Targeting cannabinoid CB2 receptors in the central nervous system. Medicinal chemistry approaches with focus on neurodegenerative disorders

Frontiers in Neuroscience

Volumn 10, Issue SEP, 2016, Pages

  Navarro, Gemma ^a,b   Morales, Paula ^c,d   Rodríguez Cueto, Carmen ^b,e,f   Fernández Ruiz, Javier ^b,e,f   Jagerovic, Nadine ^c   Franco, Rafael ^a,b  

^a UNIVERSITY OF BARCELONA   (Spain)

^b CENTRO DE INVESTIGACIÓN BIOMÉDICA EN RED SOBRE ENFERMEDADES NEURODEGENERATIVAS CIBERNED   (Spain)

^c INSTITUTO DE QUÍMICA MÉDICA   (Spain)

^d UNIVERSITY OF NORTH CAROLINA AT GREENSBORO   (United States)

^e UNIVERSIDAD COMPLUTENSE DE MADRID   (Spain)

^f INSTITUTO RAMÓN Y CAJAL DE INVESTIGACIÓN SANITARIA IRYCIS   (Spain)

Author keywords

Amyotrophic lateral sclerosis; Astroglia; GPCR; Heteromer; M0 M1 M2 phenotype; Microglia; Neuroprotection; Neurorestoration

Indexed keywords

CANNABINOID 1 RECEPTOR; CANNABINOID 2 RECEPTOR; CANNABINOID 2 RECEPTOR AGONIST; REAGENT;

DEGENERATIVE DISEASE; DRUG BINDING; DRUG DESIGN; DRUG STRUCTURE; DRUG TARGETING; HUMAN; LIGAND BINDING; MEDICINAL CHEMISTRY; NERVE CELL; NEUROIMAGING; NONHUMAN; POSITRON EMISSION TOMOGRAPHY; PROTEIN EXPRESSION; RECEPTOR BINDING; REVIEW;

EID: 85053361470     PISSN: 16624548     EISSN: 1662453X     Source Type: Journal    
DOI: 10.3389/fnins.2016.00406     Document Type: Review

References (112)

1. Aghazadeh Tabrizi, M., Baraldi, P. G., Borea, P. A., and Varani, K. (2016). Medicinal chemistry, pharmacology, and potential therapeutic benefits of cannabinoid CB2 Receptor Agonists. Chem. Rev. 116, 519-560. doi: 10.1021/acs.chemrev.5b00411
2. Ahmad, R., Koole, M., Evens, N., Serdons, K., Verbruggen, A., Bormans, G., et al. (2013). Whole-body biodistribution and radiation dosimetry of the cannabinoid type 2 receptor ligand [11C]-NE40 in healthy subjects. Mol. Imaging Bio. 15, 384-390. doi: 10.1007/s11307-013-0626-y
3. Alger, B. E. (2002). Retrograde signaling in the regulation of synaptic transmission: focus on endocannabinoids. Prog. Neurobiol. 68, 247-286. doi: 10.1016/S0301-0082(02)00080-1
4. Alshaarawy, O., and Anthony, J. C. (2015). Cannabis smoking and serum C-reactive protein: a quantile regressions approach based on NHANES 2005-2010. Drug Alcohol Depend. 147, 203-207. doi: 10.1016/j.drugalcdep.2014.11.017
5. Amenta, P. S., Jallo, J. I., Tuma, R. F., and Elliott, M. B. (2012). A cannabinoid type 2 receptor agonist attenuates blood-brain barrier damage and neurodegeneration in a murine model of traumatic brain injury. J. Neurosci. Res. 90, 2293-2305. doi: 10.1002/jnr.23114
6. Aracil-Fernández, A., Trigo, J. M., García-Gutiérrez, M. S., Ortega-álvaro, A., Ternianov, A., Navarro, D., et al. (2012). Decreased cocaine motor sensitization and self-administration in mice overexpressing cannabinoid CB2 receptors. Neuropsychopharmacology 37, 1749-1763. doi: 10.1038/npp.2012.22
7. Ashton, J. C., Friberg, D., Darlington, C. L., and Smith, P. F. (2006). Expression of the cannabinoid CB2 receptor in the rat cerebellum: an immunohistochemical study. Neurosci. Lett. 396, 113-116. doi: 10.1016/j.neulet.2005.11.038
8. Atwood, B. K., and Mackie, K. (2010). CB2: a cannabinoid receptor with an identity crisis. Br. J. Pharmacol. 160, 467-479. doi: 10.1111/j.1476-5381.2010.00729.x
9. Atwood, B. K., Straiker, A., and Mackie, K. (2012). CB2: therapeutic target-in-waiting. Prog. Neuropsychopharmacol. Biol. Psychiatry 38, 16-20. doi: 10.1016/j.pnpbp.2011.12.001
10. Avraham, H. K., Jiang, S., Fu, Y., Rockenstein, E., Makriyannis, A., Zvonok, A., et al. (2014). The cannabinoid CB2 receptor agonist AM1241 enhances neurogenesis in GFAP/Gp120 transgenic mice displaying deficits in neurogenesis. Br. J. Pharmacol. 171, 468-479. doi: 10.1111/bph.12478
11. Bahi, A., Al Mansouri, S., Al Memari, E., Al Ameri, M., Nurulain, S. M., and Ojha, S. (2014). β-Caryophyllene, a CB2 receptor agonist produces multiple behavioral changes relevant to anxiety and depression in mice. Physiol. Behav. 135, 119-124. doi: 10.1016/j.physbeh.2014.06.003
12. Birnkammer, T., Spickenreither, A., Brunskole, I., Lopuch, M., Kagermeier, N., Bernhardt, G., et al. (2012). The bivalent ligand approach leads to highly potent and selective acylguanidine-type histamine H 2 receptor agonists. J. Med. Chem. 55, 1147-1160. doi: 10.1021/jm201128q
13. Blanco-Calvo, E., Rivera, P., Arrabal, S., Vargas, A., Pavón, F. J., Serrano, A., et al. (2014). Pharmacological blockade of either cannabinoid CB1 or CB2 receptors prevents both cocaine-induced conditioned locomotion and cocaine-induced reduction of cell proliferation in the hippocampus of adult male rat. Front. Integr. Neurosci. 7:106. doi: 10.3389/fnint.2013.00106
14. Borroto-Escuela, D. O., Brito, I., Romero-Fernandez, W., Di Palma, M., Oflijan, J., Skieterska, K., et al. (2014). The G protein-coupled receptor heterodimer network (GPCR-HetNet) and its hub components. Int. J. Mol. Sci. 15, 8570-8590. doi: 10.3390/ijms15058570
15. Brusco, A., Tagliaferro, P., Saez, T., and Onaivi, E. S. (2008). Postsynaptic localization of CB2 cannabinoid receptors in the rat hippocampus. Synapse 62, 944-949. doi: 10.1002/syn.20569
16. Callén, L., Moreno, E., Barroso-Chinea, P., Moreno-Delgado, D., Cortés, A., Mallol, J., et al. (2012). Cannabinoid receptors CB1 and CB2 form functional heteromers in brain. J. Biol. Chem. 287, 20851-20865. doi: 10.1074/jbc.M111.335273
17. Campillo, N. E., and Páez, J. A. (2009). Cannabinoid system in neurodegeneration: new perspectives in Alzheimer's disease. Mini Rev. Med. Chem. 9, 539-559. doi: 10.2174/138955709788167628
18. Carai, M. A. M., Colombo, G., Maccioni, P., and Gessa, G. L. (2006). Efficacy of rimonabant and other cannabinoid CB1 receptor antagonists in reducing food intake and body weight: preclinical and clinical data. CNS Drug Rev. 12, 91-99. doi: 10.1111/j.1527-3458.2006.00091.x
19. Carrier, E. J., Kearn, C. S., Barkmeier, A. J., Breese, N. M., Yang, W., Nithipatikom, K., et al. (2004). Cultured rat microglial cells synthesize the endocannabinoid 2-arachidonylglycerol, which increases proliferation via a CB2 receptor-dependent mechanism. Mol. Pharmacol. 65, 999-1007. doi: 10.1124/mol.65.4.999
20. Chicca, A., Gachet, M. S., Petrucci, V., Schuehly, W., Charles, R.-P., and Gertsch, J. (2015). 4'-O-methylhonokiol increases levels of 2-arachidonoyl glycerol in mouse brain via selective inhibition of its COX-2-mediated oxygenation. J. Neuroinflammation 12, 89. doi: 10.1186/s12974-015-0307-7
21. Chung, Y. C., Shin, W.-H., Baek, J. Y., Cho, E. J., Baik, H. H., Kim, S. R., et al. (2016). CB2 receptor activation prevents glial-derived neurotoxic mediator production, BBB leakage and peripheral immune cell infiltration and rescues dopamine neurons in the MPTP model of Parkinson's disease. Exp. Mol. Med. 48:e205. doi: 10.1038/emm.2015.100
22. Contartese, A., Valoti, M., Corelli, F., Pasquini, S., Mugnaini, C., Pessina, F., et al. (2012). A novel CB2 agonist, COR167, potently protects rat brain cortical slices against OGD and reperfusion injury. Pharmacol. Res. 66, 555-563. doi: 10.1016/j.phrs.2012.08.003
23. Cordomí, A., Navarro, G., Aymerich, M. S., and Franco, R. (2015). Structures for G-protein-coupled receptor tetramers in complex with g proteins. Trends Biochem. Sci. 40, 548-551. doi: 10.1016/j.tibs.2015.07.007
24. den Boon, F. S., Chameau, P., Schaafsma-zhao, Q., Van Aken, W., Bari, M., Oddi, S., et al. (2012). Excitability of prefrontal cortical pyramidal neurons is modulated by activation of intracellular type-2 cannabinoid receptors. Proc. Natl. Acad. Sci. U.S.A. 109, 1-6. doi: 10.1073/pnas.1118167109
25. Dhopeshwarkar, A., and Mackie, K. (2014). CB2 Cannabinoid receptors as a therapeutic target-what does the future hold? Mol. Pharmacol. 86, 430-437. doi: 10.1124/mol.114.094649
26. Di Napoli, M., Godoy, D. A., Campi, V., Masotti, L., Smith, C. J., Parry Jones, A. R., et al. (2012). C-reactive protein in intracerebral hemorrhage: time course, tissue localization, and prognosis. Neurology 79, 690-699. doi: 10.1212/WNL.0b013e318264e3be
27. Di Napoli, M., Zha, A. M., Godoy, D. A., Masotti, L., Schreuder, F. H. B. M., Popa-Wagner, A., et al. (2016). Prior cannabis use is associated with outcome after intracerebral hemorrhage. Cerebrovasc. Dis. 41, 248-255. doi: 10.1159/000443532
28. Dowie, M. J., Grimsey, N. L., Hoffman, T., Faull, R. L. M., and Glass, M. (2014). Cannabinoid receptor CB2 is expressed on vascular cells, but not astroglial cells in the post-mortem human Huntington's disease brain. J. Chem. Neuroanat. 59, 62-71. doi: 10.1016/j.jchemneu.2014.06.004
29. Espejo-Porras, F., Piscitelli, F., Verde, R., Ramos, J. A., Di Marzo, V., de Lago, E., et al. (2015). Changes in the endocannabinoid signaling system in CNS structures of TDP-43 transgenic mice: relevance for a neuroprotective therapy in TDP-43-related disorders. J. Neuroimmune Pharmacol. 10, 233-244. doi: 10.1007/s11481-015-9602-4
30. Evens, N., and Bormans, G. M. (2010). Non-invasive imaging of the type 2 cannabinoid receptor, focus on positron emission tomography. Curr. Top. Med. Chem. 10, 1527-1543. doi: 10.2174/156802610793176819
31. Fernández-Ruiz, J., de Lago, E., Gómez-Ruiz, M., García, C., Sagredo, O., and García-Arencíbia, M. (2014). "Neurodegenerative disorders other than multiple sclerosis," in Handbook of Cannabis, ed R. Pertwee (Oxford: Oxford University Press), 505-525. doi: 10.1093/acprof:oso/9780199662685.003.0027
32. Fernández-Ruiz, J., Romero, J., and Ramos, J. A. (2015). Endocannabinoids and neurodegenerative disorders: Parkinson's Disease, Huntington's Chorea, Alzheimer's Disease, and Others. Handb. Exp. Pharmacol. 231, 233-259. doi: 10.1007/978-3-319-20825-1_8
33. Fernández-Ruiz, J., Romero, J., Velasco, G., Tolón, R. M., Ramos, J. A., and Guzmán, M. (2007). Cannabinoid CB2 receptor: a new target for controlling neural cell survival? Trends Pharmacol. Sci. 28, 39-45. doi: 10.1016/j.tips.2006.11.0 01
34. Ferré, S., Baler, R., Bouvier, M., Caron, M. G., Devi, L. A., Durroux, T., et al. (2009). Building a new conceptual framework for receptor heteromers. Nat. Chem. Biol. 5, 131-134. doi: 10.1038/nchembio0309-131
35. Franco, R., and Fernández-Suárez, D. (2015). Alternatively activated microglia and macrophages in the central nervous system. Prog. Neurobiol. 131, 65-86. doi: 10.1016/j.pneurobio.2015.05.003
36. Franco, R., Martínez-Pinilla, E., Lanciego, J. L., and Navarro, G. (2016). Basic pharmacological and structural evidence for class a g-protein-coupled receptor heteromerization. Front. Pharmacol. 7:76. doi: 10.3389/fphar.2016.00076
37. Fujii, M., Sherchan, P., Krafft, P. R., Rolland, W. B., and Soejima, Y. Z. J. (2014). Cannabinoid type 2 receptor stimulation attenuates brain edema by reducing cerebral leukocyte infiltration following subarachnoid hemorrhage in rats. J. Neurol. Sci. 342, 101-106. doi: 10.1016/j.jns.2014.04.034
38. Fulton, B. S., Knapp, B. L., Bidlack, J. M., and Neumeyer, J. L. (2010). Effect of linker substitution on the binding of butorphan univalent and bivalent ligands to opioid receptors. Bioorganic Med. Chem. Lett. 20, 1507-1509. doi: 10.1016/j.bmcl.2010.01.101
39. García, C., Palomo-Garo, C., Gómez-Gálvez, Y., and Fernández-Ruiz, J. (2016). Cannabinoid-dopamine interactions in the physiology and physiopathology of the basal ganglia. Br. J. Pharmacol. 173, 2069-2079. doi: 10.1111/bph.13215
40. García-Cabrerizo, R., and García-Fuster, M. J. (2016). Opposite regulation of cannabinoid CB1 and CB2 receptors in the prefrontal cortex of rats treated with cocaine during adolescence. Neurosci. Lett. 615, 60-65. doi: 10.1016/j.neulet.2016.01.018
41. García-Gutiérrez, M. S., and Manzanares, J. (2011). Overexpression of CB2 cannabinoid receptors decreased vulnerability to anxiety and impaired anxiolytic action of alprazolam in mice. J. Psychopharmacol. 25, 111-120. doi: 10.1177/0269881110379507
42. García-Gutiérrez, M. S., Pérez-Ortiz, J. M., Gutiérrez-Adán, A., and Manzanares, J. (2010). Depression-resistant endophenotype in mice overexpressing cannabinoid CB(2) receptors. Br. J. Pharmacol. 160, 1773-1784. doi: 10.1111/j.1476-5381.2010.00819.x
43. Glass, M., Govindpani, K., Furkert, D. P., Hurst, D. P., Reggio, P. H., and Flanagan, J. U. (2016). One for the Price of two...are bivalent ligands targeting cannabinoid receptor dimers capable of simultaneously binding to both receptors? Trends Pharmacol. Sci. 37, 353-363. doi: 10.1016/j.tips.2016.01.010
44. Gogoi, S., Biswas, S., Modi, G., Antonio, T., Reith, M. E. A., and Dutta, A. K. (2012). Novel bivalent ligands for D2/D3 dopamine receptors: significant cooperative gain in D2 affinity and potency. ACS Med. Chem. Lett. 3, 991-996. doi: 10.1021/ml3002117
45. Gómez-Cañas, M., Morales, P., García-Toscano, L., Navarrete, C., Muñoz, E., Jagerovic, N., et al. (2016). Biological characterization of PM226, a chromenoisoxazole, as a selective CB2 receptor agonist with neuroprotective profile. Pharmacol. Res. 110, 205-215. doi: 10.1016/j.phrs.2016.03.021
46. Gómez-Gálvez, Y., Palomo-Garo, C., Fernández-Ruiz, J., and García, C. (2016). Potential of the cannabinoid CB2 receptor as a pharmacological target against inflammation in Parkinson's disease. Prog. Neuropsychopharmacol. Biol. Psychiatry 64, 200-208. doi: 10.1016/j.pnpbp.2015.03.017
47. Gomez, O., Arevalo-Martin, A., Garcia-Ovejero, D., Ortega-Gutierrez, S., Cisneros, J. A., Almazan, G., et al. (2010). The constitutive production of the endocannabinoid 2-arachidonoylglycerol participates in oligodendrocyte differentiation. Glia 58, 1913-1927. doi: 10.1002/glia.21061
48. Gomez, O., Sanchez-Rodriguez, A., Le, M., Sanchez-Caro, C., Molina-Holgado, F., and Molina-Holgado, E. (2011). Cannabinoid receptor agonists modulate oligodendrocyte differentiation by activating PI3K/Akt and the mammalian target of rapamycin (mTOR) pathways. Br. J. Pharmacol. 163, 1520-1532. doi: 10.1111/j.1476-5381.2011.01414.x
49. Goncalves, M. B., Suetterlin, P., Yip, P., Molina-Holgado, F., Walker, D. J., Oudin, M. J., et al. (2008). A diacylglycerol lipase-CB2 cannabinoid pathway regulates adult subventricular zone neurogenesis in an age-dependent manner. Mol. Cell. Neurosci. 38, 526-536. doi: 10.1016/j.mcn.2008.05.001
50. Gong, J.-P., Onaivi, E. S., Ishiguro, H., Liu, Q.-R., Tagliaferro, P. A., Brusco, A., et al. (2006). Cannabinoid CB2 receptors: immunohistochemical localization in rat brain. Brain Res. 1071, 10-23. doi: 10.1016/j.brainres.2005.11.035
51. Green, S. T., Nathwani, D., Goldberg, D. J., and Kennedy, D. H. (1989). Nabilone as effective therapy for intractable nausea and vomiting in AIDS. Br. J. Clin. Pharmacol. 28, 494-495. doi: 10.1111/j.1365-2125.1989.tb03533.x
52. Guo, J., Pavlopoulos, S., Tian, X., Lu, D., Nikas, S. P., Yang, D., et al. (2003). Conformational study of lipophilic ligands in phospholipid model membrane systems by solution NMR. J. Med. Chem. 46, 4838-4846. doi: 10.1021/jm020385r
53. Guo, K., Mou, X., Huang, J., Xiong, N., and Li, H. (2014). Trans-caryophyllene suppresses hypoxia-induced neuroinflammatory responses by inhibiting NF-κB activation in microglia. J. Mol. Neurosci. 54, 41-48. doi: 10.1007/s12031-014-0243-5
54. Han, S., Chen, J. J., and Chen, J.-Z. (2014). Latest progress in the identification of novel synthetic ligands for the cannabinoid CB2 receptor. Mini Rev. Med. Chem. 14, 426-443. doi: 10.2174/1389557514666140428105753
55. Han, S., Zhang, F.-F., Qian, H.-Y., Chen, L.-L., Pu, J.-B., Xie, X., et al. (2015). Development of quinoline-2, 4(1 H, 3 H)-diones as potent and selective ligands of the cannabinoid type 2 receptor. J. Med. Chem. 58, 5751-5769. doi: 10.1021/acs.jmedchem.5b00227
56. Hortala, L., Arnaud, J., Roux, P., Oustric, D., Boulu, L., Oury-Donat, F., et al. (2014). Synthesis and preliminary evaluation of a new fluorine-18 labelled triazine derivative for PET imaging of cannabinoid CB2 receptor. Bioorganic Med. Chem. Lett. 24, 283-287. doi: 10.1016/j.bmcl.2013.11.023
57. Hu, B., Doods, H., Treede, R.-D., and Ceci, A. (2009). Depression-like behaviour in rats with mononeuropathy is reduced by the CB2-selective agonist GW405833. Pain 143, 206-212. doi: 10.1016/j.pain.2009.02.018
58. Hu, S. S.-J., and Mackie, K. (2015). Distribution of the endocannabinoid system in the central nervous system. Handb. Exp. Pharmacol. 231, 59-93. doi: 10.1007/978-3-319-20825-1_3
59. Hurst, D. P., Grossfield, A., Lynch, D. L., Feller, S., Romo, T. D., Gawrisch, K., et al. (2010). A lipid pathway for ligand binding is necessary for a cannabinoid G protein-coupled receptor. J. Biol. Chem. 285, 17954-17964. doi: 10.1074/jbc.M109.041590
60. Ishiguro, H., Carpio, O., Horiuchi, Y., Shu, A., Higuchi, S., Schanz, N., et al. (2010a). A nonsynonymous polymorphism in cannabinoid CB2 receptor gene is associated with eating disorders in humans and food intake is modified in mice by its ligands. Synapse 64, 92-96. doi: 10.1002/syn.20714
61. Ishiguro, H., Horiuchi, Y., Ishikawa, M., Koga, M., Imai, K., Suzuki, Y., et al. (2010b). Brain cannabinoid CB2 receptor in schizophrenia. Biol. Psychiatry 67, 974-982. doi: 10.1016/j.biopsych.2009.09.024
62. Jhaveri, M. D., Sagar, D. R., Elmes, S. J. R., Kendall, D. A., and Chapman, V. (2007). Cannabinoid CB2 receptor-mediated anti-nociception in models of acute and chronic pain. Mol. Neurobiol. 36, 26-35. doi: 10.1007/s12035-007-8007-7
63. Jia, J., Peng, J., Li, Z., Wu, Y., Wu, Q., Tu, W., et al. (2016). Cannabinoid CB2 receptor mediates nicotine-induced anti-inflammation in n9 microglial cells exposed to β amyloid via protein kinase C. Mediat. Inflamm. 2016:4854378. doi: 10.1155/2016/4854378
64. Khajehali, E., Malone, D. T., Glass, M., Sexton, P. M., Christopoulos, A., and Leach, K. (2015). Biased agonism and biased allosteric modulation at the CB1 cannabinoid receptors. Mol. Pharmacol. 88, 368-379. doi: 10.1124/mol.115.099192
65. Köfalvi, A., Lemos, C., Martín-Moreno, A. M., Pinheiro, B. S., García-García, L., Pozo, M. A., et al. (2016). Stimulation of brain glucose uptake by cannabinoid CB2 receptors and its therapeutic potential in Alzheimer's disease. Neuropharmacology. doi: 10.1016/j.neuropharm.2016.03.015. [Epub ahead of print].
66. Lanciego, J. L., Barroso-Chinea, P., Rico, A. J., Conte-Perales, L., Callén, L., Roda, E., et al. (2011). Expression of the mRNA coding the cannabinoid receptor 2 in the pallidal complex of Macaca fascicularis. J. Psychopharmacol. 25, 97-104. doi: 10.1177/0269881110367732
67. Makriyannis, A., Tian, X., and Guo, J. (2005). How lipophilic cannabinergic ligands reach their receptor sites. Neurobiol. Dis. 77, 210-218. doi: 10.1016/j.prostaglandins.2004.01.010
68. Malek, N., Popiolek-Barczyk, K., Mika, J., Przewlocka, B., and Starowicz, K. (2015). Anandamide, acting via CB2 receptors, alleviates LPS-induced neuroinflammation in rat primary microglial cultures. Neural Plast. 2015:130639. doi: 10.1155/2015/130639
69. Mecha, M., Feliú, A., Iñigo, P. M., Mestre, L., and Guaza, C. (2013). Cannabidiol provides long-lasting protection against the deleterious effects of inflammation in a viral model of multiple sclerosis: a role for A2A receptors. Neurobiol. Dis. 59, 141-150. doi: 10.1016/j.nbd.2013.06.016
70. Micale, V., Mazzola, C., and Drago, F. (2007). Endocannabinoids and neurodegenerative diseases. Pharmacol. Res. 56, 382-392. doi: 10.1016/j.phrs.2007.09.008
71. Molina-Holgado, E., Vela, J. M., Arévalo-Martín, A., Almazán, G., Molina-Holgado, F., Borrell, J., et al. (2002). Cannabinoids promote oligodendrocyte progenitor survival: involvement of cannabinoid receptors and phosphatidylinositol-3 kinase/Akt signaling. J. Neurosci. 22, 9742-9753.
72. Molina-Holgado, F., Pinteaux, E., Moore, J. D., Molina-Holgado, E., Guaza, C., Gibson, R. M., et al. (2003). Endogenous interleukin-1 receptor antagonist mediates anti-inflammatory and neuroprotective actions of cannabinoids in neurons and glia. J. Neurosci. 23, 6470-6474.
73. Morales, P., Goya, P., Jagerovic, N., and Hernandez-Folgado, L. (2016). Allosteric modulators of the CB 1 cannabinoid receptor: a structural update review. Cannabis Cannabinoid Res. 1, 22-30. doi: 10.1089/can.2015.0005
74. Mu, L., Bieri, D., Slavik, R., Drandarov, K., Muller, A., Cermak, S., et al. (2013). Radiolabeling and in vitro /in vivo evaluation of N-(1-adamantyl)-8-methoxy-4-oxo-1-phenyl-1, 4-dihydroquinoline-3-carboxamide as a PET probe for imaging cannabinoid type 2 receptor. J. Neurochem. 126, 616-624. doi: 10.1111/jnc.12354
75. Navarrete, F., Pérez-Ortiz, J. M., and Manzanares, J. (2012). Cannabinoid CB2 receptor-mediated regulation of impulsive-like behaviour in DBA/2 mice. Br. J. Pharmacol. 165, 260-273. doi: 10.1111/j.1476-5381.2011.01542.x
76. Navarrete, F., Rodríguez-Arias, M., Martín-García, E., Navarro, D., García-Gutiérrez, M. S., Aguilar, M. A., et al. (2013). Role of CB2 cannabinoid receptors in the rewarding, reinforcing, and physical effects of nicotine. Neuropsychopharmacology 38, 2515-2524. doi: 10.1038/npp.2013.157
77. Nimczick, M., and Decker, M. (2015). New approaches in the design and development of cannabinoid receptor ligands: multifunctional and bivalent compounds. ChemMedChem 10, 773-786. doi: 10.1002/cmdc.201500041
78. Nimczick, M., Pemp, D., Darras, F. H., Chen, X., Heilmann, J., and Decker, M. (2014). Synthesis and biological evaluation of bivalent cannabinoid receptor ligands based on hCB2 R selective benzimidazoles reveal unexpected intrinsic properties. Bioorg. Med. Chem. 22, 3938-3946. doi: 10.1016/j.bmc.2014.06.008
79. Núñez, E., Benito, C., Pazos, M. R., Barbachano, A., Fajardo, O., González, S., et al. (2004). Cannabinoid CB2 receptors are expressed by perivascular microglial cells in the human brain: an immunohistochemical study. Synapse 53, 208-213. doi: 10.1002/syn.20050
80. Onaivi, E. S., Carpio, O., Ishiguro, H., Schanz, N., Uhl, G. R., and Benno, R. (2008a). Behavioral effects of CB2 cannabinoid receptor activation and its influence on food and alcohol consumption. Ann. N.Y. Acad. Sci. 1139, 426-433. doi: 10.1196/annals.1432.035
81. Onaivi, E. S., Chaudhuri, G., Abaci, A. S., Parker, M., Manier, D. H., Martin, P. R., et al. (1999). Expression of cannabinoid receptors and their gene transcripts in human blood cells. Prog. Neuropsychopharmacol. Biol. Psychiatry 23, 1063-1077.
82. Onaivi, E. S., Ishiguro, H., Gong, J.-P., Patel, S., Meozzi, P. A., Myers, L., et al. (2008b). Brain neuronal CB2 cannabinoid receptors in drug abuse and depression: from mice to human subjects. PLoS ONE 3:e1640. doi: 10.1371/journal.pone.0001640
83. Onaivi, E. S., Ishiguro, H., Gong, J.-P., Patel, S., Meozzi, P. A., Myers, L., et al. (2008c). Functional expression of brain neuronal CB2 cannabinoid receptors are involved in the effects of drugs of abuse and in depression. Ann. N.Y. Acad. Sci. 1139, 434-449. doi: 10.1196/annals.1432.036
84. Ortega-Alvaro, A., Aracil-Fernández, A., García-Gutiérrez, M. S., Navarrete, F., and Manzanares, J. (2011). Deletion of CB2 cannabinoid receptor induces schizophrenia-related behaviors in mice. Neuropsychopharmacology 36, 1489-1504. doi: 10.1038/npp.2011.34
85. Ortega-álvaro, A., Ternianov, A., Aracil-Fernández, A., Navarrete, F., García-Gutiérrez, M. S., and Manzanares, J. (2015). Role of cannabinoid CB2 receptor in the reinforcing actions of ethanol. Addict. Biol. 20, 43-55. doi: 10.1111/adb.12076
86. Palazuelos, J., Aguado, T., Egia, A., Mechoulam, R., Guzmán, M., and Galve-Roperh, I. (2006). Non-psychoactive CB2 cannabinoid agonists stimulate neural progenitor proliferation. FASEB J. 20, 2405-2407. doi: 10.1096/fj.06-6164fje
87. Palazuelos, J., Aguado, T., Pazos, M. R., Julien, B., Carrasco, C., Resel, E., et al. (2009). Microglial CB2 cannabinoid receptors are neuroprotective in Huntington's disease excitotoxicity. Brain 132, 3152-3164. doi: 10.1093/brain/awp239
88. Palazuelos, J., Ortega, Z., Díaz-Alonso, J., Guzmán, M., and Galve-Roperh, I. (2012). CB2 cannabinoid receptors promote neural progenitor cell proliferation via mTORC1 signaling. J. Biol. Chem. 287, 1198-1209. doi: 10.1074/jbc.M111.291294
89. Presley, C. S., Mustafa, S. M., Abidi, A. H., and Moore, B. M. (2015). Synthesis and biological evaluation of (3', 5'-dichloro-2, 6-dihydroxy-biphenyl-4-yl)-aryl/alkyl-methanone selective CB2 inverse agonist. Bioorg. Med. Chem. 23, 5390-5401. doi: 10.1016/j.bmc.2015.07.057
90. Price, D. A., Martinez, A. A., Seillier, A., Koek, W., Acosta, Y., Fernandez, E., et al. (2009). WIN55, 212-2, a cannabinoid receptor agonist, protects against nigrostriatal cell loss in the 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine mouse model of Parkinson's disease. Eur. J. Neurosci. 29, 2177-2186. doi: 10.1111/j.1460-9568.2009.06764.x
91. Reiner, A., Heldt, S. A., Presley, C. S., Guley, N. H., Elberger, A. J., Deng, Y., et al. (2015). Motor, visual and emotional deficits in mice after closed-head mild traumatic brain injury are alleviated by the novel CB2 inverse agonist SMM-189. Int. J. Mol. Sci. 16, 758-787. doi: 10.3390/ijms16010758
92. Ribeiro, R., Wen, J., Li, S., and Zhang, Y. (2013). Involvement of ERK1/2, cPLA2 and NF-κB in microglia suppression by cannabinoid receptor agonists and antagonists. Prostaglandins Other Lipid Mediat. 100-101, 1-14. doi: 10.1016/j.prostaglandins.2012.11.003
93. Rodríguez-Arias, M., Navarrete, F., Blanco-Gandia, M. C., Arenas, M. C., Aguilar, M. A., Bartoll-Andrés, A., et al. (2015). Role of CB2 receptors in social and aggressive behavior in male mice. Psychopharmacology 232, 3019-3031. doi: 10.1007/s00213-015-3939-5
94. Rodríguez-Cueto, C., Benito, C., Fernández-Ruiz, J., Romero, J., Hernández-Gálvez, M., and Gómez-Ruiz, M. (2014). Changes in CB(1) and CB(2) receptors in the post-mortem cerebellum of humans affected by spinocerebellar ataxias. Br. J. Pharmacol. 171, 1472-1489. doi: 10.1111/bph.12283
95. Sagredo, O., González, S., Aroyo, I., Pazos, M. R., Benito, C., Lastres-Becker, I., et al. (2009). Cannabinoid CB2 receptor agonists protect the striatum against malonate toxicity: relevance for Huntington's disease. Glia 57, 1154-1167. doi: 10.1002/glia.20838
96. Sam, A. H., Salem, V., and Ghatei, M. A. (2011). Rimonabant: from RIO to Ban. J. Obes. 2011:432607. doi: 10.1155/2011/432607
97. Savonenko, A. V., Melnikova, T., Wang, Y., Ravert, H., Gao, Y., Koppel, J., et al. (2015). Cannabinoid CB2 receptors in a mouse model of Aβ amyloidosis: immunohistochemical analysis and suitability as a PET biomarker of neuroinflammation. PLoS ONE 10:e0129618. doi: 10.1371/journal.pone.0129618
98. Sheng, W. S., Hu, S., Ni, H. T., Rock, R. B., and Peterson, P. K. (2009). WIN55, 212-2 Inhibits production of CX3CL1 by human astrocytes: involvement of p38 MAP Kinase. J. Neuroimmune Pharmacol. 4, 244-248. doi: 10.1007/s11481-009-9147-5
99. Shoemaker, J. L., Seely, K. A., Reed, R. L., Crow, J. P., and Prather, P. L. (2007). The CB2 cannabinoid agonist AM-1241 prolongs survival in a transgenic mouse model of amyotrophic lateral sclerosis when initiated at symptom onset. J. Neurochem. 101, 87-98. doi: 10.1111/j.1471-4159.2006.04346.x
100. Sierra, S., Luquin, N., Rico, A. J., Gómez-Bautista, V., Roda, E., Dopeso-Reyes, I. G., et al. (2015). Detection of cannabinoid receptors CB1 and CB2 within basal ganglia output neurons in macaques: changes following experimental parkinsonism. Brain Struct. Funct. 220, 2721-2738. doi: 10.1007/s00429-014-0823-8
101. Skaper, S. D., Buriani, A., Dal Toso, R., Petrelli, L., Romanello, S., Facci, L., et al. (1996). The ALIAmide palmitoylethanolamide and cannabinoids, but not anandamide, are protective in a delayed postglutamate paradigm of excitotoxic death in cerebellar granule neurons. Proc. Natl. Acad. Sci. U.S.A. 93, 3984-3989. doi: 10.1073/pnas.93.9.3984
102. Slavik, R., Grether, U., Müller Herde, A., Gobbi, L., Fingerle, J., Ullmer, C., et al. (2015a). Discovery of a high affinity and selective pyridine analog as a potential positron emission tomography imaging agent for cannabinoid type 2 receptor. J. Med. Chem. 58, 4266-4277. doi: 10.1021/acs.jmedchem.5b00283
103. Slavik, R., Herde, A. M., Bieri, D., Weber, M., Schibli, R., Krämer, S. D., et al. (2015b). Synthesis, radiolabeling and evaluation of novel 4-oxo-quinoline derivatives as PET tracers for imaging cannabinoid type 2 receptor. Eur. J. Med. Chem. 92, 554-564. doi: 10.1016/j.ejmech.2015.01.028
104. Smith, S. R., Terminelli, C., and Denhardt, G. (2000). Effects of cannabinoid receptor agonist and antagonist ligands on production of inflammatory cytokines and anti-inflammatory interleukin-10 in endotoxemic mice. J. Pharmacol. Exp. Ther. 293, 136-50.
105. Stella, N. (2010). Cannabinoid and cannabinoid-like receptors in microglia, astrocytes, and astrocytomas. Glia 58, 1017-1030. doi: 10.1002/glia.20983
106. Tao, Q., McAllister, S. D., Andreassi, J., Nowell, K. W., Cabral, G. A., Hurst, D. P., et al. (1999). Role of a conserved lysine residue in the peripheral cannabinoid receptor (CB2): evidence for subtype specificity. Mol. Pharmacol. 55, 605-613.
107. Van Sickle, M. D., Duncan, M., Kingsley, P. J., Mouihate, A., Urbani, P., Mackie, K., et al. (2005). Identification and functional characterization of brainstem cannabinoid CB2 receptors. Science 310, 329-332. doi: 10.1126/science.1115740
108. Vendel, E., and de Lange, E. C. M. (2014). Functions of the CB1 and CB 2 receptors in neuroprotection at the level of the blood-brain barrier. Neuromolecular Med. 16, 620-642. doi: 10.1007/s12017-014-8314-x
109. Walter, L., Franklin, A., Witting, A., Wade, C., Xie, Y., Kunos, G., et al. (2003). Nonpsychotropic cannabinoid receptors regulate microglial cell migration. J. Neurosci. 23, 1398-1405.
110. Yiangou, Y., Facer, P., Durrenberger, P., Chessell, I. P., Naylor, A., Bountra, C., et al. (2006). COX-2, CB2 and P2X7-immunoreactivities are increased in activated microglial cells/macrophages of multiple sclerosis and amyotrophic lateral sclerosis spinal cord. BMC Neurol. 6:12. doi: 10.1186/1471-2377-6-12
111. Zarruk, J. G., Fernandez-Lopez, D., Garcia-Yebenes, I., Garcia-Gutierrez, M. S., Vivancos, J., Nombela, F., et al. (2012). Cannabinoid type 2 receptor activation downregulates stroke-induced classic and alternative brain macrophage/microglial activation concomitant to neuroprotection. Stroke 49, 211-219. doi: 10.1161/STROKEAHA.111.631044
112. Zhang, L., Kline, R. H., McNearney, T. A., Johnson, M. P., and Westlund, K. N. (2014). Cannabinoid receptor 2 agonist attenuates pain related behavior in rats with chronic alcohol/high fat diet induced pancreatitis. Mol. Pain 10:66. doi: 10.1186/1744-8069-10-66