Advances in the Understanding of the Cannabinoid Receptor 1 – Focusing on the Inverse Agonists Interactions

Author(s): Silvana Russo, Walter Filgueira De Azevedo*

Journal Name: Current Medicinal Chemistry

Volume 26 , Issue 10 , 2019

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Abstract:

Background: Cannabinoid Receptor 1 (CB1) is a membrane protein prevalent in the central nervous system, whose crystallographic structure has recently been solved. Studies will be needed to investigate CB1 complexes with its ligands and its role in the development of new drugs.

Objective: Our goal here is to review the studies on CB1, starting with general aspects and focusing on the recent structural studies, with emphasis on the inverse agonists bound structures.

Methods: We start with a literature review, and then we describe recent studies on CB 1 crystallographic structure and docking simulations. We use this structural information to depict protein-ligand interactions. We also describe the molecular docking method to obtain complex structures of CB 1 with inverse agonists.

Results: Analysis of the crystallographic structure and docking results revealed the residues responsible for the specificity of the inverse agonists for CB 1. Most of the intermolecular interactions involve hydrophobic residues, with the participation of the residues Phe 170 and Leu 359 in all complex structures investigated in the present study. For the complexes with otenabant and taranabant, we observed intermolecular hydrogen bonds involving residues His 178 (otenabant) and Thr 197 and Ser 383 (taranabant).

Conclusion: Analysis of the structures involving inverse agonists and CB 1 revealed the pivotal role played by residues Phe 170 and Leu 359 in their interactions and the strong intermolecular hydrogen bonds highlighting the importance of the exploration of intermolecular interactions in the development of novel inverse agonists.

Keywords: Cannabinoid receptor, drug design, docking, inverse agonist, membrane protein, GPCR.

[1]
Watson, H. Biological membranes. Essays Biochem., 2015, 59, 43-69.
[2]
Jacob, L.; Hoffmann, B.; Stoven, V.; Vert, J.P. Virtual screening of GPCRs: An in silico chemogenomics approach. BMC Bioinformatics, 2008, 9, 363.
[3]
Pertwee, R.G.; Howlett, A.C.; Abood, M.E.; Alexander, S.P.H.; Di Marzo, V.; Elphick, M.R.; Greasley, P.J.; Hansen, H.S.; Kunos, G.; Mackie, K.; Mechoulam, R.; Rosset, R.A. International Union of Basic and Clinical Pharmacology. LXXIX. Cannabinoid Receptors and Their Ligands: Beyond CB1 and CB2. Pharmacol. Rev., 2010, 62(4), 588-631.
[4]
Busquets-Garcia, A.; Soria-Gomez, E.; Bellocchio, L.; Marsicano, G. Cannabinoid receptor type-1: breaking the dogmas. F1000 Res, 2016, 5, pii: F1000 Faculty Rev-990.
[5]
Zheng, H.; Hou, J.; Zimmerman, M.D.; Wlodawer, A.; Minor, W. The future of crystallography in drug discovery. Expert Opin. Drug Discov., 2014, 9(2), 125-137.
[6]
Hua, T. Vemuri, K.; Nikas, S.P.; Laprairie, R.B.; Wu, Y.; Qu, L.; Pu, M.; Korde, A.; Jiang, S4.; Ho, J.H.; Han, G.W.; Ding, K.; Li, X.; Liu, H.; Hanson, M.A.; Zhao, S.; Bohn, L.M.; Makriyannis, A.; Stevens, R.C.; Liu, Z.J. Crystal structures of agonist-bound human cannabinoid receptor CB1. Nature, 2017, 547(7664), 468-471.
[7]
Hua, T.; Vemuri, K.; Pu, M.; Qu, L.; Han, G.W.; Wu, Y.; Zhao, S.; Shui, W.; Li, S.; Korde, A.; Laprairie, R.B.; Stahl, E.L.; Ho, J.H.; Zvonok, N.; Zhou, H.; Kufareva, I.; Wu, B.; Zhao, Q.; Hanson, M.A.; Bohn, L.M.; Makriyannis, A.; Stevens, R.C.; Liu, Z.J. Crystal structure of the human cannabinoid receptor CB1. Cell, 2016, 167(3), 750-762.
[8]
Shao, Z.; Yin, J.; Chapman, K.; Grzemska, M.; Clark, L.; Wang, J.; Rosenbaum, D.M. High-resolution crystal structure of the human CB1 cannabinoid receptor. Nature, 2016, 540, 602-606.
[9]
Console-Bram, L.; Marcu, J.; Abood, M.E. Cannabinoid receptors: nomenclature and pharmacological principles. Prog. Neuropsychopharmacol. Biol. Psychiatry, 2012, 38(1), 4-15.
[10]
Di Marzo, V.; Piscitelli, F. The endocannabinoid system and its modulation by phytocannabinoids. Neurotherapeutics, 2015, 12(4), 692-698.
[11]
Ogawa, S.; Kunugi, H. Inhibitors of fatty acid amide hydrolase and monoacylglycerol lipase: new targets for future antidepressants. Curr. Neuropharmacol., 2015, 13(6), 760-775.
[12]
Howlett, A.C.; Blume, L.C.; Dalton, G.D. CB1 cannabinoid receptors and their associated proteins. Curr. Med. Chem., 2010, 17(14), 1382-1393.
[13]
Alexander, S.P.; Christopoulos, A.; Davenport, A.P.; Kelly, E.; Marrion, N.V.; Peters, J.A.; Faccenda, E.; Harding, S.D.; Pawson, A.J.; Sharman, J.L.; Southan, C.; Davies, J.A. CGTP Collaborators. The concise guide to pharmacology 2017/18: G protein‐coupled receptors. Br. J. Pharmacol., 2017, 174(Suppl. 1), S17-S129.
[14]
Sugiura, T.; Kondo, S.; Kishimoto, S.; Miyashita, T.; Nakane, S.; Kodaka, T.; Suhara, Y.; Takayama, H.; Waku, K. Evidence that 2-arachidonoylglycerol but not n-palmitoylethanolamine or anandamide is the physiological ligand for the cannabinoid cb2 receptor. comparison of the agonistic activities of various cannabinoid receptor ligands in HL-60 cells. J. Biol. Chem., 2000, 275, 605-612.
[15]
Lu, H.C.; Mackie, K. An introduction to the endogenous cannabinoid system. Biol. Psychiatry, 2016, 79(7), 516-525.
[16]
Di Marzo, V.; De Petrocellis, L. Why do cannabinoid receptors have more than one endogenous ligand? Philos. Trans. R. Soc. Lond. B Biol. Sci., 2012, 367(1607), 3216-3228.
[17]
Koch, M. Cannabinoid receptor signaling in central regulation of feeding behavior: A mini-review. Front. Neurosci., 2017, 11, 293.
[18]
Kawahara, H.; Drew, G.M.; Christie, M.J.; Vaughan, C.W. Inhibition of fatty acid amide hydrolase unmasks CB1 receptor and TRPV1 channel-mediated modulation of glutamatergic synaptic transmission in midbrain periaqueductal grey. Br. J. Pharmacol., 2011, 163(6), 1214-1222.
[19]
Gaoni, Y.; Mechoulam, R. Isolation, structure, and partial synthesis of an active constituent of hashish. J. Am. Chem. Soc., 1964, 86(8), 1646-1647.
[20]
Gobbi, G.; Bambico, F.R.; Mangieri, R.; Bortolato, M.; Campolongo, P.; Solinas, M.; Cassano, T.; Morgese, M.G.; Debonnel, G.; Duranti, A.; Tontini, A.; Tarzia, G.; Mor, M.; Trezza, V.; Goldberg, S.R.; Cuomo, V.; Piomelli, D. Antidepressant-like activity and modulation of brain monoaminergic transmission by blockade of anandamide hydrolysis. Proc. Natl. Acad. Sci. USA, 2005, 102(51), 18620-18625.
[21]
Castillo, P.E.; Younts, T.J.; Chávez, A.E.; Hashimotodani, Y. Endocannabinoid signaling and synaptic function. Neuron, 2012, 76(1), 70-81.
[22]
Blankman, J.L.; Cravatt, B.F. Chemical probes of endocannabinoid metabolism. Pharmacol. Rev., 2013, 65(2), 849-871.
[23]
Scheerer, P.; Sommer, M.E. Structural mechanism of arrestin activation. Curr. Opin. Struct. Biol., 2017, 45, 160-169.
[24]
Busquets-Garcia, A.; Desprez, T.; Metna-Laurent, M.; Bellocchio, L.; Marsicano, G.; Soria-Gomez, E. Dissecting the cannabinergic control of behavior: The where matters. BioEssays, 2015, 37(11), 1215-1225.
[25]
Bénard, G.; Massa, F.; Puente, N.; Lourenço, J.; Bellocchio, L.; Soria-Gómez, E.; Matias, I.; Delamarre, A.; Metna-Laurent, M.; Cannich, A.; Hebert-Chatelain, E.; Mulle, C.; Ortega-Gutiérrez, S.; Martín-Fontecha, M.; Klugmann, M.; Guggenhuber, S.; Lutz, B.; Gertsch, J.; Chaouloff, F.; López-Rodríguez, M.L.; Grandes, P.; Rossignol, R.; Marsicano, G. Mitochondrial CB1 receptors regulate neuronal energy metabolism. Nat. Neurosci., 2012, 15(4), 558-564.
[26]
Hebert-Chatelain, E.; Desprez, T.; Serrat, R.; Bellocchio, L.; Soria-Gomez, E.; Busquets-Garcia, A.; Pagano Zottola, A.C.; Delamarre, A.; Cannich, A.; Vincent, P.; Varilh, M.; Robin, L.M.; Terral, G.; García-Fernández, M.D.; Colavita, M.; Mazier, W.; Drago, F.; Puente, N.; Reguero, L.; Elezgarai, I.; Dupuy, J.W.; Cota, D. Lopez-Rodriguez, M.L.; Barreda-Gómez, G.; Massa, F.; Grandes, P.; Bénard, G.; Marsicano, G. A cannabinoid link between mitochondria and memory. Nature, 2016, 539(7630), 555-559.
[27]
Janero, D.R. Cannabinoid receptor antagonists: pharmacological opportunities, clinical experience, and translational prognosis. Expert Opin. Emerg. Drugs, 2009, 14(1), 43-65.
[28]
Martín-García, E.J. Central and peripheral consequences of the chronic blockade of CB1 cannabinoid receptor with rimonabant or taranabant. Neurochem, 2010, 112(5), 1338-13351.
[29]
Pertwee, R.G. Inverse agonism and neutral antagonism at cannabinoid CB1 receptors. Life Sci., 2005, 76(12), 1307-1324.
[30]
Sam, A.H.; Salem, V.; Ghatei, M.A. Rimonabant: From RIO to Ban. J. Obes., 2011.432607
[31]
Ibsen, M.S.; Connor, M.; Glass, M. Cannabinoid CB1 and CB2 receptor signaling and bias. Cannabis Cannabinoid Res., 2017, 2(1), 48-60.
[32]
Pertwee, R.G. Emerging strategies for exploiting cannabinoid receptor agonists as medicines. Br. J. Pharmacol., 2009, 156(3), 397-411.
[33]
Berman, H.M.; Westbrook, J.; Feng, Z.; Gilliland, G.; Bhat, T.N.; Weissig, H.; Shindyalov, I.N.; Bourne, P.E. the protein data bank. Nucleic Acids Res., 2000, 28(1), 235-242.
[34]
Berman, H.M.; Battistuz, T.; Bhat, T.N.; Bluhm, W.F.; Bourne, P.E.; Burkhardt, K.; Feng, Z.; Gilliland, G.L.; Iype, L.; Jain, S.; Fagan, P.; Marvin, J.; Padilla, D.; Ravichandran, V.; Schneider, B.; Thanki, N.; Weissig, H.; Westbrook, J.D.; Zardecki, C. The protein data bank. Acta Crystallogr. D Biol. Crystallogr, 2002, 58(Pt 6 No 1), 899- 907.
[35]
Westbrook, J.; Feng, Z.; Chen, L.; Yang, H.; Berman, H.M. The protein data bank and structural genomics. Nucleic Acids Res., 2003, 31(1), 489-491.
[36]
Humphrey, W.; Dalke, A.; Schulten, K. VMD - Visual molecular dynamics. J. Mol. Graph., 1996, 14, 33-38.
[37]
Friesner, R.A.; Banks, J.L.; Murphy, R.B.; Halgren, T.A.; Klicic, J.J.; Mainz, D.T.; Repasky, M.P.; Knoll, E.H.; Shelley, M.; Perry, J.K.; Shaw, D.E.; Francis, P.; Shenkin, P.S. Glide: a new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy. J. Med. Chem., 2004, 47, 1739-1749.
[38]
Friesner, R.A.; Murphy, R.B.; Repasky, M.P.; Frye, L.L.; Greenwood, J.R.; Halgren, T.A.; Sanschagrin, P.C.; Mainz, D.T. Extra precision glide: docking and scoring incorporating a model of hydrophobic enclosure for protein-ligand complexes. J. Med. Chem., 2006, 49, 6177-6196.
[39]
Halgren, T.A.; Murphy, R.B.; Friesner, R.A.; Beard, H.S.; Frye, L.L.; Pollard, W.T.; Banks, J.L. Glide: a new approach for rapid, accurate docking and scoring. 2. Enrichment factors in database screening. J. Med. Chem., 2004, 47, 1750-1759.
[40]
Thomsen, R.; Christensen, M.H. MolDock: a new technique for high-accuracy molecular docking. J. Med. Chem., 2006, 49, 3315-3321.
[41]
Heberlé, G.; de Azevedo, W.F., Jr Bio-inspired algorithms applied to molecular docking simulations. Curr. Med. Chem., 2011, 18(9), 1339-1352.
[42]
De Azevedo, W.F., Jr MolDock applied to structure-based virtual screening. Curr. Drug Targets, 2010, 11(3), 327-334.
[43]
Azevedo, L.S.; Moraes, F.P.; Xavier, M.M.; Pantoja, E.O.; Villavicencio, B.; Finck, J.A.; Proenca, A.M.; Rocha, K.B.; de Azevedo, W.F., Jr recent progress of molecular docking simulations applied to development of drugs. Curr. Bioinform., 2012, 7(4), 352-365.
[44]
Xavier, M.M.; Heck, G.S.; de Avila, M.B.; Levin, N.M.; Pintro, V.O.; Carvalho, N.L.; Azevedo, W.F., Jr SAnDReS a computational tool for statistical analysis of docking results and development of scoring functions. Comb. Chem. High Throughput Screen., 2016, 19(10), 801-812.
[45]
Heck, G.S.; Pintro, V.O.; Pereira, R.R.; de Ávila, M.B.; Levin, N.M.B.; de Azevedo, W.F., Jr Supervised machine learning methods applied to predict ligand-binding affinity. Curr. Med. Chem., 2017, 24(23), 2459-2470.
[46]
De Ávila, M.B.; Xavier, M.M.; Pintro, V.O.; de Azevedo, W.F., Jr Supervised machine learning techniques to predict binding affinity. A study for cyclin-dependent kinase 2. Biochem. Biophys. Res. Commun., 2017, 494, 305-310.
[47]
Pintro, V.O.; Azevedo, W.F., Jr Optimized virtual screening workflow. towards target-based polynomial scoring functions for HIV-1 protease. Comb. Chem. High Throughput Screen., 2017, 20(9), 820-827.
[48]
Irwin, J.J.; Shoichet, B.K. ZINC--a free database of commercially available compounds for virtual screening. J. Chem. Inf. Model., 2005, 45(1), 177-182.
[49]
Irwin, J.J.; Sterling, T.; Mysinger, M.M.; Bolstad, E.S.; Coleman, R.G. ZINC: a free tool to discover chemistry for biology. J. Chem. Inf. Model., 2012, 52(7), 1757-1768.
[50]
Dore, A.S.; Robertson, N.; Errey, J.C.; Ng, I.; Hollenstein, K.; Tehan, B.; Hurrell, E.; Bennett, K.; Congreve, M.; Magnani, F.; Tate, C.G.; Weir, M.; Marshall, F.H. Structure of the adenosine A(2A) receptor in complex with ZM241385 and the xanthines XAC and caffeine. Structure, 2011, 19, 1283-1293.
[51]
Congreve, M.; Andrews, S.P.; Doré, A.S.; Hollenstein, K.; Hurrell, E.; Langmead, C.J.; Mason, J.S.; Ng, I.W.; Tehan, B.; Zhukov, A.; Weir, M.; Marshall, F.H. Discovery of 1,2,4-triazine derivatives as adenosine A(2A) antagonists using structure-based drug design. J. Med. Chem., 2012, 55, 1898-1903.
[52]
Palczewski, K.; Kumasaka, T.; Hori, T.; Behnke, C.A.; Motoshima, H.; Fox, B.A.; Le Trong, I.; Teller, D.C.; Okada, T.; Stenkamp, R.E.; Yamamoto, M.; Miyano, M. Crystal structure of rhodopsin: a G protein-coupled receptor. Science, 2000, 289(5480), 739-745.
[53]
Edgar, R.C. MUSCLE: multiple sequence alignment with high accuracy and high throughput. Nucleic Acids Res., 2004, 32(5), 1792-1797.
[54]
Edgar, R.C. MUSCLE: a multiple sequence alignment method with reduced time and space complexity. BMC Bioinformatics, 2004, 5, 113.
[55]
Wallace, A.C.; Laskowski, R.A.; Thornton, J.M. LIGPLOT: a program to generate schematic diagrams of protein-ligand interactions. Protein Eng., 1995, 8(2), 127-134.
[56]
Laskowski, R.A.; Swindells, M.B. LigPlot+: multiple ligand-protein interaction diagrams for drug discovery. J. Chem. Inf. Model., 2011, 51, 2778-2786.
[57]
De Azevedo, W.F., Jr; Leclerc, S.; Meijer, L.; Havlicek, L.; Strnad, M.; Kim, S.H. Inhibition of cyclin-dependent kinases by purine analogues: crystal structure of human cdk2 complexed with roscovitine. Eur. J. Biochem., 1997, 243(1-2), 518-526.
[58]
De Azevedo, W.F., Jr; Mueller-Dieckmann, H.J.; Schulze-Gahmen, U.; Worland, P.J.; Sausville, E.; S.H, Kim S.H. Structural basis for specificity and potency of a flavonoid inhibitor of human CDK2, a cell cycle kinase. Proc. Natl. Acad. Sci. USA, 1996, 93(7), 2735-2740.
[59]
Canduri, F.; Teodoro, L.G.; Fadel, V.; Lorenzi, C.C.; Hial, V.; Gomes, R.A.; Neto, J.R.; de Azevedo, W.F., Jr Structure of human uropepsin at 2.45 A resolution. Acta Crystallogr. D Biol. Crystallogr., 2001, 57(Pt 11), 1560-1570.
[60]
De Azevedo, W.F., Jr; Canduri, F.; da Silveira, N.J. Structural basis for inhibition of cyclin-dependent kinase 9 by flavopiridol. Biochem. Biophys. Res. Commun., 2002, 293(1), 566-571.
[61]
De Azevedo, W.F., Jr; Gaspar, R.T.; Canduri, F.; Camera, J.C., Jr; da Silveira, N.J.F. Molecular model of cyclin-dependent kinase 5 complexed with roscovitine. Biochem. Biophys. Res. Commun., 2002, 297(5), 1154-1158.
[62]
Janero, D.R.; Lindsley, L.; Vemuri, V.K.; Makriyannis, A. Cannabinoid 1 G protein-coupled receptor (periphero-)neutral antagonists: emerging therapeutics for treating obesity-driven metabolic disease and reducing cardiovascular risk. Expert Opin. Drug Discov., 2011, 6, 995-1025.
[63]
Mazier, W.; Saucisse, N.; Gatta-Cherifi, B.; Cota, D. The endocannabinoid system: Pivotal orchestrator of obesity and metabolic disease. Trends Endocrinol. Metab., 2015, 26, 524-537.
[64]
Cota, D. The brain strikes back: hypothalamic targets for peripheral CB1 receptor inverse agonism. Mol. Metab., 2017, 6(10), 1077-1078.
[65]
Tam, J.; Szanda, G.; Drori, A.; Liu, Z.; Cinar, R.; Kashiwaya, Y.; Reitman, M.L.; Kunos, G. Peripheral cannabinoid-1 receptor blockade restores hypothalamic leptin signaling. Mol. Metab., 2017, 6(10), 1113-1125.


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Article Details

VOLUME: 26
ISSUE: 10
Year: 2019
Page: [1908 - 1919]
Pages: 12
DOI: 10.2174/0929867325666180417165247
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