Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTYP9P43)

• DOT Name: Cannabinoid receptor 2 (CNR2)
• Synonyms: CB-2; CB2; hCB2; CX5
• Gene Name: CNR2
• UniProt ID: CNR2_HUMAN
• PDB ID: 2KI9; 5ZTY; 6KPC; 6KPF; 6PT0; 8GUQ; 8GUR; 8GUS; 8GUT
• Pfam ID: PF00001
• Sequence:
  MEECWVTEIANGSKDGLDSNPMKDYMILSGPQKTAVAVLCTLLGLLSALENVAVLYLILS
  SHQLRRKPSYLFIGSLAGADFLASVVFACSFVNFHVFHGVDSKAVFLLKIGSVTMTFTAS
  VGSLLLTAIDRYLCLRYPPSYKALLTRGRALVTLGIMWVLSALVSYLPLMGWTCCPRPCS
  ELFPLIPNDYLLSWLLFIAFLFSGIIYTYGHVLWKAHQHVASLSGHQDRQVPGMARMRLD
  VRLAKTLGLVLAVLLICWFPVLALMAHSLATTLSDQVKKAFAFCSMLCLINSMVNPVIYA
  LRSGEIRSSAHHCLAHWKKCVRGLGSEAKEEAPRSSVTETEADGKITPWPDSRDLDLSDC
• Function: Heterotrimeric G protein-coupled receptor for endocannabinoid 2-arachidonoylglycerol mediating inhibition of adenylate cyclase. May function in inflammatory response, nociceptive transmission and bone homeostasis.
• Tissue Specificity: Preferentially expressed in cells of the immune system with higher expression in B-cells and NK cells (at protein level). Expressed in skin in suprabasal layers and hair follicles (at protein level). Highly expressed in tonsil and to a lower extent in spleen, peripheral blood mononuclear cells, and thymus. PubMed:14657172 could not detect expression in normal brain. Expressed in brain by perivascular microglial cells and dorsal root ganglion sensory neurons (at protein level). Two isoforms are produced by alternative promoter usage and differ only in the 5' UTR: isoform CB2A is observed predominantly in testis with some expression in brain, while isoform CB2B is predominant in spleen and leukocytes.
• KEGG Pathway: Neuroactive ligand-receptor interaction (hsa04080)
• Reactome Pathway:
  G alpha (i) signalling events (R-HSA-418594)
  Class A/1 (Rhodopsin-like receptors) (R-HSA-373076)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
2-arachidonoylglycerol	DMM0KOJ	Investigative	Cannabinoid receptor 2 (CNR2) affects the response to substance of 2-arachidonoylglycerol.	[18]

13 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Cannabinoid receptor 2 (CNR2).	[1]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Cannabinoid receptor 2 (CNR2).	[2]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of Cannabinoid receptor 2 (CNR2).	[3]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Cannabinoid receptor 2 (CNR2).	[4]
Marinol	DM70IK5	Approved	Marinol increases the activity of Cannabinoid receptor 2 (CNR2).	[5]
Cannabidiol	DM0659E	Approved	Cannabidiol affects the expression of Cannabinoid receptor 2 (CNR2).	[6]
Menthol	DMG2KW7	Approved	Menthol decreases the expression of Cannabinoid receptor 2 (CNR2).	[7]
Amphotericin B	DMTAJQE	Approved	Amphotericin B increases the expression of Cannabinoid receptor 2 (CNR2).	[8]
Gemcitabine	DMSE3I7	Approved	Gemcitabine increases the expression of Cannabinoid receptor 2 (CNR2).	[9]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Cannabinoid receptor 2 (CNR2).	[4]
Forskolin	DM6ITNG	Investigative	Forskolin increases the activity of Cannabinoid receptor 2 (CNR2).	[14]
Anandamide	DMCKH3P	Investigative	Anandamide affects the activity of Cannabinoid receptor 2 (CNR2).	[15]
O-arachidonoyl ethanolamine	DML0P72	Investigative	O-arachidonoyl ethanolamine increases the activity of Cannabinoid receptor 2 (CNR2).	[17]

5 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Guanfacine extended release	DMB1CZ8	Approved	Guanfacine extended release affects the binding of Cannabinoid receptor 2 (CNR2).	[10]
Nabilone	DMVRYT2	Approved	Nabilone affects the binding of Cannabinoid receptor 2 (CNR2).	[11]
JWH-015	DMGTSCP	Patented	JWH-015 affects the binding of Cannabinoid receptor 2 (CNR2).	[13]
5'-Guanosine-Diphosphate-Monothiophosphate	DMIARG7	Investigative	5'-Guanosine-Diphosphate-Monothiophosphate affects the binding of Cannabinoid receptor 2 (CNR2).	[16]
SR144528	DMBRVXY	Investigative	SR144528 affects the binding of Cannabinoid receptor 2 (CNR2).	[13]

1 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Cannabinoid receptor 2 (CNR2).	[12]

References

• [1] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [2] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [3] Comparison of protective effect of ascorbic acid on redox and endocannabinoid systems interactions in in vitro cultured human skin fibroblasts exposed to UV radiation and hydrogen peroxide. Arch Dermatol Res. 2017 May;309(4):285-303. doi: 10.1007/s00403-017-1729-0. Epub 2017 Mar 11.
• [4] Regulation of opioid and cannabinoid receptor genes in human neuroblastoma and T cells by the epigenetic modifiers trichostatin A and 5-aza-2'-deoxycytidine. Neuroimmunomodulation. 2012;19(3):180-6. doi: 10.1159/000331474. Epub 2012 Jan 18.
• [5] Delta9-tetrahydrocannabinol inhibits cell cycle progression in human breast cancer cells through Cdc2 regulation. Cancer Res. 2006 Jul 1;66(13):6615-21. doi: 10.1158/0008-5472.CAN-05-4566.
• [6] hiPSC-Based Model of Prenatal Exposure to Cannabinoids: Effect on Neuronal Differentiation. Front Mol Neurosci. 2020 Jul 6;13:119. doi: 10.3389/fnmol.2020.00119. eCollection 2020.
• [7] Repurposing L-menthol for systems medicine and cancer therapeutics? L-menthol induces apoptosis through caspase 10 and by suppressing HSP90. OMICS. 2016 Jan;20(1):53-64.
• [8] Differential expression of microRNAs and their predicted targets in renal cells exposed to amphotericin B and its complex with copper (II) ions. Toxicol Mech Methods. 2017 Sep;27(7):537-543. doi: 10.1080/15376516.2017.1333554. Epub 2017 Jun 8.
• [9] Gemcitabine/cannabinoid combination triggers autophagy in pancreatic cancer cells through a ROS-mediated mechanism. Cell Death Dis. 2011 Apr 28;2(4):e152. doi: 10.1038/cddis.2011.36.
• [10] 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 Jan 7;275(1):605-12. doi: 10.1074/jbc.275.1.605.
• [11] Cloning and pharmacological characterization of the dog cannabinoid CB?receptor. Eur J Pharmacol. 2011 Nov 1;669(1-3):24-31. doi: 10.1016/j.ejphar.2011.08.002. Epub 2011 Aug 19.
• [12] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [13] Cloning and pharmacological characterization of the rat CB(2) cannabinoid receptor. J Pharmacol Exp Ther. 2000 Mar;292(3):886-94.
• [14] Affinity and Efficacy Studies of Tetrahydrocannabinolic Acid A at Cannabinoid Receptor Types One and Two. Cannabis Cannabinoid Res. 2017 May 1;2(1):87-95. doi: 10.1089/can.2016.0032. eCollection 2017.
• [15] Localization and function of cannabinoid receptors in the corpus cavernosum: basis for modulation of nitric oxide synthase nerve activity. Eur Urol. 2010 Feb;57(2):342-8. doi: 10.1016/j.eururo.2008.12.024. Epub 2009 Jan 3.
• [16] Tamoxifen Isomers and Metabolites Exhibit Distinct Affinity and Activity at Cannabinoid Receptors: Potential Scaffold for Drug Development. PLoS One. 2016 Dec 9;11(12):e0167240. doi: 10.1371/journal.pone.0167240. eCollection 2016.
• [17] (Endo)cannabinoids mediate different Ca2+ entry mechanisms in human bronchial epithelial cells. Naunyn Schmiedebergs Arch Pharmacol. 2009 Jul;380(1):67-77. doi: 10.1007/s00210-009-0406-z. Epub 2009 Mar 3.
• [18] Functional consequences of nonsynonymous single nucleotide polymorphisms in the CB2 cannabinoid receptor. Pharmacogenet Genomics. 2010 Mar;20(3):157-66. doi: 10.1097/FPC.0b013e3283367c6b.