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CB2 receptor

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Immunopharmacology Ligand target has curated data in GtoImmuPdb

Target id: 57

Nomenclature: CB2 receptor

Family: Cannabinoid receptors

Contents:

Gene and Protein Information Click here for help
class A G protein-coupled receptor
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 7 360 1p36.11 CNR2 cannabinoid receptor 2 42,56
Mouse 7 347 4 D3 Cnr2 cannabinoid receptor 2 58
Rat 7 360 5q36 Cnr2 cannabinoid receptor 2 9
Previous and Unofficial Names Click here for help
rCB2 | cannabinoid receptor 2 (spleen) | CB2-R | Peripheral cannabinoid receptor | cannabinoid receptor 2 (macrophage)
Database Links Click here for help
Specialist databases
GPCRdb cnr2_human (Hs), cnr2_mouse (Mm), cnr2_rat (Rn)
Other databases
Alphafold P34972 (Hs), P47936 (Mm), Q9QZN9 (Rn)
ChEMBL Target CHEMBL253 (Hs), CHEMBL5373 (Mm), CHEMBL2470 (Rn)
DrugBank Target P34972 (Hs)
Ensembl Gene ENSG00000188822 (Hs), ENSMUSG00000062585 (Mm), ENSRNOG00000009260 (Rn)
Entrez Gene 1269 (Hs), 12802 (Mm), 57302 (Rn)
Human Protein Atlas ENSG00000188822 (Hs)
KEGG Gene hsa:1269 (Hs), mmu:12802 (Mm), rno:57302 (Rn)
OMIM 605051 (Hs)
Pharos P34972 (Hs)
RefSeq Nucleotide NM_001841 (Hs), NM_009924 (Mm), NM_020543 (Rn)
RefSeq Protein NP_001832 (Hs), NP_034054 (Mm), NP_065418 (Rn)
UniProtKB P34972 (Hs), P47936 (Mm), Q9QZN9 (Rn)
Wikipedia CNR2 (Hs)
Natural/Endogenous Ligands Click here for help
anandamide
2-arachidonoylglycerol
Comments: Endogenous ligands include other endocannabinoids

Download all structure-activity data for this target as a CSV file go icon to follow link

Agonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
[3H]HU-243 Small molecule or natural product Ligand is labelled Ligand is radioactive Hs Full agonist 10.2 pKd 4
⤷ pKd 10.2 [4]
[3H]CP55940 Small molecule or natural product Click here for species-specific activity table Ligand is labelled Ligand is radioactive Ligand has a PDB structure Hs Full agonist 8.1 – 9.7 pKd 8,17,42,57-59
⤷ pKd 8.1 – 9.7 [8,17,42,57-59]
[3H]WIN55212-2 Small molecule or natural product Click here for species-specific activity table Ligand is labelled Ligand is radioactive Hs Full agonist 8.4 – 8.7 pKd 42,60
⤷ pKd 8.4 – 8.7 [42,60]
AM7499 Small molecule or natural product Mm Agonist 10.0 pKi 33
⤷ pKi 10.0 (Ki 1x10-10 M) [33]
MDMB-Fubinaca Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Agonist 9.9 pKi 55
⤷ pKi 9.9 (Ki 1.3x10-10 M) [55]
HU-210 Small molecule or natural product Click here for species-specific activity table Hs Full agonist 9.3 – 9.8 pKi 17,50,59
⤷ pKi 9.3 – 9.8 [17,50,59]
Sch.336 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Immunopharmacology Ligand Hs Inverse agonist 8.7 – 9.4 pKi 35,38
⤷ pKi 9.4 (Ki 4x10-10 M) [35]
pKi 8.7 (Ki 1.8x10-9 M) [38]
Description: Measuring competitin binding with [3H]CP55,940 for binding to human CB2 on Sf9 cell membranes.
AZD1940 Small molecule or natural product Click here for species-specific activity table Hs Agonist 9.1 pKi 36
⤷ pKi 9.1 (Ki 8.7x10-10 M) [36]
WIN55212-2 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Full agonist 8.4 – 9.6 pKi 17,58-59
⤷ pKi 8.4 – 9.6 [17,58-59]
CP55940 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Full agonist 8.6 – 9.2 pKi 17,54,59
⤷ pKi 8.6 – 9.2 [17,54,59]
AM2201 Small molecule or natural product Mm Agonist 8.6 pKi 39
⤷ pKi 8.6 (Ki 2.6x10-9 M) [39]
Description: Binding affinity vs. mouse spleen membranes.
AM7499 Small molecule or natural product Hs Agonist 8.5 pKi 33
⤷ pKi 8.5 (Ki 3.1x10-9 M) [33]
JWH-133 Small molecule or natural product Hs Full agonist 8.5 pKi 30,47
⤷ pKi 8.5 (Ki 3.16x10-9 M) [30,47]
JWH-018 Small molecule or natural product Click here for species-specific activity table Hs Full agonist 8.5 pKi 12
⤷ pKi 8.5 [12]
nabilone Small molecule or natural product Approved drug Click here for species-specific activity table Hs Agonist 8.2 pKi 7
⤷ pKi 8.2 (Ki 6.31x10-9 M) [7]
AM1710 Small molecule or natural product Mm Agonist 8.2 pKi 32
⤷ pKi 8.2 (Ki 6.7x10-9 M) [32]
AM1241 Small molecule or natural product Hs Agonist 8.1 pKi 61
⤷ pKi 8.1 (Ki 7.94x10-9 M) [61]
L-759,633 Small molecule or natural product Hs Full agonist 7.7 – 8.2 pKi 21,54
⤷ pKi 7.7 – 8.2 (Ki 1.99x10-8 – 6.31x10-9 M) [21,54]
cannabinor Small molecule or natural product Rn Agonist 7.9 pKi 23
⤷ pKi 7.9 (Ki 1.35x10-8 M) [23]
L-759,656 Small molecule or natural product Hs Full agonist 7.7 – 7.9 pKi 21,54
⤷ pKi 7.7 – 7.9 (Ki 1.99x10-8 – 1.26x10-8 M) [21,54]
cannabinor Small molecule or natural product Hs Agonist 7.8 pKi 23
⤷ pKi 7.8 (Ki 1.6x10-8 M) [23]
onternabez Small molecule or natural product Click here for species-specific activity table Hs Full agonist 7.6 pKi 26
⤷ pKi 7.6 (Ki 2.51x10-8 M) [26]
LY2828360 Small molecule or natural product Rn Agonist 7.4 pKi 27
⤷ pKi 7.4 (Ki 3.67x10-8 M) [27]
Description: Binding affinity
LY2828360 Small molecule or natural product Hs Agonist 7.4 pKi 27
⤷ pKi 7.4 (Ki 4.03x10-8 M) [27]
Description: Binding affinity
BAY-593074 Small molecule or natural product Click here for species-specific activity table Hs Partial agonist 7.3 pKi 14
⤷ pKi 7.3 (Ki 4.55x10-8 M) [14]
Δ9-tetrahydrocannabinol Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Hs Partial agonist 7.1 – 7.5 pKi 5,17,50,59
⤷ pKi 7.1 – 7.5 [5,17,50,59]
lenabasum Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Agonist 6.8 pKi 24,51
⤷ pKi 6.8 (Ki 1.7x10-7 M) [24,51]
VCE-004.3 Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Hs Agonist 6.7 pKi 15
⤷ pKi 6.7 (Ki 2.04x10-7 M) [15]
taranabant Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs - 6.5 pKi 18
⤷ pKi 6.5 (Ki 2.9x10-7 M) [18]
phenylacetylrinvanil Small molecule or natural product Click here for species-specific activity table Hs Agonist 6.5 pKi 2
⤷ pKi 6.5 (Ki 3x10-7 M) [2]
Description: Binding affinity for recombinant human CB2 receptors expressed in COS cells, displacing [3H]-CP-55,940.
2-arachidonoylglycerol Small molecule or natural product Click here for species-specific activity table Ligand is endogenous in the given species Ligand has a PDB structure Hs Partial agonist 5.8 – 6.8 pKi 6,41
⤷ pKi 5.8 – 6.8 [6,41]
anandamide Small molecule or natural product Click here for species-specific activity table Ligand is endogenous in the given species Ligand has a PDB structure Hs Partial agonist 5.7 – 6.4 pKi 17,41,59
⤷ pKi 5.7 – 6.4 [17,41,59]
vicasinabin Small molecule or natural product Hs Agonist 8.9 pEC50 1
⤷ pEC50 8.9 (EC50 1.4x10-9 M) [1]
Description: cAMP assay using CHO cells expressing hCB2 receptor
olorinab Small molecule or natural product Primary target of this compound Click here for species-specific activity table Ligand has a PDB structure Hs Full agonist 8.2 pEC50 25
⤷ pEC50 8.2 (EC50 6.2x10-9 M) [25]
Description: In a DiscoverX PathHunter β-arrestin recruitment assay.
olorinab Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Rn Full agonist 8.1 pEC50 25
⤷ pEC50 8.1 (EC50 7.6x10-9 M) [25]
Description: In a DiscoverX PathHunter β-arrestin recruitment assay.
cannabinor Small molecule or natural product Hs Agonist 7.8 pEC50 23
⤷ pEC50 7.8 (EC50 1.74x10-8 M) [23]
Description: Determined in a GTPγS assay
LY2828360 Small molecule or natural product Hs Agonist 7.7 pEC50 27
⤷ pEC50 7.7 (EC50 2.01x10-8 M) [27]
Description: Dtermined in a GTPγS assay
AM2201 Small molecule or natural product Click here for species-specific activity table Hs Agonist 7.2 pEC50 3
⤷ pEC50 7.2 (EC50 5.88x10-8 M) [3]
GW842166 Small molecule or natural product Hs Agonist 7.2 pEC50 22
⤷ pEC50 7.2 (EC50 6.3x10-8 M) [22]
GW842166 Small molecule or natural product Rn Agonist 7.0 pEC50 22
⤷ pEC50 7.0 (EC50 9.1x10-8 M) [22]
GW405833 Small molecule or natural product Hs Partial agonist 7.0 pEC50 40
⤷ pEC50 7.0 [40]
Description: cAMP assay using hCB2 ‐CHO cells.
BMS-202 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Agonist 6.9 pEC50 3
⤷ pEC50 6.9 (EC50 1.31x10-7 M) [3]
(E)-beta-caryophyllene Small molecule or natural product Hs Agonist 5.7 pEC50 43
⤷ pEC50 5.7 (EC50 1.9x10-6 M) [43]
Description: Agonist potency at recombinant human CB2 receptor expressed in CHOK1 cells; determined as inhibition of forskolin-stimulated cAMP formation.
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 [28,45-46]
Antagonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
AM10257 Small molecule or natural product Hs Antagonist 10.1 pKi 37
⤷ pKi 10.1 (Ki 7.5x10-11 M) [37]
Description: Antagonism of [3H]CP55940 binding to human CB2.
SR144528 Small molecule or natural product Immunopharmacology Ligand Hs Antagonist 8.3 – 9.2 pKi 53-54
⤷ pKi 8.3 – 9.2 (Ki 5.01x10-9 – 6.3x10-10 M) [53-54]
AM-630 Small molecule or natural product Hs Antagonist 7.5 pKi 54
⤷ pKi 7.5 (Ki 3.16x10-8 M) [54]
surinabant Small molecule or natural product Click here for species-specific activity table Hs Antagonist 6.3 pKi 52
⤷ pKi 6.3 (Ki 4.42x10-7 M) [52]
Description: Inhbition of [3H]-CP 55,940 binding to human CB2 receptors expressed in CHO cells
ibipinabant Small molecule or natural product Click here for species-specific activity table Hs Antagonist 5.1 pKi 34
⤷ pKi 5.1 (Ki 7.943x10-6 M) [34]
Description: Displacement of specific CP-55,940 binding in CHO cells stably transfected with human CB2 receptor
TM38837 Small molecule or natural product Click here for species-specific activity table Hs Antagonist 6.2 pIC50 31
⤷ pIC50 6.2 (IC50 6.05x10-7 M) [31]
Allosteric Modulators
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
pepcan-12 Peptide Click here for species-specific activity table Hs Positive ~7.3 pKi 48
⤷ pKi ~7.3 (Ki ~5x10-8 M) [48]
compound C2 [PMID: 29990428] Small molecule or natural product Hs Positive - - 19
⤷ [19]
Immunopharmacology Comments
CB2 receptor on eosinophils mainly mediates anti-inflammatory and immunomodulatory actions e.g. downregulation of pro-inflammatory mediator release. Pharmacological targeting with the CB2 receptor selective antagonist SR144528 attenuates the recruitment of eosinophils and ear swelling in a murine chronic contact dermatitis model [44].
Cell Type Associations
Immuno Cell Type:  Mast cells
Cell Ontology Term:   mast cell (CL:0000097)
Comment:  Mast cells express both cannabinoid receptors.
Immuno Cell Type:  Granulocytes
Cell Ontology Term:   eosinophil (CL:0000771)
Comment:  Eosinophils do not express CB1 receptor.
Immuno Cell Type:  T cells
Cell Ontology Term:   CD8-positive, alpha-beta T cell (CL:0000625)
Comment:  CB2 receptor expression was detected in human CD8+ T cells by single cell RNA-sequencing. Expression was lowest in CD4+ T cells by this method.
References:  29
Immuno Cell Type:  B cells
Cell Ontology Term:   B cell (CL:0000236)
Comment:  CB2 receptor expression was detected in human B cells by single cell RNA-sequencing.
References:  29
Immuno Cell Type:  Natural killer cells
Cell Ontology Term:   natural killer cell (CL:0000623)
Comment:  CB2 receptor expression was detected in human NK cells by single cell RNA-sequencing.
References:  29
Immuno Process Associations
Immuno Process:  Inflammation
Immuno Process:  Immune regulation
Immuno Process:  Chemotaxis & migration
Immuno Process:  Cellular signalling
Primary Transduction Mechanisms Click here for help
Transducer Effector/Response
Gi/Go family Adenylyl cyclase inhibition
Other - See Comments
Comments:  Activation of MAP kinase leading to immediate early gene expression[28,57].
References:  8-9,17,28,58-60
Secondary Transduction Mechanisms Click here for help
Transducer Effector/Response
Gs family Adenylyl cyclase stimulation
References:  28,49
Tissue Distribution Click here for help
Spleen, tonsils, bone marrow and peripheral blood leukocytes
Species:  Human
Technique:  RT-PCR
References:  20,28,42,45
Monocytes, macrophages, and microglial cells,
Species:  Rat
Technique:  RT-PCR
References:  11,13,16,28,42
Expression Datasets Click here for help

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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 Click here for help
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:  10
Phenotypes, Alleles and Disease Models Click here for help 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[28,45]

References

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1. Adam J-M, Bissantz C, Grether U, Kimbara A, Nettekoven M, Roever S, Rogers-Evans M. (2013) [1, 2, 3] triazolo [4, 5 -d] pyrimidine derivatives as agonists of the cannabinoid receptor 2. Patent number: WO2013068306A1. Assignee: Hoffmann-La Roche Ag. Priority date: 08/11/2011. Publication date: 16/05/2013.

2. Appendino G, De Petrocellis L, Trevisani M, Minassi A, Daddario N, Moriello AS, Gazzieri D, Ligresti A, Campi B, Fontana G et al.. (2005) Development of the first ultra-potent "capsaicinoid" agonist at transient receptor potential vanilloid type 1 (TRPV1) channels and its therapeutic potential. J Pharmacol Exp Ther, 312 (2): 561-70. [PMID:15356216]

3. 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 Neurosci, 6 (8): 1445-58. [PMID:25921407]

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5. Bayewitch M, Rhee MH, Avidor-Reiss T, Breuer A, Mechoulam R, Vogel Z. (1996) (-)-Delta9-tetrahydrocannabinol antagonizes the peripheral cannabinoid receptor-mediated inhibition of adenylyl cyclase. J Biol Chem, 271 (17): 9902-5. [PMID:8626625]

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12. 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]

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14. De Vry J, Denzer D, Reissmueller E, Eijckenboom M, Heil M, Meier H, Mauler F. (2004) 3-[2-cyano-3-(trifluoromethyl)phenoxy]phenyl-4,4,4-trifluoro-1-butanesulfonate (BAY 59-3074): a novel cannabinoid Cb1/Cb2 receptor partial agonist with antihyperalgesic and antiallodynic effects. J Pharmacol Exp Ther, 310 (2): 620-32. [PMID:15140913]

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16. 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 USA, 92 (8): 3376-80. [PMID:7724569]

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19. Gado F, Di Cesare Mannelli L, Lucarini E, Bertini S, Cappelli E, Digiacomo M, Stevenson LA, Macchia M, Tuccinardi T, Ghelardini C et al.. (2019) Identification of the First Synthetic Allosteric Modulator of the CB2 Receptors and Evidence of Its Efficacy for Neuropathic Pain Relief. J Med Chem, 62 (1): 276-287. [PMID:29990428]

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21. 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.

22. Giblin GM, Bit RA, Brown SH, Chaignot HM, Chowdhury A, Chessell IP, Clayton NM, Coleman T, Hall A, Hammond B et al.. (2007) The discovery of 6-[2-(5-chloro-2-{[(2,4-difluorophenyl)methyl]oxy}phenyl)-1-cyclopenten-1-yl]-2-pyridinecarboxylic acid, GW848687X, a potent and selective prostaglandin EP1 receptor antagonist for the treatment of inflammatory pain. Bioorg Med Chem Lett, 17 (2): 385-9. [PMID:17084082]

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25. Han S, Thoresen L, Jung JK, Zhu X, Thatte J, Solomon M, Gaidarov I, Unett DJ, Yoon WH, Barden J et al.. (2017) Discovery of APD371: Identification of a Highly Potent and Selective CB2 Agonist for the Treatment of Chronic Pain. ACS Med Chem Lett, 8 (12): 1309-1313. [PMID:29259753]

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27. Hollinshead SP, Tidwell MW, Palmer J, Guidetti R, Sanderson A, Johnson MP, Chambers MG, Oskins J, Stratford R, Astles PC. (2013) 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, 56 (14): 5722-33. [PMID:23795771]

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29. Hu Y, Ranganathan M, Shu C, Liang X, Ganesh S, Osafo-Addo A, Yan C, Zhang X, Aouizerat BE, Krystal JH et al.. (2020) Single-cell Transcriptome Mapping Identifies Common and Cell-type Specific Genes Affected by Acute Delta9-tetrahydrocannabinol in Humans. Sci Rep, 10 (1): 3450. [PMID:32103029]

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