Details of Drug Off-Target (DOT)

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

• DOT Name: D(2) dopamine receptor (DRD2)
• Synonyms: Dopamine D2 receptor
• Gene Name: DRD2
• UniProt ID: DRD2_HUMAN
• PDB ID: 5AER; 6CM4; 6LUQ; 6VMS; 7DFP; 7JVR; 8IRS
• Pfam ID: PF00001
• Sequence:
  MDPLNLSWYDDDLERQNWSRPFNGSDGKADRPHYNYYATLLTLLIAVIVFGNVLVCMAVS
  REKALQTTTNYLIVSLAVADLLVATLVMPWVVYLEVVGEWKFSRIHCDIFVTLDVMMCTA
  SILNLCAISIDRYTAVAMPMLYNTRYSSKRRVTVMISIVWVLSFTISCPLLFGLNNADQN
  ECIIANPAFVVYSSIVSFYVPFIVTLLVYIKIYIVLRRRRKRVNTKRSSRAFRAHLRAPL
  KGNCTHPEDMKLCTVIMKSNGSFPVNRRRVEAARRAQELEMEMLSSTSPPERTRYSPIPP
  SHHQLTLPDPSHHGLHSTPDSPAKPEKNGHAKDHPKIAKIFEIQTMPNGKTRTSLKTMSR
  RKLSQQKEKKATQMLAIVLGVFIICWLPFFITHILNIHCDCNIPPVLYSAFTWLGYVNSA
  VNPIIYTTFNIEFRKAFLKILHC
• Function: Dopamine receptor whose activity is mediated by G proteins which inhibit adenylyl cyclase. Positively regulates postnatal regression of retinal hyaloid vessels via suppression of VEGFR2/KDR activity, downstream of OPN5.
• Tissue Specificity: .Expressed in the anterior pituitary gland.; [Isoform 2]: Expressed in the anterior pituitary gland.
• KEGG Pathway:
  Rap1 sig.ling pathway (hsa04015)
  cAMP sig.ling pathway (hsa04024)
  Neuroactive ligand-receptor interaction (hsa04080)
  Gap junction (hsa04540)
  Dopaminergic sy.pse (hsa04728)
  Parkinson disease (hsa05012)
  Cocaine addiction (hsa05030)
  Alcoholism (hsa05034)
• Reactome Pathway: Dopamine receptors (R-HSA-390651)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 19 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Ethanol	DMDRQZU	Approved	D(2) dopamine receptor (DRD2) increases the Pancreatitis chronic ADR of Ethanol.	[15]
Clozapine	DMFC71L	Approved	D(2) dopamine receptor (DRD2) increases the response to substance of Clozapine.	[16]
Methamphetamine	DMPM4SK	Approved	D(2) dopamine receptor (DRD2) increases the response to substance of Methamphetamine.	[17]
Olanzapine	DMPFN6Y	Approved	D(2) dopamine receptor (DRD2) increases the response to substance of Olanzapine.	[16]
Thioridazine	DM35M8J	Approved	D(2) dopamine receptor (DRD2) increases the Tardive dyskinesia ADR of Thioridazine.	[15]
Amphetamine	DMSZQAK	Approved	D(2) dopamine receptor (DRD2) affects the response to substance of Amphetamine.	[18]
Lamotrigine	DM8SXYG	Approved	D(2) dopamine receptor (DRD2) increases the response to substance of Lamotrigine.	[19]
Bupropion	DM5PCS7	Approved	D(2) dopamine receptor (DRD2) increases the response of Bupropion.	[20]
Risperidone	DMN6DXL	Approved	D(2) dopamine receptor (DRD2) increases the response to substance of Risperidone.	[21]
Bromocriptine	DMVE3TK	Approved	D(2) dopamine receptor (DRD2) increases the response to substance of Bromocriptine.	[22]
Trifluoperazine	DMKBYWI	Approved	D(2) dopamine receptor (DRD2) increases the Tardive dyskinesia ADR of Trifluoperazine.	[15]
Naltrexone	DMUL45H	Approved	D(2) dopamine receptor (DRD2) affects the response to substance of Naltrexone.	[23]
Droperidol	DM0DXA8	Approved	D(2) dopamine receptor (DRD2) increases the Tardive dyskinesia ADR of Droperidol.	[15]
Zuclopenthixol	DMKYD5N	Approved	D(2) dopamine receptor (DRD2) increases the Tardive dyskinesia ADR of Zuclopenthixol.	[15]
Bromperidol	DM24XYQ	Approved	D(2) dopamine receptor (DRD2) affects the response to substance of Bromperidol.	[24]
Chlorpromazine	DMBGZI3	Phase 3 Trial	D(2) dopamine receptor (DRD2) decreases the response to substance of Chlorpromazine.	[25]
PMID28870136-Compound-52	DMFDERP	Patented	D(2) dopamine receptor (DRD2) affects the response to substance of PMID28870136-Compound-52.	[26]
Flupenthixol	DMY9P37	Withdrawn from market	D(2) dopamine receptor (DRD2) increases the Tardive dyskinesia ADR of Flupenthixol.	[15]
QUINPIROLE	DMDNHEP	Investigative	D(2) dopamine receptor (DRD2) increases the response to substance of QUINPIROLE.	[27]

8 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 D(2) dopamine receptor (DRD2).	[1]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of D(2) dopamine receptor (DRD2).	[2]
Cocaine	DMSOX7I	Approved	Cocaine decreases the expression of D(2) dopamine receptor (DRD2).	[3]
Heroin diacetylmorphine	DMDBWHY	Approved	Heroin diacetylmorphine decreases the expression of D(2) dopamine receptor (DRD2).	[4]
Pergolide mesylate	DM5GKOV	Approved	Pergolide mesylate increases the activity of D(2) dopamine receptor (DRD2).	[6]
Bardoxolone methyl	DMODA2X	Phase 3	Bardoxolone methyl decreases the activity of D(2) dopamine receptor (DRD2).	[8]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of D(2) dopamine receptor (DRD2).	[11]
Manganese	DMKT129	Investigative	Manganese affects the expression of D(2) dopamine receptor (DRD2).	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Sulpiride	DMF54ZG	Approved	Sulpiride affects the binding of D(2) dopamine receptor (DRD2).	[5]
Meglitinides	DM1OFHN	Approved	Meglitinides affects the binding of D(2) dopamine receptor (DRD2).	[7]
Sarizotan	DMH7IPW	Phase 2/3	Sarizotan affects the binding of D(2) dopamine receptor (DRD2).	[9]
Fluphenazine	DMIT8LX	Investigative	Fluphenazine affects the binding of D(2) dopamine receptor (DRD2).	[13]
[3H]spiperone	DMWHEV8	Investigative	[3H]spiperone affects the binding of D(2) dopamine receptor (DRD2).	[14]

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 affects the methylation of D(2) dopamine receptor (DRD2).	[10]

References

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• [2] 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.
• [3] Gene expression in human hippocampus from cocaine abusers identifies genes which regulate extracellular matrix remodeling. PLoS One. 2007 Nov 14;2(11):e1187. doi: 10.1371/journal.pone.0001187.
• [4] Dopamine D1 receptor protein is elevated in nucleus accumbens of human, chronic methamphetamine users. Mol Psychiatry. 2000 Nov;5(6):664-72. doi: 10.1038/sj.mp.4000760.
• [5] Positron emission tomography measurement of dopamine D? receptor occupancy in the pituitary and cerebral cortex: relation to antipsychotic-induced hyperprolactinemia. J Clin Psychiatry. 2010 Sep;71(9):1131-7. doi: 10.4088/JCP.08m04307yel. Epub 2010 Feb 23.
• [6] Pergolide is an inhibitor of voltage-gated potassium channels, including Kv1.5, and causes pulmonary vasoconstriction. Circulation. 2005 Sep 6;112(10):1494-9. doi: 10.1161/CIRCULATIONAHA.105.556704. Epub 2005 Aug 29.
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• [8] 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.
• [9] Sarizotan, a serotonin 5-HT1A receptor agonist and dopamine receptor ligand. 1. Neurochemical profile. J Neural Transm (Vienna). 2004 Feb;111(2):113-26. doi: 10.1007/s00702-003-0094-7. Epub 2003 Dec 31.
• [10] 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.
• [11] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.
• [12] Principal Component Analysis of Striatal and Extrastriatal D2 Dopamine Receptor Positron Emission Tomography in Manganese-Exposed Workers. Toxicol Sci. 2021 Jul 16;182(1):132-141. doi: 10.1093/toxsci/kfab045.
• [13] Discovery of antiandrogen activity of nonsteroidal scaffolds of marketed drugs. Proc Natl Acad Sci U S A. 2007 Jul 17;104(29):11927-32. doi: 10.1073/pnas.0609752104. Epub 2007 Jul 2.
• [14] Melittin stimulates fatty acid release through non-phospholipase-mediated mechanisms and interacts with the dopamine transporter and other membrane-spanning proteins. Eur J Pharmacol. 2011 Jan 15;650(2-3):501-10. doi: 10.1016/j.ejphar.2010.10.023. Epub 2010 Oct 20.
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• [16] Dopamine receptor D2 gene is associated with weight gain in schizophrenic patients under long-term atypical antipsychotic treatment. Pharmacogenet Genomics. 2010 Jun;20(6):359-66. doi: 10.1097/FPC.0b013e3283397d06.
• [17] A preliminary study: novelty seeking, frontal executive function, and dopamine receptor (D2) TaqI A gene polymorphism in patients with methamphetamine dependence. Compr Psychiatry. 2008 Jul-Aug;49(4):387-92. doi: 10.1016/j.comppsych.2008.01.008. Epub 2008 Mar 21.
• [18] Evaluation of genetic variability in the dopamine receptor D2 in relation to behavioral inhibition and impulsivity/sensation seeking: an exploratory study with d-amphetamine in healthy participants. Exp Clin Psychopharmacol. 2009 Dec;17(6):374-83. doi: 10.1037/a0017840.
• [19] Genetic association study of treatment response with olanzapine/fluoxetine combination or lamotrigine in bipolar I depression. J Clin Psychiatry. 2010 May;71(5):599-605. doi: 10.4088/JCP.08m04632gre. Epub 2009 Dec 15.
• [20] Bupropion efficacy for smoking cessation is influenced by the DRD2 Taq1A polymorphism: analysis of pooled data from two clinical trials. Nicotine Tob Res. 2007 Dec;9(12):1251-7. doi: 10.1080/14622200701705027.
• [21] Variants of the dopamine D2 receptor gene and risperidone-induced hyperprolactinemia in children and adolescents. Pharmacogenet Genomics. 2009 May;19(5):373-82. doi: 10.1097/FPC.0b013e328329a60f.
• [22] Imaging gene-substance interactions: the effect of the DRD2 TaqIA polymorphism and the dopamine agonist bromocriptine on the brain activation during the anticipation of reward. Neurosci Lett. 2006 Sep 25;405(3):196-201. doi: 10.1016/j.neulet.2006.07.030. Epub 2006 Aug 8.
• [23] Predicting the effect of naltrexone and acamprosate in alcohol-dependent patients using genetic indicators. Addict Biol. 2009 Jul;14(3):328-37.
• [24] The -141C Ins/Del polymorphism in the dopamine D2 receptor gene promoter region is associated with anxiolytic and antidepressive effects during treatment with dopamine antagonists in schizophrenic patients. Pharmacogenetics. 2001 Aug;11(6):545-50. doi: 10.1097/00008571-200108000-00009.
• [25] Response to chlorpromazine treatment may be associated with polymorphisms of the DRD2 gene in Chinese schizophrenic patients. Neurosci Lett. 2005 Mar 7;376(1):1-4. doi: 10.1016/j.neulet.2004.11.014. Epub 2004 Dec 2.
• [26] Association between ADORA2A and DRD2 polymorphisms and caffeine-induced anxiety. Neuropsychopharmacology. 2008 Nov;33(12):2791-800. doi: 10.1038/npp.2008.17. Epub 2008 Feb 27.
• [27] Activation of D2 Dopamine Receptors in CD133+ve Cancer Stem Cells in Non-small Cell Lung Carcinoma Inhibits Proliferation, Clonogenic Ability, and Invasiveness of These Cells. J Biol Chem. 2017 Jan 13;292(2):435-445. doi: 10.1074/jbc.M116.748970. Epub 2016 Dec 5.