.0707505] [PMID:  17934510] 
[208] 
Mulder, J.; Zilberter, M.; Pasquaré, S.J.; Alpár, A.; Schulte, G.; Ferreira, S.G.; Köfalvi, A.; Martín-Moreno, A.M.; Keimpema, E.; Tanila, H.; Watanabe, M.; Mackie, K.; Hortobágyi, T.; de Ceballos, M.L.; Harkany, T. Molecular reorganization of endocannabinoid signalling in Alzheimer’s disease. Brain,  2011, 134(Pt 4), 1041-1060.
[http://dx.doi.org/10.1093/brain/awr046] [PMID:  21459826] 
[209] 
Horti, A.G.; Gao, Y.; Ravert, H.T.; Finley, P.; Valentine, H.; Wong, D.F.; Endres, C.J.; Savonenko, A.V.; Dannals, R.F. Synthesis and biodistribution of [11C]A-836339, a new potential radioligand for PET imaging of cannabinoid type 2 receptors (CB2). Bioorg. Med. Chem.,  2010, 18(14), 5202-5207.
[http://dx.doi.org/10.1016/j.bmc.2010.05.058] [PMID:  20554448] 
[210] 
Esposito, G.; Iuvone, T.; Savani, C.; Scuderi, C.; De Filippis, D.; Papa, M.; Di Marzo, V.; Steardo, L. Opposing control of cannabinoid receptor stimulation on amyloid-beta-induced reactive gliosis: In vitro and in vivo evidence. J. Pharmacol. Exp. Ther.,  2007, 322(3), 1144-1152.
[http://dx.doi.org/10.1124/jpet.107.121566] [PMID:  17545311] 
[211] 
Haugh, O.; Penman, J.; Irving, A.J.; Campbell, V.A. The emerging role of the cannabinoid receptor family in peripheral and neuro-immune interactions. Curr. Drug Targets,  2016, 17(16), 1834-1840.
[http://dx.doi.org/10.2174/1389450117666160112113703] [PMID:  26758668] 
[212] 
Kaur, R.; Ambwani, S.R.; Singh, S. Endocannabinoid system: A multi-facet therapeutic target. Curr. Clin. Pharmacol.,  2016, 11(2), 110-117.
[http://dx.doi.org/10.2174/1574884711666160418105339] [PMID:  27086601] 
[213] 
Ranieri, R.; Laezza, C.; Bifulco, M.; Marasco, D.; Malfitano, A.M. Endocannabinoid system in neurological disorders. Recent Patents CNS Drug Discov.,  2016, 10(2), 90-112.
[http://dx.doi.org/10.2174/1574889810999160719105433] [PMID:  27364363] 
[214] 
Maccarrone, M.; Maldonado, R.; Casas, M.; Henze, T.; Centonze, D. Cannabinoids therapeutic use: what is our current understanding following the introduction of THC, THC:CBD oromucosal spray and others? Expert Rev. Clin. Pharmacol.,  2017, 10(4), 443-455.
[http://dx.doi.org/10.1080/17512433.2017.1292849] [PMID:  28276775] 
[215] 
Milton, N.G. Anandamide and noladin ether prevent neurotoxicity of the human amyloid-beta peptide. Neurosci. Lett.,  2002, 332(2), 127-130.
[http://dx.doi.org/10.1016/S0304-3940(02)00936-9] [PMID:  12384227] 
[216] 
Eljaschewitsch, E.; Witting, A.; Mawrin, C.; Lee, T.; Schmidt, P.M.; Wolf, S.; Hoertnagl, H.; Raine, C.S.; Schneider-Stock, R.; Nitsch, R.; Ullrich, O. The endocannabinoid anandamide protects neurons during CNS inflammation by induction of MKP-1 in microglial cells. Neuron,  2006, 49(1), 67-79.
[http://dx.doi.org/10.1016/j.neuron.2005.11.027] [PMID:  16387640] 
[217] 
Eubanks, L.M.; Rogers, C.J.; Beuscher, A.E., IV; Koob, G.F.; Olson, A.J.; Dickerson, T.J.; Janda, K.D. A molecular link between the active component of marijuana and Alzheimer’s disease pathology. Mol. Pharm.,  2006, 3(6), 773-777.
[http://dx.doi.org/10.1021/mp060066m] [PMID:  17140265] 
[218] 
Janefjord, E.; Mååg, J.L.; Harvey, B.S.; Smid, S.D. Cannabinoid effects on β amyloid fibril and aggregate formation, neuronal and microglial-activated neurotoxicity in vitro. Cell. Mol. Neurobiol.,  2014, 34(1), 31-42.
[http://dx.doi.org/10.1007/s10571-013-9984-x] [PMID:  24030360] 
[219] 
Iuvone, T.; Esposito, G.; Esposito, R.; Santamaria, R.; Di Rosa, M.; Izzo, A.A. Neuroprotective effect of cannabidiol, a non-psychoactive component from Cannabis sativa, on beta-amyloid-induced toxicity in PC12 cells. J. Neurochem.,  2004, 89(1), 134-141.
[http://dx.doi.org/10.1111/j.1471-4159.2003.02327.x] [PMID:  15030397] 
[220] 
Ehrhart, J.; Obregon, D.; Mori, T.; Hou, H.; Sun, N.; Bai, Y.; Klein, T.; Fernandez, F.; Tan, J.; Shytle, R.D. Stimulation of cannabinoid receptor 2 (CB2) suppresses microglial activation. J. Neuroinflammation,  2005, 2, 29.
[http://dx.doi.org/10.1186/1742-2094-2-29] [PMID:  16343349] 
[221] 
Martín-Moreno, A.M.; Reigada, D.; Ramírez, B.G.; Mechoulam, R.; Innamorato, N.; Cuadrado, A.; de Ceballos, M.L. Cannabidiol and other cannabinoids reduce microglial activation in vitro and in vivo: relevance to Alzheimer’s disease. Mol. Pharmacol.,  2011, 79(6), 964-973.
[http://dx.doi.org/10.1124/mol.111.071290] [PMID:  21350020] 
[222] 
Fakhfouri, G.; Ahmadiani, A.; Rahimian, R.; Grolla, A.A.; Moradi, F.; Haeri, A. WIN55212-2 attenuates amyloid-beta-induced neuroinflammation in rats through activation of cannabinoid receptors and PPAR-γ pathway. Neuropharmacology,  2012, 63(4), 653-666.
[http://dx.doi.org/10.1016/j.neuropharm.2012.05.013] [PMID:  22634229] 
[223] 
Sheng, W.S.; Hu, S.; Min, X.; Cabral, G.A.; Lokensgard, J.R.; Peterson, P.K. Synthetic cannabinoid WIN55,212-2 inhibits generation of inflammatory mediators by IL-1beta-stimulated human astrocytes. Glia,  2005, 49(2), 211-219.
[http://dx.doi.org/10.1002/glia.20108] [PMID:  15390091] 
[224] 
Tolón, R.M.; Núñez, E.; Pazos, M.R.; Benito, C.; Castillo, A.I.; Martínez-Orgado, J.A.; Romero, J. The activation of cannabinoid CB2 receptors stimulates in situ and in vitro beta-amyloid removal by human macrophages. Brain Res.,  2009, 1283, 148-154.
[http://dx.doi.org/10.1016/j.brainres.2009.05.098] [PMID:  19505450] 
[225] 
Esposito, G.; De Filippis, D.; Carnuccio, R.; Izzo, A.A.; Iuvone, T. The marijuana component cannabidiol inhibits beta-amyloid-induced tau protein hyperphosphorylation through Wnt/beta-catenin pathway rescue in PC12 cells. J. Mol. Med. (Berl.),  2006, 84(3), 253-258.
[http://dx.doi.org/10.1007/s00109-005-0025-1] [PMID:  16389547] 
[226] 
Cao, C.; Li, Y.; Liu, H.; Bai, G.; Mayl, J.; Lin, X.; Sutherland, K.; Nabar, N.; Cai, J. The potential therapeutic effects of THC on Alzheimer’s disease. J. Alzheimers Dis.,  2014, 42(3), 973-984.
[http://dx.doi.org/10.3233/JAD-140093] [PMID:  25024327] 
[227] 
Libro, R.; Diomede, F.; Scionti, D.; Piattelli, A.; Grassi, G.; Pollastro, F.; Bramanti, P.; Mazzon, E.; Trubiani, O. Cannabidiol modulates the expression of Alzheimer’s disease-related genes in mesenchymal stem cells. Int. J. Mol. Sci.,  2016, 18(1), E26.
[http://dx.doi.org/10.3390/ijms18010026] [PMID:  28025562] 
[228] 
Esposito, G.; De Filippis, D.; Steardo, L.; Scuderi, C.; Savani, C.; Cuomo, V.; Iuvone, T. CB1 receptor selective activation inhibits beta-amyloid-induced iNOS protein expression in C6 cells and subsequently blunts tau protein hyperphosphorylation in co-cultured neurons. Neurosci. Lett.,  2006, 404(3), 342-346.
[http://dx.doi.org/10.1016/j.neulet.2006.06.012] [PMID:  16837132] 
[229] 
Wang, L.; Liu, B.J.; Cao, Y.; Xu, W.Q.; Sun, D.S.; Li, M.Z.; Shi, F.X.; Li, M.; Tian, Q.; Wang, J.Z.; Zhou, X.W. Deletion of type-2 cannabinoid receptor induces alzheimer’s Disease-like tau pathology and memory impairment through AMPK/GSK3beta pathway. Mol. Neurobiol., 2017.
[PMID:  28717968] 
[230] 
González-Naranjo, P.; Campillo, N.E.; Pérez, C.; Páez, J.A. Multitarget cannabinoids as novel strategy for Alzheimer disease. Curr. Alzheimer Res.,  2013, 10(3), 229-239.
[http://dx.doi.org/10.2174/1567205011310030002] [PMID:  23369066] 
[231] 
van der Stelt, M.; Mazzola, C.; Esposito, G.; Matias, I.; Petrosino, S.; De Filippis, D.; Micale, V.; Steardo, L.; Drago, F.; Iuvone, T.; Di Marzo, V. Endocannabinoids and beta-amyloid-induced neurotoxicity in vivo: Effect of pharmacological elevation of endocannabinoid levels. Cell. Mol. Life Sci.,  2006, 63(12), 1410-1424.
[http://dx.doi.org/10.1007/s00018-006-6037-3] [PMID:  16732431] 
[232] 
Chen, R.; Zhang, J.; Fan, N.; Teng, Z.Q.; Wu, Y.; Yang, H.; Tang, Y.P.; Sun, H.; Song, Y.; Chen, C.Δ. 9-THC-caused synaptic and memory impairments are mediated through COX-2 signaling. Cell,  2013, 155(5), 1154-1165.
[http://dx.doi.org/10.1016/j.cell.2013.10.042] [PMID:  24267894] 
[233] 
Aso, E.; Sánchez-Pla, A.; Vegas-Lozano, E.; Maldonado, R.; Ferrer, I. Cannabis-based medicine reduces multiple pathological processes in AβPP/PS1 mice. J. Alzheimers Dis.,  2015, 43(3), 977-991.
[http://dx.doi.org/10.3233/JAD-141014] [PMID:  25125475] 
[234] 
Casarejos, M.J.; Perucho, J.; Gomez, A.; Muñoz, M.P.; Fernandez-Estevez, M.; Sagredo, O.; Fernandez Ruiz, J.; Guzman, M.; de Yebenes, J.G.; Mena, M.A. Natural cannabinoids improve dopamine neurotransmission and tau and amyloid pathology in a mouse model of tauopathy. J. Alzheimers Dis.,  2013, 35(3), 525-539.
[http://dx.doi.org/10.3233/JAD-130050] [PMID:  23478312] 
[235] 
Esposito, G.; Scuderi, C.; Savani, C.; Steardo, L., Jr; De Filippis, D.; Cottone, P.; Iuvone, T.; Cuomo, V.; Steardo, L. Cannabidiol in vivo blunts beta-amyloid induced neuroinflammation by suppressing IL-1beta and iNOS expression. Br. J. Pharmacol.,  2007, 151(8), 1272-1279.
[http://dx.doi.org/10.1038/sj.bjp.0707337] [PMID:  17592514] 
[236] 
Martín-Moreno, A.M.; Brera, B.; Spuch, C.; Carro, E.; García-García, L.; Delgado, M.; Pozo, M.A.; Innamorato, N.G.; Cuadrado, A.; de Ceballos, M.L. Prolonged oral cannabinoid administration prevents neuroinflammation, lowers β-amyloid levels and improves cognitive performance in Tg APP 2576 mice. J. Neuroinflammation,  2012, 9, 8.
[http://dx.doi.org/10.1186/1742-2094-9-8] [PMID:  22248049] 
[237] 
Navarro-Dorado, J.; Villalba, N.; Prieto, D.; Brera, B.; Martín-Moreno, A.M.; Tejerina, T.; de Ceballos, M.L. Vascular dysfunction in a transgenic model of alzheimer’s Disease: Effects of CB1R and CB2R cannabinoid agonists. Front. Neurosci.,  2016, 10, 422.
[http://dx.doi.org/10.3389/fnins.2016.00422] [PMID:  27695396] 
[238] 
Aso, E.; Juvés, S.; Maldonado, R.; Ferrer, I. CB2 cannabinoid receptor agonist ameliorates Alzheimer-like phenotype in AβPP/PS1 mice. J. Alzheimers Dis.,  2013, 35(4), 847-858.
[http://dx.doi.org/10.3233/JAD-130137] [PMID:  23515018] 
[239] 
Chen, B.; Bromley-Brits, K.; He, G.; Cai, F.; Zhang, X.; Song, W. Effect of synthetic cannabinoid HU210 on memory deficits and neuropathology in Alzheimer’s disease mouse model. Curr. Alzheimer Res.,  2010, 7(3), 255-261.
[http://dx.doi.org/10.2174/156720510791050948] [PMID:  20043809] 
[240] 
Cheng, Y.; Dong, Z.; Liu, S. β-Caryophyllene ameliorates the Alzheimer-like phenotype in APP/PS1 Mice through CB2 receptor activation and the PPARγ pathway. Pharmacology,  2014, 94(1-2), 1-12.
[http://dx.doi.org/10.1159/000362689] [PMID:  25171128] 
[241] 
Wu, J.; Bie, B.; Yang, H.; Xu, J.J.; Brown, D.L.; Naguib, M. Activation of the CB2 receptor system reverses amyloid-induced memory deficiency. Neurobiol. Aging,  2013, 34(3), 791-804.
[http://dx.doi.org/10.1016/j.neurobiolaging.2012.06.011] [PMID:  22795792] 
[242] 
Mendizábal, V.E.; Adler-Graschinsky, E. Cannabinoids as therapeutic agents in cardiovascular disease: A tale of passions and illusions. Br. J. Pharmacol.,  2007, 151(4), 427-440.
[http://dx.doi.org/10.1038/sj.bjp.0707261] [PMID:  17450170] 
[243] 
Kaschina, E. Cannabinoid CB1/CB2 receptors in the heart: Expression, regulation, and function.Cannabinoids in Health and Disease; Meccariello, R.C.R., Ed.; InTech, 2016. 
[http://dx.doi.org/10.5772/62822] 
[244] 
Bátkai, S.; Pacher, P. Endocannabinoids and cardiac contractile function: pathophysiological implications. Pharmacol. Res.,  2009, 60(2), 99-106.
[http://dx.doi.org/10.1016/j.phrs.2009.04.003] [PMID:  19569260] 
[245] 
Steffens, S.; Pacher, P. Targeting cannabinoid receptor CB(2) in cardiovascular disorders: Promises and controversies. Br. J. Pharmacol.,  2012, 167(2), 313-323.
[http://dx.doi.org/10.1111/j.1476-5381.2012.02042.x] [PMID:  22612332] 
[246] 
Zubrzycki, M.; Liebold, A.; Janecka, A.; Zubrzycka, M. A new face of endocannabinoids in pharmacotherapy. Part II: role of endocannabinoids in inflammation-derived cardiovaascular diseases. J. Physiol. Pharmacol.,  2014, 65(2), 183-191.
[PMID:  24781728] 
[247] 
Mukhopadhyay, P.; Rajesh, M.; Pan, H.; Patel, V.; Mukhopadhyay, B.; Bátkai, S.; Gao, B.; Haskó, G.; Pacher, P. Cannabinoid-2 receptor limits inflammation, oxidative/nitrosative stress, and cell death in nephropathy. Free Radic. Biol. Med.,  2010, 48(3), 457-467.
[http://dx.doi.org/10.1016/j.freeradbiomed.2009.11.022] [PMID:  19969072] 
[248] 
Mach, F.; Steffens, S. The role of the endocannabinoid system in atherosclerosis. J. Neuroendocrinol.,  2008, 20(Suppl. 1), 53-57.
[http://dx.doi.org/10.1111/j.1365-2826.2008.01685.x] [PMID:  18426500] 
[249] 
Chiurchiù, V.; Lanuti, M.; Catanzaro, G.; Fezza, F.; Rapino, C.; Maccarrone, M. Detailed characterization of the endocannabinoid system in human macrophages and foam cells, and anti-inflammatory role of type-2 cannabinoid receptor. Atherosclerosis,  2014, 233(1), 55-63.
[http://dx.doi.org/10.1016/j.atherosclerosis.2013.12.042] [PMID:  24529123] 
[250] 
McLaren, J.E.; Michael, D.R.; Ashlin, T.G.; Ramji, D.P. Cytokines, macrophage lipid metabolism and foam cells: implications for cardiovascular disease therapy. Prog. Lipid Res.,  2011, 50(4), 331-347.
[http://dx.doi.org/10.1016/j.plipres.2011.04.002] [PMID:  21601592] 
[251] 
Libby, P. Inflammation in atherosclerosis. Nature,  2002, 420(6917), 868-874.
[http://dx.doi.org/10.1038/nature01323] [PMID:  12490960] 
[252] 
Libby, P. Inflammation in atherosclerosis. Arterioscler. Thromb. Vasc. Biol.,  2012, 32(9), 2045-2051.
[http://dx.doi.org/10.1161/ATVBAHA.108.179705] [PMID:  22895665] 
[253] 
Swirski, F.K.; Nahrendorf, M. Leukocyte behavior in atherosclerosis, myocardial infarction, and heart failure. Science,  2013, 339(6116), 161-166.
[http://dx.doi.org/10.1126/science.1230719] [PMID:  23307733] 
[254] 
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(7034), 782-786.
[http://dx.doi.org/10.1038/nature03389] [PMID:  15815632] 
[255] 
Carbone, F.; Mach, F.; Vuilleumier, N.; Montecucco, F. Cannabinoid receptor type 2 activation in atherosclerosis and acute cardiovascular diseases. Curr. Med. Chem.,  2014, 21(35), 4046-4058.
[http://dx.doi.org/10.2174/0929867321666140915141332] [PMID:  25245379] 
[256] 
Zhao, Y.; Yuan, Z.; Liu, Y.; Xue, J.; Tian, Y.; Liu, W.; Zhang, W.; Shen, Y.; Xu, W.; Liang, X.; Chen, T. Activation of cannabinoid CB2 receptor ameliorates atherosclerosis associated with suppression of adhesion molecules. J. Cardiovasc. Pharmacol.,  2010, 55(3), 292-298.
[http://dx.doi.org/10.1097/FJC.0b013e3181d2644d] [PMID:  20075743] 
[257] 
Willecke, F.; Zeschky, K.; Ortiz Rodriguez, A.; Colberg, C.; Auwärter, V.; Kneisel, S.; Hutter, M.; Lozhkin, A.; Hoppe, N.; Wolf, D.; von zur Mühlen, C.; Moser, M.; Hilgendorf, I.; Bode, C.; Zirlik, A. Cannabinoid receptor 2 signaling does not modulate atherogenesis in mice. PLoS One,  2011, 6(4), e19405.
[http://dx.doi.org/10.1371/journal.pone.0019405] [PMID:  21541300] 
[258] 
Kalogeris, T.; Baines, C.P.; Krenz, M.; Korthuis, R.J. Cell biology of ischemia/reperfusion injury. Int. Rev. Cell Mol. Biol.,  2012, 298, 229-317.
[http://dx.doi.org/10.1016/B978-0-12-394309-5.00006-7] [PMID:  22878108] 
[259] 
Wang, P.F.; Jiang, L.S.; Bu, J.; Huang, X.J.; Song, W.; Du, Y.P.; He, B. Cannabinoid-2 receptor activation protects against infarct and ischemia-reperfusion heart injury. J. Cardiovasc. Pharmacol.,  2012, 59(4), 301-307.
[http://dx.doi.org/10.1097/FJC.0b013e3182418997] [PMID:  22113346] 
[260] 
Pacher, P.; Haskó, G. Endocannabinoids and cannabinoid receptors in ischaemia-reperfusion injury and preconditioning. Br. J. Pharmacol.,  2008, 153(2), 252-262.
[http://dx.doi.org/10.1038/sj.bjp.0707582] [PMID:  18026124] 
[261] 
Lépicier, P.; Bibeau-Poirier, A.; Lagneux, C.; Servant, M.J.; Lamontagne, D. Signaling pathways involved in the cardioprotective effects of cannabinoids. J. Pharmacol. Sci.,  2006, 102(2), 155-166.
[http://dx.doi.org/10.1254/jphs.CRJ06011X] [PMID:  17031075] 
[262] 
Carbone, F.; Nencioni, A.; Mach, F.; Vuilleumier, N.; Montecucco, F. Pathophysiological role of neutrophils in acute myocardial infarction. Thromb. Haemost.,  2013, 110(3), 501-514.
[http://dx.doi.org/10.1160/TH13-03-0211] [PMID:  23740239] 
[263] 
Lagneux, C.; Lamontagne, D. Involvement of cannabinoids in the cardioprotection induced by lipopolysaccharide. Br. J. Pharmacol.,  2001, 132(4), 793-796.
[http://dx.doi.org/10.1038/sj.bjp.0703902] [PMID:  11181418] 
[264] 
Joyeux, M.; Arnaud, C.; Godin-Ribuot, D.; Demenge, P.; Lamontagne, D.; Ribuot, C. Endocannabinoids are implicated in the infarct size-reducing effect conferred by heat stress preconditioning in isolated rat hearts. Cardiovasc. Res.,  2002, 55(3), 619-625.
[http://dx.doi.org/10.1016/S0008-6363(02)00268-7] 
[265] 
Di Filippo, C.; Rossi, F.; Rossi, S.; D’Amico, M. Cannabinoid CB2 receptor activation reduces mouse myocardial ischemia-reperfusion injury: involvement of cytokine/chemokines and PMN. J. Leukoc. Biol.,  2004, 75(3), 453-459.
[http://dx.doi.org/[https://doi.org/10.1189/jlb.0703303] 
[266] 
Montecucco, F.; Lenglet, S.; Braunersreuther, V.; Burger, F.; Pelli, G.; Bertolotto, M.; Mach, F.; Steffens, S. CB(2) cannabinoid receptor activation is cardioprotective in a mouse model of ischemia/reperfusion. J. Mol. Cell. Cardiol.,  2009, 46(5), 612-620.
[http://dx.doi.org/10.1016/j.yjmcc.2008.12.014] [PMID:  19162037] 
[267] 
Defer, N.; Wan, J.; Souktani, R.; Escoubet, B.; Perier, M.; Caramelle, P.; Manin, S.; Deveaux, V.; Bourin, M.C.; Zimmer, A.; Lotersztajn, S.; Pecker, F.; Pavoine, C. The cannabinoid receptor type 2 promotes cardiac myocyte and fibroblast survival and protects against ischemia/reperfusion-induced cardiomyopathy. FASEB J.,  2009, 23(7), 2120-2130.
[http://dx.doi.org/10.1096/fj.09-129478] [PMID:  19246487] 
[268] 
Li, Q.; Wang, F.; Zhang, Y.M.; Zhou, J.J.; Zhang, Y. Activation of cannabinoid type 2 receptor by JWH133 protects heart against ischemia/reperfusion-induced apoptosis. Cell. Physiol. Biochem.,  2013, 31(4-5), 693-702.
[http://dx.doi.org/10.1159/000350088] [PMID:  23711495] 
[269] 
Wang, Y.; Ma, S.; Wang, Q.; Hu, W.; Wang, D.; Li, X.; Su, T.; Qin, X.; Zhang, X.; Ma, K.; Chen, J.; Xiong, L.; Cao, F. Effects of cannabinoid receptor type 2 on endogenous myocardial regeneration by activating cardiac progenitor cells in mouse infarcted heart. Sci. China Life Sci.,  2014, 57(2), 201-208.
[http://dx.doi.org/10.1007/s11427-013-4604-z] [PMID:  24430557] 
[270] 
Krylatov, A.V.; Ugdyzhekova, D.S.; Bernatskaya, N.A.; Maslov, L.N.; Mekhoulam, R.; Pertwee, R.G.; Stephano, G.B. Activation of type II cannabinoid receptors improves myocardial tolerance to arrhythmogenic effects of coronary occlusion and reperfusion. Bull. Exp. Biol. Med.,  2001, 131(6), 523-525.
[http://dx.doi.org/10.1023/A:1012381914518] [PMID:  11586395] 
[271] 
Hillard, C.J. Role of cannabinoids and endocannabinoids in cerebral ischemia. Curr. Pharm. Des.,  2008, 14(23), 2347-2361.
[http://dx.doi.org/10.2174/138161208785740054] [PMID:  18781985] 
[272] 
Zhang, M.; Martin, B.R.; Adler, M.W.; Razdan, R.K.; Jallo, J.I.; Tuma, R.F. Cannabinoid CB(2) receptor activation decreases cerebral infarction in a mouse focal ischemia/reperfusion model. J. Cereb. Blood Flow Metab.,  2007, 27(7), 1387-1396.
[http://dx.doi.org/10.1038/sj.jcbfm.9600447] [PMID:  17245417] 
[273] 
Zhang, M.; Martin, B.R.; Adler, M.W.; Razdan, R.K.; Ganea, D.; Tuma, R.F. Modulation of the balance between cannabinoid CB(1) and CB(2) receptor activation during cerebral ischemic/reperfusion injury. Neuroscience,  2008, 152(3), 753-760.
[http://dx.doi.org/10.1016/j.neuroscience.2008.01.022] [PMID:  18304750] 
[274] 
Murikinati, S.; Jüttler, E.; Keinert, T.; Ridder, D.A.; Muhammad, S.; Waibler, Z.; Ledent, C.; Zimmer, A.; Kalinke, U.; Schwaninger, M. Activation of cannabinoid 2 receptors protects against cerebral ischemia by inhibiting neutrophil recruitment. FASEB J.,  2010, 24(3), 788-798.
[http://dx.doi.org/10.1096/fj.09-141275] [PMID:  19884325] 
[275] 
Zarruk, J.G.; Fernández-López, D.; García-Yébenes, I.; García-Gutiérrez, M.S.; Vivancos, J.; Nombela, F.; Torres, M.; Burguete, M.C.; Manzanares, J.; Lizasoain, I.; Moro, M.A. Cannabinoid type 2 receptor activation downregulates stroke-induced classic and alternative brain macrophage/microglial activation concomitant to neuroprotection. Stroke,  2012, 43(1), 211-219.
[http://dx.doi.org/10.1161/STROKEAHA.111.631044] [PMID:  22020035] 
[276] 
Fernández-López, D.; Faustino, J.; Derugin, N.; Wendland, M.; Lizasoain, I.; Moro, M.A.; Vexler, Z.S. Reduced infarct size and accumulation of microglia in rats treated with WIN 55,212-2 after neonatal stroke. Neuroscience,  2012, 207, 307-315.
[http://dx.doi.org/10.1016/j.neuroscience.2012.01.008] [PMID:  22285309] 
[277] 
Bravo-Ferrer, I.; Cuartero, M.I.; Zarruk, J.G.; Pradillo, J.M.; Hurtado, O.; Romera, V.G.; Díaz-Alonso, J.; García-Segura, J.M.; Guzmán, M.; Lizasoain, I.; Galve-Roperh, I.; Moro, M.A. Cannabinoid type-2 receptor drives neurogenesis and improves functional outcome after stroke. Stroke,  2017, 48(1), 204-212.
[http://dx.doi.org/10.1161/STROKEAHA.116.014793] [PMID:  27899748] 
[278] 
Zamberletti, E.; Gabaglio, M.; Parolaro, D. The endocannabinoid system and autism spectrum disorders: Insights from animal models. Int. J. Mol. Sci.,  2017, 18(9), E1916.
[http://dx.doi.org/10.3390/ijms18091916] [PMID:  28880200] 
[279] 
Elsabbagh, M.; Divan, G.; Koh, Y.J.; Kim, Y.S.; Kauchali, S.; Marcín, C.; Montiel-Nava, C.; Patel, V.; Paula, C.S.; Wang, C.; Yasamy, M.T.; Fombonne, E. Global prevalence of autism and other pervasive developmental disorders. Autism Res.,  2012, 5(3), 160-179.
[http://dx.doi.org/10.1002/aur.239] [PMID:  22495912] 
[280] 
Habib, S.S.; Al-Regaiey, K.; Bashir, S.; Iqbal, M. Role of endocannabinoids on neuroinflammation in autism spectrum disorder prevention. J. Clin. Diagn. Res.,  2017, 11(6), CE01-CE03.
[http://dx.doi.org/10.7860/JCDR/2017/23862.9969] [PMID:  28764155] 
[281] 
Turcotte, C.; Blanchet, M.R.; Laviolette, M.; Flamand, N. The CB2 receptor and its role as a regulator of inflammation. Cell. Mol. Life Sci.,  2016, 73(23), 4449-4470.
[http://dx.doi.org/10.1007/s00018-016-2300-4] [PMID:  27402121] 
[282] 
Zoppi, S.; Madrigal, J.L.; Caso, J.R.; García-Gutiérrez, M.S.; Manzanares, J.; Leza, J.C.; García-Bueno, B. Regulatory role of the cannabinoid CB2 receptor in stress-induced neuroinflammation in mice. Br. J. Pharmacol.,  2014, 171(11), 2814-2826.
[http://dx.doi.org/10.1111/bph.12607] [PMID:  24467609] 
[283] 
Kini, U.N. Physiology of Bone Formation, Remodeling, and Metabolism. In Radionuclide and Hybrid Bone Imaging [Online] Fogelman. In: Springer; I. Gnanasegaran, G.; van der Wall, H., Eds; , 2012. 
[284] 
Bab, I.; Ofek, O.; Tam, J.; Rehnelt, J.; Zimmer, A. Endocannabinoids and the regulation of bone metabolism. J. Neuroendocrinol.,  2008, 20(Suppl. 1), 69-74.
[http://dx.doi.org/10.1111/j.1365-2826.2008.01675.x] [PMID:  18426503] 
[285] 
Tam, J.; Trembovler, V.; Di Marzo, V.; Petrosino, S.; Leo, G.; Alexandrovich, A.; Regev, E.; Casap, N.; Shteyer, A.; Ledent, C.; Karsak, M.; Zimmer, A.; Mechoulam, R.; Yirmiya, R.; Shohami, E.; Bab, I. The cannabinoid CB1 receptor regulates bone formation by modulating adrenergic signaling. FASEB J.,  2008, 22(1), 285-294.
[http://dx.doi.org/10.1096/fj.06-7957com] [PMID:  17704191] 
[286] 
Zimmer, A. A collaboration investigating endocannabinoid signalling in brain and bone. J. Basic Clin. Physiol. Pharmacol.,  2016, 27(3), 229-235.
[http://dx.doi.org/10.1515/jbcpp-2015-0125] [PMID:  26887036] 
[287] 
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(3), 696-701.
[http://dx.doi.org/10.1073/pnas.0504187103] [PMID:  16407142] 
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DOI https://dx.doi.org/10.2174/0929867325666180226095132	Print ISSN 0929-8673
Publisher Name Bentham Science Publisher	Online ISSN 1875-533X
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