Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTLZPBT7)

• DOT Name: D(1A) dopamine receptor (DRD1)
• Synonyms: Dopamine D1 receptor
• Gene Name: DRD1
• UniProt ID: DRD1_HUMAN
• PDB ID: 7CKW; 7CKX; 7CKY; 7CKZ; 7CRH; 7F0T; 7F1O; 7F1Z; 7F23; 7F24; 7JOZ; 7JV5; 7JVP; 7JVQ; 7LJC; 7LJD; 7X2C; 7X2D; 7X2F; 8IRR
• Pfam ID: PF00001
• Sequence:
  MRTLNTSAMDGTGLVVERDFSVRILTACFLSLLILSTLLGNTLVCAAVIRFRHLRSKVTN
  FFVISLAVSDLLVAVLVMPWKAVAEIAGFWPFGSFCNIWVAFDIMCSTASILNLCVISVD
  RYWAISSPFRYERKMTPKAAFILISVAWTLSVLISFIPVQLSWHKAKPTSPSDGNATSLA
  ETIDNCDSSLSRTYAISSSVISFYIPVAIMIVTYTRIYRIAQKQIRRIAALERAAVHAKN
  CQTTTGNGKPVECSQPESSFKMSFKRETKVLKTLSVIMGVFVCCWLPFFILNCILPFCGS
  GETQPFCIDSNTFDVFVWFGWANSSLNPIIYAFNADFRKAFSTLLGCYRLCPATNNAIET
  VSINNNGAAMFSSHHEPRGSISKECNLVYLIPHAVGSSEDLKKEEAAGIARPLEKLSPAL
  SVILDYDTDVSLEKIQPITQNGQHPT
• Function: Dopamine receptor whose activity is mediated by G proteins which activate adenylyl cyclase.
• Tissue Specificity: Detected in caudate, nucleus accumbens and in the olfactory tubercle.
• KEGG Pathway:
  Calcium sig.ling pathway (hsa04020)
  cAMP sig.ling pathway (hsa04024)
  Neuroactive ligand-receptor interaction (hsa04080)
  Gap junction (hsa04540)
  Dopaminergic sy.pse (hsa04728)
  Parkinson disease (hsa05012)
  Cocaine addiction (hsa05030)
  Amphetamine addiction (hsa05031)
  Morphine addiction (hsa05032)
  Alcoholism (hsa05034)
• Reactome Pathway:
  G alpha (s) signalling events (R-HSA-418555)
  Dopamine receptors (R-HSA-390651)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 3 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Clozapine	DMFC71L	Approved	D(1A) dopamine receptor (DRD1) affects the response to substance of Clozapine.	[14]
Gabapentin	DM6T924	Approved	D(1A) dopamine receptor (DRD1) increases the Akathisia ADR of Gabapentin.	[15]
Lithium	DMZ3OU6	Phase 2	D(1A) dopamine receptor (DRD1) increases the response to substance of Lithium.	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of D(1A) dopamine receptor (DRD1).	[1]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of D(1A) dopamine receptor (DRD1).	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Methamphetamine	DMPM4SK	Approved	Methamphetamine increases the expression of D(1A) dopamine receptor (DRD1).	[2]
Acocantherin	DM7JT24	Approved	Acocantherin decreases the expression of D(1A) dopamine receptor (DRD1).	[3]
Haloperidol	DM96SE0	Approved	Haloperidol affects the activity of D(1A) dopamine receptor (DRD1).	[4]
Dopamine	DMPGUCF	Approved	Dopamine increases the activity of D(1A) dopamine receptor (DRD1).	[5]
Pergolide mesylate	DM5GKOV	Approved	Pergolide mesylate increases the activity of D(1A) dopamine receptor (DRD1).	[7]
Chlorpromazine	DMBGZI3	Phase 3 Trial	Chlorpromazine decreases the activity of D(1A) dopamine receptor (DRD1).	[4]
Bardoxolone methyl	DMODA2X	Phase 3	Bardoxolone methyl decreases the activity of D(1A) dopamine receptor (DRD1).	[8]
Afimoxifene	DMFORDT	Phase 2	Afimoxifene increases the expression of D(1A) dopamine receptor (DRD1).	[9]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of D(1A) dopamine receptor (DRD1).	[11]
SL65.0472	DMU5RKC	Discontinued in Phase 2	SL65.0472 affects the activity of D(1A) dopamine receptor (DRD1).	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Flupentixol	DM0DJ9O	Approved	Flupentixol affects the binding of D(1A) dopamine receptor (DRD1).	[6]
LE-300	DMGJL16	Preclinical	LE-300 affects the binding of D(1A) dopamine receptor (DRD1).	[12]
A 77636	DM0NY6K	Terminated	A 77636 affects the localization of D(1A) dopamine receptor (DRD1).	[13]
SKF-81297	DM4LGPT	Terminated	SKF-81297 affects the localization of D(1A) dopamine receptor (DRD1).	[13]
A-68930	DMUJ94B	Terminated	A-68930 affects the localization of D(1A) dopamine receptor (DRD1).	[13]

References

• [1] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [2] 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.
• [3] Dopamine-mediated inhibition of renal Na+/K+-ATPase in HK-2 cells is reduced by ouabain. Clin Exp Pharmacol Physiol. 2010 May;37(5-6):613-8. doi: 10.1111/j.1440-1681.2010.05364.x. Epub 2010 Feb 4.
• [4] Profiling 976 ToxCast chemicals across 331 enzymatic and receptor signaling assays. Chem Res Toxicol. 2013 Jun 17;26(6):878-95.
• [5] Characterizing fucoxanthin as a selective dopamine D(3)/D(4) receptor agonist: Relevance to Parkinson's disease. Chem Biol Interact. 2019 Sep 1;310:108757. doi: 10.1016/j.cbi.2019.108757. Epub 2019 Jul 16.
• [6] Positron emission tomographic analysis of central D1 and D2 dopamine receptor occupancy in patients treated with classical neuroleptics and clozapine. Relation to extrapyramidal side effects. Arch Gen Psychiatry. 1992 Jul;49(7):538-44. doi: 10.1001/archpsyc.1992.01820070032005.
• [7] 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.
• [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] Regulation of aryl hydrocarbon receptor function by selective estrogen receptor modulators. Mol Endocrinol. 2010 Jan;24(1):33-46.
• [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] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [12] Chiral indolo[3,2-f][3]benzazecine-type dopamine receptor antagonists: synthesis and activity of racemic and enantiopure derivatives. J Med Chem. 2011 Oct 27;54(20):7422-6. doi: 10.1021/jm200676f. Epub 2011 Sep 29.
• [13] Differential activation of adenylate cyclase and receptor internalization by novel dopamine D1 receptor agonists. Mol Pharmacol. 2005 Oct;68(4):1039-48. doi: 10.1124/mol.105.012153. Epub 2005 Jun 28.
• [14] Association study of four dopamine D1 receptor gene polymorphisms and clozapine treatment response. J Psychopharmacol. 2007 Sep;21(7):718-27. doi: 10.1177/0269881106072341. Epub 2006 Nov 8.
• [15] 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.
• [16] Dopamine D1 receptor gene polymorphism is associated with prophylactic lithium response in bipolar disorder. Pharmacopsychiatry. 2009 Jan;42(1):20-2. doi: 10.1055/s-0028-1085441. Epub 2009 Jan 19.