Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT16AAT8)

• DOT Name: Mu-type opioid receptor (OPRM1)
• Synonyms: M-OR-1; MOR-1; Mu opiate receptor; Mu opioid receptor; MOP; hMOP
• Gene Name: OPRM1
• UniProt ID: OPRM_HUMAN
• PDB ID: 8EF5; 8EF6; 8EFB; 8EFL; 8EFO; 8EFQ; 8F7Q; 8F7R
• Pfam ID: PF00001
• Sequence:
  MDSSAAPTNASNCTDALAYSSCSPAPSPGSWVNLSHLDGNLSDPCGPNRTDLGGRDSLCP
  PTGSPSMITAITIMALYSIVCVVGLFGNFLVMYVIVRYTKMKTATNIYIFNLALADALAT
  STLPFQSVNYLMGTWPFGTILCKIVISIDYYNMFTSIFTLCTMSVDRYIAVCHPVKALDF
  RTPRNAKIINVCNWILSSAIGLPVMFMATTKYRQGSIDCTLTFSHPTWYWENLLKICVFI
  FAFIMPVLIITVCYGLMILRLKSVRMLSGSKEKDRNLRRITRMVLVVVAVFIVCWTPIHI
  YVIIKALVTIPETTFQTVSWHFCIALGYTNSCLNPVLYAFLDENFKRCFREFCIPTSSNI
  EQQNSTRIRQNTRDHPSTANTVDRTNHQLENLEAETAPLP
• Function: Receptor for endogenous opioids such as beta-endorphin and endomorphin. Receptor for natural and synthetic opioids including morphine, heroin, DAMGO, fentanyl, etorphine, buprenorphin and methadone. Also activated by enkephalin peptides, such as Met-enkephalin or Met-enkephalin-Arg-Phe, with higher affinity for Met-enkephalin-Arg-Phe. Agonist binding to the receptor induces coupling to an inactive GDP-bound heterotrimeric G-protein complex and subsequent exchange of GDP for GTP in the G-protein alpha subunit leading to dissociation of the G-protein complex with the free GTP-bound G-protein alpha and the G-protein beta-gamma dimer activating downstream cellular effectors. The agonist- and cell type-specific activity is predominantly coupled to pertussis toxin-sensitive G(i) and G(o) G alpha proteins, GNAI1, GNAI2, GNAI3 and GNAO1 isoforms Alpha-1 and Alpha-2, and to a lesser extent to pertussis toxin-insensitive G alpha proteins GNAZ and GNA15. They mediate an array of downstream cellular responses, including inhibition of adenylate cyclase activity and both N-type and L-type calcium channels, activation of inward rectifying potassium channels, mitogen-activated protein kinase (MAPK), phospholipase C (PLC), phosphoinositide/protein kinase (PKC), phosphoinositide 3-kinase (PI3K) and regulation of NF-kappa-B. Also couples to adenylate cyclase stimulatory G alpha proteins. The selective temporal coupling to G-proteins and subsequent signaling can be regulated by RGSZ proteins, such as RGS9, RGS17 and RGS4. Phosphorylation by members of the GPRK subfamily of Ser/Thr protein kinases and association with beta-arrestins is involved in short-term receptor desensitization. Beta-arrestins associate with the GPRK-phosphorylated receptor and uncouple it from the G-protein thus terminating signal transduction. The phosphorylated receptor is internalized through endocytosis via clathrin-coated pits which involves beta-arrestins. The activation of the ERK pathway occurs either in a G-protein-dependent or a beta-arrestin-dependent manner and is regulated by agonist-specific receptor phosphorylation. Acts as a class A G-protein coupled receptor (GPCR) which dissociates from beta-arrestin at or near the plasma membrane and undergoes rapid recycling. Receptor down-regulation pathways are varying with the agonist and occur dependent or independent of G-protein coupling. Endogenous ligands induce rapid desensitization, endocytosis and recycling. Heterooligomerization with other GPCRs can modulate agonist binding, signaling and trafficking properties; [Isoform 12]: Couples to GNAS and is proposed to be involved in excitatory effects; [Isoform 16]: Does not bind agonists but may act through oligomerization with binding-competent OPRM1 isoforms and reduce their ligand binding activity; [Isoform 17]: Does not bind agonists but may act through oligomerization with binding-competent OPRM1 isoforms and reduce their ligand binding activity.
• Tissue Specificity: Expressed in brain. Isoform 16 and isoform 17 are detected in brain.
• KEGG Pathway:
  Neuroactive ligand-receptor interaction (hsa04080)
  Estrogen sig.ling pathway (hsa04915)
  Morphine addiction (hsa05032)
• Reactome Pathway:
  G-protein activation (R-HSA-202040)
  Peptide ligand-binding receptors (R-HSA-375276)
  G alpha (i) signalling events (R-HSA-418594)
  Interleukin-4 and Interleukin-13 signaling (R-HSA-6785807)
  MECP2 regulates neuronal receptors and channels (R-HSA-9022699)
  Opioid Signalling (R-HSA-111885)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 7 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Ethanol	DMDRQZU	Approved	Mu-type opioid receptor (OPRM1) increases the response to substance of Ethanol.	[15]
Cocaine	DMSOX7I	Approved	Mu-type opioid receptor (OPRM1) increases the response to substance of Cocaine.	[15]
Methamphetamine	DMPM4SK	Approved	Mu-type opioid receptor (OPRM1) increases the response to substance of Methamphetamine.	[16]
Morphine	DMRMS0L	Approved	Mu-type opioid receptor (OPRM1) increases the response of Morphine.	[17]
Naltrexone	DMUL45H	Approved	Mu-type opioid receptor (OPRM1) affects the response to substance of Naltrexone.	[18]
Pilocarpine	DMV9ADG	Approved	Mu-type opioid receptor (OPRM1) increases the Seizures (incl subtypes) ADR of Pilocarpine.	[19]
Formaldehyde	DM7Q6M0	Investigative	Mu-type opioid receptor (OPRM1) increases the Drug dependence ADR of Formaldehyde.	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Mu-type opioid receptor (OPRM1).	[1]
Fentanyl	DM8WAHT	Approved	Fentanyl increases the phosphorylation of Mu-type opioid receptor (OPRM1).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Mu-type opioid receptor (OPRM1).	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Mu-type opioid receptor (OPRM1).	[2]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Mu-type opioid receptor (OPRM1).	[3]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Mu-type opioid receptor (OPRM1).	[4]
Marinol	DM70IK5	Approved	Marinol increases the expression of Mu-type opioid receptor (OPRM1).	[5]
Tianeptine	DMYN8MA	Approved	Tianeptine increases the activity of Mu-type opioid receptor (OPRM1).	[7]
Butorphanol	DM5KYPJ	Approved	Butorphanol increases the activity of Mu-type opioid receptor (OPRM1).	[7]
Bardoxolone methyl	DMODA2X	Phase 3	Bardoxolone methyl decreases the activity of Mu-type opioid receptor (OPRM1).	[9]
phorbol 12-myristate 13-acetate	DMJWD62	Phase 2	phorbol 12-myristate 13-acetate increases the expression of Mu-type opioid receptor (OPRM1).	[10]
JWH-015	DMGTSCP	Patented	JWH-015 increases the expression of Mu-type opioid receptor (OPRM1).	[5]
UNC0379	DMD1E4J	Preclinical	UNC0379 increases the expression of Mu-type opioid receptor (OPRM1).	[12]
Paraquat	DMR8O3X	Investigative	Paraquat decreases the expression of Mu-type opioid receptor (OPRM1).	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Oliceridine	DM6MDCF	Approved	Oliceridine affects the binding of Mu-type opioid receptor (OPRM1).	[6]
Alvimopan	DMHR8KW	Approved	Alvimopan affects the binding of Mu-type opioid receptor (OPRM1).	[8]
CYCLORPHAN	DMB1U8V	Investigative	CYCLORPHAN affects the binding of Mu-type opioid receptor (OPRM1).	[14]

References

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• [3] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
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• [5] Cannabinoid receptor type 2 agonists induce transcription of the mu-opioid receptor gene in Jurkat T cells. Mol Pharmacol. 2006 Apr;69(4):1486-91. doi: 10.1124/mol.105.018325. Epub 2006 Jan 24.
• [6] A G protein-biased ligand at the ?-opioid receptor is potently analgesic with reduced gastrointestinal and respiratory dysfunction compared with morphine. J Pharmacol Exp Ther. 2013 Mar;344(3):708-17.
• [7] In vitro functional characterization of a panel of non-fentanyl opioid new psychoactive substances. Arch Toxicol. 2020 Nov;94(11):3819-3830. doi: 10.1007/s00204-020-02855-7. Epub 2020 Jul 31.
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• [9] Characterization of the potent, selective Nrf2 activator, 3-(pyridin-3-ylsulfonyl)-5-(trifluoromethyl)-2H-chromen-2-one, in cellular and in vivo models of pulmonary oxidative stress. J Pharmacol Exp Ther. 2017 Oct;363(1):114-125.
• [10] Involvement of activator protein-1 in transcriptional regulation of the human mu-opioid receptor gene. Mol Pharmacol. 2002 Apr;61(4):800-5. doi: 10.1124/mol.61.4.800.
• [11] 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.
• [12] Epigenetic siRNA and chemical screens identify SETD8 inhibition as a therapeutic strategy for p53 activation in high-risk neuroblastoma. Cancer Cell. 2017 Jan 9;31(1):50-63.
• [13] Proteasome subunit and opioid receptor gene expression down-regulation induced by paraquat and maneb in human neuroblastoma SH-SY5Y cells. Environ Toxicol Pharmacol. 2015 Nov;40(3):895-900. doi: 10.1016/j.etap.2015.09.019. Epub 2015 Oct 3.
• [14] Aminothiazolomorphinans with mixed and opioid activity. J Med Chem. 2011 Mar 24;54(6):1903-13. doi: 10.1021/jm101542c. Epub 2011 Feb 25.
• [15] Haplotypes at the OPRM1 locus are associated with susceptibility to substance dependence in European-Americans. Am J Med Genet B Neuropsychiatr Genet. 2003 Jul 1;120B(1):97-108. doi: 10.1002/ajmg.b.20034.
• [16] Linkage disequilibrium and association with methamphetamine dependence/psychosis of mu-opioid receptor gene polymorphisms. Pharmacogenomics J. 2006 May-Jun;6(3):179-88. doi: 10.1038/sj.tpj.6500355.
• [17] Association of ABCB1/MDR1 and OPRM1 gene polymorphisms with morphine pain relief. Clin Pharmacol Ther. 2008 Apr;83(4):559-66.
• [18] An evaluation of mu-opioid receptor (OPRM1) as a predictor of naltrexone response in the treatment of alcohol dependence: results from the Combined Pharmacotherapies and Behavioral Interventions for Alcohol Dependence (COMBINE) study. Arch Gen Psychiatry. 2008 Feb;65(2):135-44.
• [19] ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.