Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTXCZF4L)

• DOT Name: Kappa-type opioid receptor (OPRK1)
• Synonyms: K-OR-1; KOR-1
• Gene Name: OPRK1
• UniProt ID: OPRK_HUMAN
• PDB ID: 4DJH; 6B73; 6VI4; 7T10; 7T11; 7UL2; 7UL3; 7UL5; 7Y1F; 7YIT; 7YMJ; 8DZP; 8DZQ; 8DZR; 8DZS; 8F7W; 8FEG; 8HNN; 8K2W
• Pfam ID: PF00001
• Sequence:
  MDSPIQIFRGEPGPTCAPSACLPPNSSAWFPGWAEPDSNGSAGSEDAQLEPAHISPAIPV
  IITAVYSVVFVVGLVGNSLVMFVIIRYTKMKTATNIYIFNLALADALVTTTMPFQSTVYL
  MNSWPFGDVLCKIVISIDYYNMFTSIFTLTMMSVDRYIAVCHPVKALDFRTPLKAKIINI
  CIWLLSSSVGISAIVLGGTKVREDVDVIECSLQFPDDDYSWWDLFMKICVFIFAFVIPVL
  IIIVCYTLMILRLKSVRLLSGSREKDRNLRRITRLVLVVVAVFVVCWTPIHIFILVEALG
  STSHSTAALSSYYFCIALGYTNSSLNPILYAFLDENFKRCFRDFCFPLKMRMERQSTSRV
  RNTVQDPAYLRDIDGMNKPV
• Function: G-protein coupled opioid receptor that functions as a receptor for endogenous alpha-neoendorphins and dynorphins, but has low affinity for beta-endorphins. Also functions as a receptor for various synthetic opioids and for the psychoactive diterpene salvinorin A. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors, such as adenylate cyclase. Signaling leads to the inhibition of adenylate cyclase activity. Inhibits neurotransmitter release by reducing calcium ion currents and increasing potassium ion conductance. Plays a role in the perception of pain. Plays a role in mediating reduced physical activity upon treatment with synthetic opioids. Plays a role in the regulation of salivation in response to synthetic opioids. May play a role in arousal and regulation of autonomic and neuroendocrine functions.
• Tissue Specificity: Detected in brain and placenta.
• KEGG Pathway: Neuroactive ligand-receptor interaction (hsa04080)
• Reactome Pathway:
  G alpha (i) signalling events (R-HSA-418594)
  MECP2 regulates neuronal receptors and channels (R-HSA-9022699)
  Peptide ligand-binding receptors (R-HSA-375276)

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
Clonidine	DM6RZ9Q	Approved	Kappa-type opioid receptor (OPRK1) increases the Adverse drug reaction ADR of Clonidine.	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Kappa-type opioid receptor (OPRK1).	[1]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Kappa-type opioid receptor (OPRK1).	[2]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Kappa-type opioid receptor (OPRK1).	[3]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Kappa-type opioid receptor (OPRK1).	[4]
Panobinostat	DM58WKG	Approved	Panobinostat decreases the expression of Kappa-type opioid receptor (OPRK1).	[3]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Kappa-type opioid receptor (OPRK1).	[5]
Ethanol	DMDRQZU	Approved	Ethanol decreases the expression of Kappa-type opioid receptor (OPRK1).	[6]
Nicotine	DMWX5CO	Approved	Nicotine decreases the expression of Kappa-type opioid receptor (OPRK1).	[7]
Morphine	DMRMS0L	Approved	Morphine increases the activity of Kappa-type opioid receptor (OPRK1).	[8]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Kappa-type opioid receptor (OPRK1).	[9]
Bardoxolone methyl	DMODA2X	Phase 3	Bardoxolone methyl decreases the activity of Kappa-type opioid receptor (OPRK1).	[10]
Celastrol	DMWQIJX	Preclinical	Celastrol decreases the expression of Kappa-type opioid receptor (OPRK1).	[12]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Kappa-type opioid receptor (OPRK1).	[3]
Cycloheximide	DMGDA3C	Investigative	Cycloheximide increases the expression of Kappa-type opioid receptor (OPRK1).	[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 Kappa-type opioid receptor (OPRK1).	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
CYCLORPHAN	DMB1U8V	Investigative	CYCLORPHAN affects the binding of Kappa-type opioid receptor (OPRK1).	[14]
[3H]U69593	DM6RSZ9	Investigative	[3H]U69593 affects the binding of Kappa-type opioid receptor (OPRK1).	[15]

References

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• [2] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [3] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [4] The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
• [5] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [6] The role of acetaldehyde in mediating effects of alcohol on expression of endogenous opioid system genes in a neuroblastoma cell line. FASEB J. 2008 Mar;22(3):662-70. doi: 10.1096/fj.07-8346com. Epub 2007 Oct 12.
• [7] Effects of tobacco compounds on gene expression in fetal lung fibroblasts. Environ Toxicol. 2008 Aug;23(4):423-34.
• [8] In vivo and in vitro evaluation of novel -opioid receptor agonist compounds. Eur J Pharmacol. 2015 Nov 15;767:193-200. doi: 10.1016/j.ejphar.2015.10.025. Epub 2015 Oct 20.
• [9] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [10] 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.
• [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] Gene expression signature-based chemical genomic prediction identifies a novel class of HSP90 pathway modulators. Cancer Cell. 2006 Oct;10(4):321-30.
• [13] Comparative analysis of AhR-mediated TCDD-elicited gene expression in human liver adult stem cells. Toxicol Sci. 2009 Nov;112(1):229-44.
• [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] Structural determinants of opioid and NOP receptor activity in derivatives of buprenorphine. J Med Chem. 2011 Oct 13;54(19):6531-7. doi: 10.1021/jm2003238. Epub 2011 Sep 7.
• [16] 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.