CB2 receptor

Target id: 57

Nomenclature: CB2 receptor

Family: Cannabinoid receptors

Annotation status:  image of a green circle Annotated and expert reviewed. Please contact us if you can help with updates.  » Email us

   GtoImmuPdb view: OFF :     Currently no data for CB2 receptor in GtoImmuPdb

Gene and Protein Information
class A G protein-coupled receptor
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 7 360 1p35-p36 CNR2 cannabinoid receptor 2 28,39
Mouse 7 347 4 D3 Cnr2 cannabinoid receptor 2 (macrophage) 41
Rat 7 410 5q36 Cnr2 cannabinoid receptor 2 7
Previous and Unofficial Names
rCB2 | cannabinoid receptor 2 (spleen) | CB2-R | Peripheral cannabinoid receptor | cannabinoid receptor 2 (macrophage)
Database Links
Specialist databases
GPCRDB cnr2_human (Hs), cnr2_mouse (Mm), cnr2_rat (Rn)
Other databases
ChEMBL Target
DrugBank Target
Ensembl Gene
Entrez Gene
GenitoUrinary Development Molecular Anatomy Project
Human Protein Atlas
KEGG Gene
OMIM
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia
Natural/Endogenous Ligands
anandamide
2-arachidonoylglycerol
Comments: Endogenous ligands include other endocannabinoids

Download all structure-activity data for this target as a CSV file

Agonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
[3H]HU-243 Hs Full agonist 10.2 pKd 2
pKd 10.2 [2]
[3H]CP55940 Hs Full agonist 8.1 – 9.7 pKd 6,13,28,40-42
pKd 8.1 – 9.7 [6,13,28,40-42]
[3H]WIN55212-2 Hs Full agonist 8.4 – 8.7 pKd 28,43
pKd 8.4 – 8.7 [28,43]
AM7499 Mm Agonist 10.0 pKi 22
pKi 10.0 (Ki 1x10-10 M) [22]
HU-210 Hs Full agonist 9.3 – 9.8 pKi 13,35,42
pKi 9.3 – 9.8 [13,35,42]
Sch.336 Hs Inverse agonist 8.7 – 9.4 pKi 24-25
pKi 9.4 (Ki 4x10-10 M) [24]
pKi 8.7 (Ki 1.8x10-9 M) [25]
Description: Measuring competitin binding with [3H]CP55,940 for binding to human CB2 on Sf9 cell membranes.
WIN55212-2 Hs Full agonist 8.4 – 9.6 pKi 13,41-42
pKi 8.4 – 9.6 [13,41-42]
CP55940 Hs Full agonist 8.6 – 9.2 pKi 13,38,42
pKi 8.6 – 9.2 [13,38,42]
AM2201 Mm Agonist 8.6 pKi 26
pKi 8.6 (Ki 2.6x10-9 M) [26]
Description: Binding affinity vs. mouse spleen membranes.
AM7499 Hs Agonist 8.5 pKi 22
pKi 8.5 (Ki 3.1x10-9 M) [22]
JWH-133 Hs Full agonist 8.5 pKi 20,32
pKi 8.5 (Ki 3.16x10-9 M) [20,32]
JWH-018 Hs Full agonist 8.5 pKi 10
pKi 8.5 [10]
nabilone Hs Agonist 8.2 pKi 5
pKi 8.2 (Ki 6.31x10-9 M) [5]
AM1241 Hs Agonist 8.1 pKi 44
pKi 8.1 (Ki 7.94x10-9 M) [44]
L-759,633 Hs Full agonist 7.7 – 8.2 pKi 16,38
pKi 7.7 – 8.2 (Ki 1.99x10-8 – 6.31x10-9 M) [16,38]
L-759,656 Hs Full agonist 7.7 – 7.9 pKi 16,38
pKi 7.7 – 7.9 (Ki 1.99x10-8 – 1.26x10-8 M) [16,38]
HU-308 Hs Full agonist 7.6 pKi 18
pKi 7.6 (Ki 2.51x10-8 M) [18]
Δ9-tetrahydrocannabinol Hs Partial agonist 7.1 – 7.5 pKi 3,13,35,42
pKi 7.1 – 7.5 [3,13,35,42]
ajulemic acid Hs Agonist 6.8 pKi 17,34
pKi 6.8 (Ki 1.7x10-7 M) [17,34]
taranabant Hs - 6.5 pKi 14
pKi 6.5 (Ki 2.9x10-7 M) [14]
2-arachidonoylglycerol Hs Partial agonist 5.8 – 6.8 pKi 4,27
pKi 5.8 – 6.8 [4,27]
anandamide Hs Partial agonist 5.7 – 6.4 pKi 13,27,42
pKi 5.7 – 6.4 [13,27,42]
AM2201 Hs Agonist 7.2 pEC50 1
pEC50 7.2 (EC50 5.88x10-8 M) [1]
BMS-202 Hs Agonist 6.9 pEC50 1
pEC50 6.9 (EC50 1.31x10-7 M) [1]
View species-specific agonist tables
Agonist Comments
The higher pKi value for anandamide (6.43) was determined in the presence of phenylmethylsulfonyl fluoride to prevent enzymic hydrolysis. For reviews, see references [19,30-31]
Antagonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
SR144528 Hs Antagonist 8.3 – 9.2 pKi 37-38
pKi 8.3 – 9.2 (Ki 5.01x10-9 – 6.3x10-10 M) [37-38]
AM-630 Hs Antagonist 7.5 pKi 38
pKi 7.5 (Ki 3.16x10-8 M) [38]
surinabant Hs Full agonist 6.3 pKi 36
pKi 6.3 (Ki 4.42x10-7 M) [36]
Description: Inhbition of [3H]-CP 55,940 binding to human CB2 receptors expressed in CHO cells
ibipinabant Hs Antagonist 5.1 pKi 23
pKi 5.1 (Ki 7.943x10-6 M) [23]
Description: Displacement of specific CP-55,940 binding in CHO cells stably transfected with human CB2 receptor
TM-38837 Hs Antagonist 6.2 pIC50 21
pIC50 6.2 (IC50 6.05x10-7 M) [21]
Primary Transduction Mechanisms
Transducer Effector/Response
Gi/Go family Adenylate cyclase inhibition
Other - See Comments
Comments:  Activation of MAP kinase leading to immediate early gene expression[19,40].
References:  6-7,13,19,41-43
Secondary Transduction Mechanisms
Transducer Effector/Response
Gs family Adenylate cyclase stimulation
References:  19,33
Tissue Distribution
Spleen, tonsils, bone marrow and peripheral blood leukocytes
Species:  Human
Technique:  RT-PCR
References:  15,19,28,30
Monocytes, macrophages, and microglial cells,
Species:  Rat
Technique:  RT-PCR
References:  9,11-12,19,28
Expression Datasets

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Log average relative transcript abundance in mouse tissues measured by qPCR from Regard, J.B., Sato, I.T., and Coughlin, S.R. (2008). Anatomical profiling of G protein-coupled receptor expression. Cell, 135(3): 561-71. [PMID:18984166] [Raw data: website]

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Physiological Consequences of Altering Gene Expression
This has been little investigated. There is one report that cannabinoid-induced inhibition of helper T cell activation is lost in macrophages obtained from CB2 knockout mice.
Species:  Mouse
Tissue: 
Technique:  Induced mutation.
References:  8
Phenotypes, Alleles and Disease Models Mouse data from MGI

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Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
Cnr2tm1Zim Cnr2tm1Zim/Cnr2tm1Zim
involves: 129 * C57BL/6
MGI:104650  MP:0002451 abnormal macrophage physiology PMID: 10822068 
Cnr2tm1Dgen Cnr2tm1Dgen/Cnr2tm1Dgen
involves: 129P2/OlaHsd * C57BL/6
MGI:104650  MP:0000414 alopecia
General Comments
Techniques used include Northern blot, in situ hybridization and receptor autoradiography[19,30]

References

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1. Banister SD, Stuart J, Kevin RC, Edington A, Longworth M, Wilkinson SM, Beinat C, Buchanan AS, Hibbs DE, Glass M et al.. (2015) Effects of bioisosteric fluorine in synthetic cannabinoid designer drugs JWH-018, AM-2201, UR-144, XLR-11, PB-22, 5F-PB-22, APICA, and STS-135. ACS Chem Neurosci6 (8): 1445-58. [PMID:25921407]

2. Bayewitch M, Avidor-Reiss T, Levy R, Barg J, Mechoulam R, Vogel Z. (1995) The peripheral cannabinoid receptor: adenylate cyclase inhibition and G protein coupling. FEBS Lett.375: 143-147. [PMID:7498464]

3. Bayewitch M, Rhee M-H, Avidor-Reiss T, Breuer A, Mechoulam R, Vogel Z. (1996) (-)-Δ9-tetrahydrocannabinol antagonizes the peripheral cannabinoid receptor-mediated inhibition of adenylyl cyclase. J. Biol. Chem.271: 9902-9905. [PMID:8626625]

4. Ben-Shabat S, Fride E, Sheskin T, Tamiri T, Rhee MH, Vogel Z, Bisogno T, De Petrocellis L, Di Marzo V, Mechoulam R. (1998) An entourage effect: inactive endogenous fatty acid glycerol esters enhance 2-arachidonoyl-glycerol cannabinoid activity. Eur. J. Pharmacol.353: 23-31. [PMID:9721036]

5. Blaazer AR, Lange JH, van der Neut MA, Mulder A, den Boon FS, Werkman TR, Kruse CG, Wadman WJ. (2011) Novel indole and azaindole (pyrrolopyridine) cannabinoid (CB) receptor agonists: design, synthesis, structure-activity relationships, physicochemical properties and biological activity. Eur J Med Chem46 (10): 5086-98. [PMID:21885167]

6. Bouaboula M, Poinot-Chazel C, Marchand J, Canat X, Bourrie B, Rinaldi-Carmona M, Calandra B, Le Fur G, Casellas P. (1996) Signalling pathway associated with stimulation of CB2 peripheral cannabinoid receptor. Involvement of both mitogen-activated protein kinases and induction of Krox-24 expression. Eur. J. Biochem.237: 704-711. [PMID:8647116]

7. Brown SM, Wager-Miller J, Mackie K. (2002) Cloning and molecular characterization of the rat CB2 cannabinoid receptor. Biochim. Biophys. Acta1576: 255-264. [PMID:12084572]

8. Buckley NE, McCoy KL, Mezey E, Bonner T, Zimmer A, Felder CC, Glass M, Zimmer A. (2000) Immunomodulation by cannabinoids is absent in mice deficient for the cannabinoid CB(2) receptor. Eur. J. Pharmacol.396 (2-3): 141-9. [PMID:10822068]

9. Carlisle SJ, Marciano-Cabral F, Staab A, Ludwick C, Cabral GA. (2002) Differential expression of the CB2 cannabinoid receptor by rodent macrophages and macrophage-like cells in relation to cell activation. Int. Immunopharmacol.2: 69-82. [PMID:11789671]

10. Chin CN, Murphy JW, Huffman JW, Kendall DA. (1999) The third transmembrane helix of the cannabinoid receptor plays a role in the selectivity of aminoalkylindoles for CB2, peripheral cannabinoid receptor. J. Pharmacol. Exp. Ther.291 (2): 837-44. [PMID:10525107]

11. Das SK, Paria BC, Chakraborty I, Dey SK. (1995) Cannabinoid ligand-receptor signaling in the mouse uterus. Proc. Natl. Acad. Sci. USA92: 4332-4336. [PMID:7753807]

12. Facci L, Dal Toso R, Romanello S, Buriani A, Skaper SD, Leon A. (1995) Mast cells express a peripheral cannabinoid receptor with differential sensitivity to anandamide and palmitoylethanolamide. Proc. Natl. Acad. Sci. U.S.A.92: 3376-3380. [PMID:7724569]

13. Felder CC, Joyce KE, Briley EM, Mansouri J, Mackie K, Blond O, Lai Y, Ma AL, Mitchell RL. (1995) Comparison of the pharmacology and signal transduction of the human cannabinoid CB1 and CB2 receptors. Mol. Pharmacol.48: 443-450. [PMID:7565624]

14. Foloppe N, Benwell K, Brooks TD, Kennett G, Knight AR, Misra A, Monck NJ. (2009) Discovery and functional evaluation of diverse novel human CB(1) receptor ligands. Bioorg. Med. Chem. Lett.19 (15): 4183-90. [PMID:19520572]

15. Galiegue S, Mary S, Marchand J, Dussossoy D, Carriere D, Carayon P, Bouaboula M, Shire D, Le Fur G, Casellas P. (1995) Expression of central and peripheral cannabinoid receptors in human immune tissues and leukocyte subpopulations. Eur. J. Biochem.232: 54-61. [PMID:7556170]

16. Gareau Y, Dufresne C, Gallant M, Rochette C, Sawyer N, Slipetz DM, Tremblay N, Weech PK, Metters KM, Labelle M. (1996) Structure activity relationships of tetrahydrocannabinol analogues on human cannabinoid receptors. Bioorg. Med. Chem. Lett.6: 189-194.

17. Han S, Thatte J, Buzard DJ, Jones RM. (2013) Therapeutic utility of cannabinoid receptor type 2 (CB(2)) selective agonists. J. Med. Chem.56 (21): 8224-56. [PMID:23865723]

18. Hanus L, Breuer A, Tchilibon S, Shiloah S, Goldenberg D, Horowitz M, Pertwee RG, Ross RA, Mechoulam R, Fride E. (1999) HU-308: a specific agonist for CB2, a peripheral cannabinoid receptor. Proc. Natl. Acad. Sci. USA96: 14228-14233. [PMID:10588688]

19. Howlett AC, Barth F, Bonner TI, Cabral G, Casellas P, Devane WA, Felder CC, Herkenham M, Mackie K, Martin BR, Mechoulam R, Pertwee RG. (2002) International Union of Pharmacology. XXVII. Classification of cannabinoid receptors. Pharmacol. Rev.54: 161-202. [PMID:12037135]

20. Huffman JW, Liddle J, Yu S, Aung MM, Abood ME, Wiley JL, Martin BR. (1999) 3-(1',1'-dimethylbutyl)-1-deoxy-Δ8-THC and related compounds: synthesis of selective ligands for the CB2 receptor. Bioorg. Med. Chem.7: 2905-2914. [PMID:10658595]

21. Hung MS, Chang CP, Li TC, Yeh TK, Song JS, Lin Y, Wu CH, Kuo PC, Amancha PK, Wong YC et al.. (2010) Discovery of 1-(2,4-dichlorophenyl)-4-ethyl-5-(5-(2-(4-(trifluoromethyl)phenyl)ethynyl)thiophen-2-yl)-N-(piperidin-1-yl)-1H-pyrazole-3-carboxamide as a potential peripheral cannabinoid-1 receptor inverse agonist. ChemMedChem5 (9): 1439-43. [PMID:20652930]

22. Kulkarni S, Nikas SP, Sharma R, Jiang S, Paronis CA, Leonard MZ, Zhang B, Honrao C, Mallipeddi S, Raghav JG et al.. (2016) Novel C-Ring-Hydroxy-Substituted Controlled Deactivation Cannabinergic Analogues. J. Med. Chem.,  [Epub ahead of print]. [PMID:27367336]

23. Lange JH, Coolen HK, van Stuivenberg HH, Dijksman JA, Herremans AH, Ronken E, Keizer HG, Tipker K, McCreary AC, Veerman W et al.. (2004) Synthesis, biological properties, and molecular modeling investigations of novel 3,4-diarylpyrazolines as potent and selective CB(1) cannabinoid receptor antagonists. J. Med. Chem.47 (3): 627-43. [PMID:14736243]

24. Lavey BJ, Kozlowski JA, Hipkin RW, Gonsiorek W, Lundell DJ, Piwinski JJ, Narula S, Lunn CA. (2005) Triaryl bis-sulfones as a new class of cannabinoid CB2 receptor inhibitors: identification of a lead and initial SAR studies. Bioorg. Med. Chem. Lett.15 (3): 783-6. [PMID:15664857]

25. Lunn CA, Fine JS, Rojas-Triana A, Jackson JV, Fan X, Kung TT, Gonsiorek W, Schwarz MA, Lavey B, Kozlowski JA et al.. (2006) A novel cannabinoid peripheral cannabinoid receptor-selective inverse agonist blocks leukocyte recruitment in vivo. J. Pharmacol. Exp. Ther.316 (2): 780-8. [PMID:16258021]

26. Makriyannis A, Deng H. (2001) Cannabimimetic indole derivatives. Patent number: WO2001028557. Assignee: University Of Connecticut. Priority date: 18/10/1999. Publication date: 26/04/2001.

27. Mechoulam R, Ben-Shabat S, Hanus L, Ligumsky M, Kaminski NE, Schatz AR, Gopher A, Almog S, Martin BR, Compton DR et al.. (1995) Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors. Biochem. Pharmacol.50: 83-90. [PMID:7605349]

28. Munro S, Thomas KL, Abu-Shaar M. (1993) Molecular characterization of a peripheral receptor for cannabinoids. Nature365: 61-65. [PMID:7689702]

29. Oka S, Wakui J, Ikeda S, Yanagimoto S, Kishimoto S, Gokoh M, Nasui M, Sugiura T. (2006) Involvement of the cannabinoid CB2 receptor and its endogenous ligand 2-arachidonoylglycerol in oxazolone-induced contact dermatitis in mice. J. Immunol.177 (12): 8796-805. [PMID:17142782]

30. Pertwee RG. (1997) Pharmacology of cannabinoid CB1 and CB2 receptors. Pharmacol. Ther.74: 129-180. [PMID:9336020]

31. Pertwee RG. (1999) Pharmacology of cannabinoid receptor ligands. Curr. Med. Chem.6: 635-664. [PMID:10469884]

32. Pertwee RG. (2000) Cannabinoid receptor ligands: clinical and neuropharmacological considerations, relevant to future drug discovery and development. Expert Opin Investig Drugs9 (7): 1553-71. [PMID:11060760]

33. Rhee M-H, Bayewitch M, Avidor-Reiss T, Levy R, Vogel Z. (1998) Cannabinoid receptor activation differentially regulates the various adenylyl cyclase isozymes. J. Neurochem.71: 1525-1534. [PMID:9751186]

34. Rhee M-H, Vogel, Z, Barg J, Bayewitch M, Levy R, Hanu L, Breuer A., Mechoulam R. (1997) Cannabinoid derivatives: binding to cannabinoid receptors and inhibition of adenylcyclase. Journal of Medicinal Chemistry40: 3228−3233.

35. Rhee MH, Vogel Z, Barg J, Bayewitch M, Levy R, Hanus L, Breuer A, Mechoulam R. (1997) Cannabinol derivatives: binding to cannabinoid receptors and inhibition of adenylylcyclase. J. Med. Chem.40 (20): 3228-33. [PMID:9379442]

36. Rinaldi-Carmona M, Barth F, Congy C, Martinez S, Oustric D, Pério A, Poncelet M, Maruani J, Arnone M, Finance O et al.. (2004) SR147778 [5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-ethyl-N-(1-piperidinyl)-1H-pyrazole-3-carboxamide], a new potent and selective antagonist of the CB1 cannabinoid receptor: biochemical and pharmacological characterization. J. Pharmacol. Exp. Ther.310 (3): 905-14. [PMID:15131245]

37. Rinaldi-Carmona M, Barth F, Millan J, Derocq JM, Casellas P, Congy C, Oustric D, Sarran M, Bouaboula M, Calandra B, Portier M, Shire D, Breliere JC, Le Fur GL. (1998) SR144528, the first potent and selective antagonist of the CB2 cannabinoid receptor. J. Pharmacol. Exp. Ther.284: 644-650. [PMID:9454810]

38. Ross RA, Brockie HC, Stevenson LA, Murphy VL, Templeton F, Makriyannis A, Pertwee RG. (1999) Agonist-inverse agonist characterization at CB1 and CB2 cannabinoid receptors of L759633, L759656 and AM630. Br. J. Pharmacol.126: 665-672. [PMID:10188977]

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40. Shire D, Calandra B, Delpech M, Dumont X, Kaghad M, Le Fur G, Caput D, Ferrara P. (1996) Structural features of the central cannabinoid CB1 receptor involved in the binding of the specific CB1 antagonist SR 141716A. J. Biol. Chem.271: 6941-6946. [PMID:8636122]

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42. Showalter VM, Compton DR, Martin BR, Abood ME. (1996) 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.278: 989-999. [PMID:8819477]

43. Slipetz DM, O'Neill GP, Favreau L, Dufresne C, Gallant M, Gareau Y, Guay D, Labelle M, Metters KM. (1995) Activation of the human peripheral cannabinoid receptor results in inhibition of adenylyl cyclase. Mol. Pharmacol.48: 352-361. [PMID:7651369]

44. Yao BB, Mukherjee S, Fan Y, Garrison TR, Daza AV, Grayson GK, Hooker BA, Dart MJ, Sullivan JP, Meyer MD. (2006) In vitro pharmacological characterization of AM1241: a protean agonist at the cannabinoid CB2 receptor?. Br. J. Pharmacol.149 (2): 145-54. [PMID:16894349]

Contributors

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How to cite this page

Mary Abood, Francis Barth, Tom I. Bonner, Guy Cabral, Pierre Casellas, Ben F. Cravatt, William A. Devane, Maurice R. Elphick, Christian C. Felder, Miles Herkenham, Allyn C. Howlett, George Kunos, Ken Mackie, Raphael Mechoulam, Roger G. Pertwee.
Cannabinoid receptors: CB2 receptor. Last modified on 27/02/2018. Accessed on 26/04/2018. IUPHAR/BPS Guide to PHARMACOLOGY, http://guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=57.