Binding and signaling studies disclose a potential allosteric site for cannabidiol in cannabinoid CB2 receptors

Frontiers in Pharmacology

Volumn 8, Issue OCT, 2017, Pages

  Martínez Pinilla, Eva ^a   Varani, Katia ^b   Reyes Resina, Irene ^c,d   Angelats, Edgar ^c,d   Vincenzi, Fabrizio ^b   Ferreiro Vera, Carlos ^e   Oyarzabal, Julen ^f   Canela, Enric I ^c,d   Lanciego, José L ^f   Nadal, Xavier ^e   Navarro, Gemma ^c,d   Borea, Pier Andrea ^b   Franco, Rafael ^c,d  

^a UNIVERSITY OF OVIEDO   (Spain)

^b UNIVERSITY OF FERRARA   (Italy)

^c UNIVERSITY OF BARCELONA   (Spain)

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

^e Phytoplant Research S L Rabanales 21 Science and Technology Park of Córdoba Astrónoma Cecilia Payne Building   (Spain)

^f UNIVERSITY OF NAVARRA   (Spain)

Author keywords

Allosterism; Endocannabinoid; G protein coupled receptor; Irreversible; Phytocannabinoids; SR144528; TR FRET

Indexed keywords

1 DEOXY 3 (1,1 DIMETHYLBUTYL) DELTA8 TETRAHYDROCANNABINOL; 2,3 DIHYDRO 5 METHYL 3 (MORPHOLINOMETHYL) 6 (1 NAPHTHOYL)PYRROLO[1,2,3 DE][1,4]BENZOXAZINE; 5 (4 CHLORO 3 METHYLPHENYL) 1 (4 METHYLBENZYL) N (1,3,3 TRIMETHYLBICYCLO[2.2.1]HEPTAN 2 YL) 3 PYRAZOLECARBOXAMIDE; CANNABIDIOL; CANNABINOID 2 RECEPTOR; CYCLIC AMP; MITOGEN ACTIVATED PROTEIN KINASE; MITOGEN ACTIVATED PROTEIN KINASE 1; MITOGEN ACTIVATED PROTEIN KINASE 3;

ALLOSTERIC SITE; ALLOSTERISM; ARTICLE; BINDING AFFINITY; BINDING ASSAY; CONCENTRATION (PARAMETERS); CONTROLLED STUDY; EMBRYO; ENZYME PHOSPHORYLATION; HEK293T CELL LINE; HUMAN; HUMAN CELL; LIGAND BINDING; PROTEIN EXPRESSION; SIGNAL TRANSDUCTION;

EID: 85032187574     PISSN: None     EISSN: 16639812     Source Type: Journal    
DOI: 10.3389/fphar.2017.00744     Document Type: Article

References (42)

1. Ahrens, J., Demir, R., Leuwer, M., de la Roche, J., Krampfl, K., Foadi, N., et al. (2009). The nonpsychotropic cannabinoid cannabidiol modulates and directly activates alpha-1 and alpha-1-Beta glycine receptor function. Pharmacology 83, 217-222. doi: 10.1159/000201556
2. Alvarez, F. J., Lafuente, H., Carmen Rey-Santano, M., Mielgo, V. E., Gastiasoro, E., Rueda, M., et al. (2008). Neuroprotective effects of the nonpsychoactive cannabinoid cannabidiol in hypoxic-ischemic newborn piglets. Pediatr. Res. 64, 653-658. doi: 10.1203/PDR.0b013e318186e5dd
3. Alves, F. H. F., Crestani, C. C., Gomes, F. V., Guimarães, F. S., Correa, F. M. A., and Resstel, L. B. M. (2010). Cannabidiol injected into the bed nucleus of the stria terminalis modulates baroreflex activity through 5-HT1A receptors. Pharmacol. Res. 62, 228-236. doi: 10.1016/j.phrs.2010.05.003
4. Bilkei-Gorzo, A. (2012). The endocannabinoid system in normal and pathological brain ageing. Philos. Trans. R. Soc. B Biol. Sci. 367, 3326-3341. doi: 10.1098/rstb.2011.0388
5. Cabral, G. A., and Marciano-Cabral, F. (2005). Cannabinoid receptors in microglia of the central nervous system: immune functional relevance. J. Leukoc. Biol. 78, 1192-1197. doi: 10.1189/jlb.0405216
6. 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
7. Castillo, C. A., Albasanz, J. L., Fernández, M., and Martín, M. (2007). Endogenous expression of adenosine A1, A2 and A3 receptors in rat C6 glioma cells. Neurochem. Res. 32, 1056-1070. doi: 10.1007/s11064-006-9273-x
8. Cheng, H. C. (2001). The power issue: determination of KB or Ki from IC50. A closer look at the Cheng-Prusoff equation, the Schild plot and related power equations. J. Pharmacol. Toxicol. Methods 46, 61-71. doi: 10.1016/S1056-8719(02)00166-1
9. Conn, P. J., Christopoulos, A., and Lindsley, C. W. (2009). Allosteric modulators of GPCRs: a novel approach for the treatment of CNS disorders. Nat. Rev. Drug Discov. 8, 41-54. doi: 10.1038/nrd2760
10. Espejo-Porras, F., Fernández-Ruiz, J., Pertwee, R. G., Mechoulam, R., and García, C. (2013). Motor effects of the non-psychotropic phytocannabinoid cannabidiol that are mediated by 5-HT1A receptors. Neuropharmacology 75, 155-163. doi: 10.1016/j.neuropharm.2013.07.024
11. 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.2006.11.001
12. Foadi, N., Leuwer, M., Demir, R., Dengler, R., Buchholz, V., de la Roche, J., et al. (2010). Lack of positive allosteric modulation of mutated alpha(1)S267I glycine receptors by cannabinoids. Naunyn. Schmiedebergs. Arch. Pharmacol. 381, 477-482. doi: 10.1007/s00210-010-0506-9
13. Griffin, G., Wray, E. J., Tao, Q., McAllister, S. D., Rorrer, W. K., Aung, M. M., et al. (1999). Evaluation of the cannabinoid CB2 receptor-selective antagonist, SR144528: further evidence for cannabinoid CB2 receptor absence in the rat central nervous system. Eur. J. Pharmacol. 377, 117-125. doi: 10.1016/S0014-2999(99)00402-1
14. Hanus, L., Tchilibon, S., Ponde, D. E., Breuer, A., Fride, E., and Mechoulam, R. (2005). Enantiomeric cannabidiol derivatives: synthesis and binding to cannabinoid receptors. Org. Biomol. Chem. 3, 1116-1123. doi: 10.1039/b416943c
15. Hind, W. H., England, T. J., and O'Sullivan, S. E. (2016). Cannabidiol protects an in vitro model of the blood-brain barrier from oxygen-glucose deprivation via PPAR? and 5-HT 1A receptors. Br. J. Pharmacol. 173, 815-825. doi: 10.1111/bph.13368
16. Ignatowska-Jankowska, B., Jankowski, M. M., and Swiergiel, A. H. (2011). Cannabidiol decreases body weight gain in rats: involvement of CB2 receptors. Neurosci. Lett. 490, 82-84. doi: 10.1016/j.neulet.2010.12.031
17. Kathmann, M., Flau, K., Redmer, A., Tränkle, C., and Schlicker, E. (2006). Cannabidiol is an allosteric modulator at mu- and delta-opioid receptors. Naunyn Schmiedebergs Arch. Pharmacol. 372, 354-361. doi: 10.1007/s00210-006-0033-x
18. Lafuente, H., Alvarez, F. J., Pazos, M. R., Alvarez, A., Rey-Santano, M. C., Mielgo, V., et al. (2011). Cannabidiol reduces brain damage and improves functional recovery after acute hypoxia-ischemia in newborn pigs. Pediatr. Res. 70, 272-277. doi: 10.1203/PDR.0b013e3182276b11
19. 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
20. Lane, J. R., Beukers, M. W., Mulder-Krieger, T., and IJzerman, A. P. (2010). The endocannabinoid 2-arachidonylglycerol is a negative allosteric modulator of the human A3 adenosine receptor. Biochem. Pharmacol. 79, 48-56. doi: 10.1016/j.bcp.2009.07.024
21. Laprairie, R. B., Bagher, A. M., Kelly, M. E. M., and Denovan-Wright, E. M. (2015). Cannabidiol is a negative allosteric modulator of the cannabinoid CB1 receptor. Br. J. Pharmacol. 172, 4790-4805. doi: 10.1111/bph.13250
22. Lu, H. C., and MacKie, K. (2016). An introduction to the endogenous cannabinoid system. Biol. Psychiatry 79, 516-525. doi: 10.1016/j.biopsych.2015.07.028
23. Magen, I., Avraham, Y., Ackerman, Z., Vorobiev, L., Mechoulam, R., and Berry, E. M. (2010). Cannabidiol ameliorates cognitive and motor impairments in bile-duct ligated mice via 5-HT 1A receptor activation. Br. J. Pharmacol. 159, 950-957. doi: 10.1111/j.1476-5381.2009.00589.x
24. Martínez-Pinilla, E., Rabal, O., Reyes-Resina, I., Zamarbide, M., Navarro, G., Sánchez-Arias, J. A., et al. (2016). Two affinity sites of the cannabinoid subtype 2 receptor identified by a novel homogeneous binding assay. J. Pharmacol. Exp. Ther. 358, 580-587. doi: 10.1124/jpet.116.234948
25. McPartland, J. M., Duncan, M., Di Marzo, V., and Pertwee, R. G. (2015). Are cannabidiol and ? 9 -tetrahydrocannabivarin negative modulators of the endocannabinoid system? A systematic review. Br. J. Pharmacol. 172, 737-753. doi: 10.1111/bph.12944
26. McPartland, J. M., Glass, M., and Pertwee, R. G. (2009). Meta-analysis of cannabinoid ligand binding affinity and receptor distribution: interspecies differences. Br. J. Pharmacol. 152, 583-593. doi: 10.1038/sj.bjp.0707399
27. 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
28. Pamplona, F. A., Ferreira, J., Menezes de Lima, O., Duarte, F. S., Bento, A. F., Forner, S., et al. (2012). Anti-inflammatory lipoxin A4 is an endogenous allosteric enhancer of CB1 cannabinoid receptor. Proc. Natl. Acad. Sci. U.S.A. 109, 21134-21139. doi: 10.1073/pnas.1202906109
29. Pazos, M. R., Mohammed, N., Lafuente, H., Santos, M., Martínez-Pinilla, E., Moreno, E., et al. (2013). Mechanisms of cannabidiol neuroprotection in hypoxic-ischemic newborn pigs: role of 5HT1A and CB2 receptors. Neuropharmacology 71, 282-291. doi: 10.1016/j.neuropharm.2013.03.027
30. Pertwee, R. G. (2008). The diverse CB 1 and CB 2 receptor pharmacology of three plant cannabinoids: ? 9 -tetrahydrocannabinol, cannabidiol and ? 9 -tetrahydrocannabivarin. Br. J. Pharmacol. 153, 199-215. doi: 10.1038/sj.bjp.0707442
31. Rimoldi, J., and Bow, E. (2016). The structure-function relationships of classical cannabinoids: CB1/CB2 modulation. Perspect. Medicin. Chem. 8, 17-39. doi: 10.4137/PMC.S32171
32. Rinaldi-Carmona, M., Barth, F., Millan, J., Derocq, J. M., Casellas, P., Congy, C., et al. (1998). SR 144528, the first potent and selective antagonist of the CB2 cannabinoid receptor. J. Pharmacol. Exp. Ther. 284, 644-650.
33. Rock, E., Bolognini, D., Limebeer, C., Cascio, M., Anavi-Goffer, S., Fletcher, P., et al. (2012). Cannabidiol, a non-psychotropic component of cannabis, attenuates vomiting and nausea-like behaviour via indirect agonism of 5-HT1A somatodendritic autoreceptors in the dorsal raphe nucleus. Br. J. Pharmacol. 165, 2620-2634. doi: 10.1111/j.1476-5381.2011.01621.x
34. Russo, E. B., Burnett, A., Hall, B., and Parker, K. K. (2005). Agonistic properties of cannabidiol at 5-HT1a receptors. Neurochem. Res. 30, 1037-1043. doi: 10.1007/s11064-005-6978-1
35. Sartim, A. G., Guimarães, F. S., and Joca, S. R. L. (2016). Antidepressant-like effect of cannabidiol injection into the ventral medial prefrontal cortex-Possible involvement of 5-HT1A and CB1 receptors. Behav. Brain Res. 303, 218-227. doi: 10.1016/j.bbr.2016.01.033
36. 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
37. Stella, N. (2010). Endocannabinoid signaling in microglial cells. Glia 58(Suppl. 1), 244-253. doi: 10.1002/glia.20983
38. Thomas, A., Baillie, G. L., Phillips, A. M., Razdan, R. K., Ross, R. A., and Pertwee, R. G. (2009). Cannabidiol displays unexpectedly high potency as an antagonist of CB1 and CB2 receptor agonists in vitro. Br. J. Pharmacol. 150, 613-623. doi: 10.1038/sj.bjp.0707133
39. Vaysse, P. J., Gardner, E. L., and Zukin, R. S. (1987). Modulation of rat brain opioid receptors by cannabinoids. J. Pharmacol. Exp. Ther. 241, 534-539.
40. Verbist, B. M. P., De Cleyn, M. A. J., Surkyn, M., Fraiponts, E., Aerssens, J., Nijsen, M. J. M. A., et al. (2008). 5-Sulfonyl-benzimidazoles as selective CB2 agonists. Bioorg. Med. Chem. Lett. 18, 2574-2579. doi: 10.1016/j.bmcl.2008.03.048
41. Yang, K.-H., Galadari, S., Isaev, D., Petroianu, G., Shippenberg, T. S., and Oz, M. (2010). The nonpsychoactive cannabinoid cannabidiol inhibits 5-hydroxytryptamine3A receptor-mediated currents in Xenopus laevis oocytes. J. Pharmacol. Exp. Ther. 333, 547-554. doi: 10.1124/jpet.109.162594
42. Zhang, J., Hoffert, C., Vu, H. K., Groblewski, T., Ahmad, S., and O'Donnell, D. (2003). Induction of CB2 receptor expression in the rat spinal cord of neuropathic but not inflammatory chronic pain models. Eur. J. Neurosci. 17, 2750-2754. doi: 10.1046/j.1460-9568.2003.02704.x