Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT0OFFKB)

• DOT Name: D(3) dopamine receptor (DRD3)
• Synonyms: Dopamine D3 receptor
• Gene Name: DRD3
• UniProt ID: DRD3_HUMAN
• PDB ID: 3PBL; 7CMU; 7CMV; 8IRT
• Pfam ID: PF00001
• Sequence:
  MASLSQLSGHLNYTCGAENSTGASQARPHAYYALSYCALILAIVFGNGLVCMAVLKERAL
  QTTTNYLVVSLAVADLLVATLVMPWVVYLEVTGGVWNFSRICCDVFVTLDVMMCTASILN
  LCAISIDRYTAVVMPVHYQHGTGQSSCRRVALMITAVWVLAFAVSCPLLFGFNTTGDPTV
  CSISNPDFVIYSSVVSFYLPFGVTVLVYARIYVVLKQRRRKRILTRQNSQCNSVRPGFPQ
  QTLSPDPAHLELKRYYSICQDTALGGPGFQERGGELKREEKTRNSLSPTIAPKLSLEVRK
  LSNGRLSTSLKLGPLQPRGVPLREKKATQMVAIVLGAFIVCWLPFFLTHVLNTHCQTCHV
  SPELYSATTWLGYVNSALNPVIYTTFNIEFRKAFLKILSC
• Function: Dopamine receptor whose activity is mediated by G proteins which inhibit adenylyl cyclase. Promotes cell proliferation.
• Tissue Specificity: Brain.
• KEGG Pathway:
  Neuroactive ligand-receptor interaction (hsa04080)
  Dopaminergic sy.pse (hsa04728)
• Reactome Pathway:
  G alpha (i) signalling events (R-HSA-418594)
  Dopamine receptors (R-HSA-390651)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 11 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Clozapine	DMFC71L	Approved	D(3) dopamine receptor (DRD3) decreases the response to substance of Clozapine.	[10]
Haloperidol	DM96SE0	Approved	D(3) dopamine receptor (DRD3) affects the binding of Haloperidol.	[11]
Olanzapine	DMPFN6Y	Approved	D(3) dopamine receptor (DRD3) increases the Tardive dyskinesia ADR of Olanzapine.	[12]
Thioridazine	DM35M8J	Approved	D(3) dopamine receptor (DRD3) increases the Tardive dyskinesia ADR of Thioridazine.	[12]
Risperidone	DMN6DXL	Approved	D(3) dopamine receptor (DRD3) increases the response to substance of Risperidone.	[13]
Trifluoperazine	DMKBYWI	Approved	D(3) dopamine receptor (DRD3) increases the Tardive dyskinesia ADR of Trifluoperazine.	[12]
Droperidol	DM0DXA8	Approved	D(3) dopamine receptor (DRD3) increases the Tardive dyskinesia ADR of Droperidol.	[12]
Zuclopenthixol	DMKYD5N	Approved	D(3) dopamine receptor (DRD3) increases the Tardive dyskinesia ADR of Zuclopenthixol.	[12]
Chlorpromazine	DMBGZI3	Phase 3 Trial	D(3) dopamine receptor (DRD3) increases the Tardive dyskinesia ADR of Chlorpromazine.	[12]
Flupenthixol	DMY9P37	Withdrawn from market	D(3) dopamine receptor (DRD3) increases the Tardive dyskinesia ADR of Flupenthixol.	[12]
Fluphenazine	DMIT8LX	Investigative	D(3) dopamine receptor (DRD3) increases the Tardive dyskinesia ADR of Fluphenazine.	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of D(3) dopamine receptor (DRD3).	[1]
Cocaine	DMSOX7I	Approved	Cocaine decreases the expression of D(3) dopamine receptor (DRD3).	[2]
Methamphetamine	DMPM4SK	Approved	Methamphetamine decreases the expression of D(3) dopamine receptor (DRD3).	[3]
Fucoxanthin	DMPQFTA	Phase 2	Fucoxanthin increases the activity of D(3) dopamine receptor (DRD3).	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Sarizotan	DMH7IPW	Phase 2/3	Sarizotan affects the binding of D(3) dopamine receptor (DRD3).	[4]
BP-897	DMAQ6DS	Discontinued in Phase 2	BP-897 affects the binding of D(3) dopamine receptor (DRD3).	[6]
LE-300	DMGJL16	Preclinical	LE-300 affects the binding of D(3) dopamine receptor (DRD3).	[7]
1,2,3,4-tetrahydroisoquinoline	DMZGCEQ	Investigative	1,2,3,4-tetrahydroisoquinoline affects the binding of D(3) dopamine receptor (DRD3).	[8]
[3H]spiperone	DMWHEV8	Investigative	[3H]spiperone affects the binding of D(3) dopamine receptor (DRD3).	[9]
ETICLOPRIDE	DM4FW3H	Investigative	ETICLOPRIDE affects the binding of D(3) dopamine receptor (DRD3).	[5]

References

• [1] 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.
• [2] Lower level of endogenous dopamine in patients with cocaine dependence: findings from PET imaging of D(2)/D(3) receptors following acute dopamine depletion. Am J Psychiatry. 2009 Oct;166(10):1170-7. doi: 10.1176/appi.ajp.2009.08121801. Epub 2009 Sep 1.
• [3] Striatal dopamine d2/d3 receptor availability is reduced in methamphetamine dependence and is linked to impulsivity. J Neurosci. 2009 Nov 25;29(47):14734-40. doi: 10.1523/JNEUROSCI.3765-09.2009.
• [4] 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.
• [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] N-(omega-(4-(2-methoxyphenyl)piperazin-1-yl)alkyl)carboxamides as dopamine D2 and D3 receptor ligands. J Med Chem. 2003 Aug 28;46(18):3883-99. doi: 10.1021/jm030836n.
• [7] Dopamine/serotonin receptor ligands. Part VIII: the dopamine receptor antagonist LE300 - modelled and X-ray structure plus further pharmacological characterization, including serotonin receptor binding, biogenic amine transporter testing and in vivo testings. Eur J Med Chem. 2004 Jun;39(6):481-9. doi: 10.1016/j.ejmech.2004.02.001.
• [8] Development of novel 1,2,3,4-tetrahydroisoquinoline derivatives and closely related compounds as potent and selective dopamine D3 receptor ligands. Chembiochem. 2004 Apr 2;5(4):508-18. doi: 10.1002/cbic.200300784.
• [9] Development of a bivalent dopamine D? receptor agonist. J Med Chem. 2011 Nov 24;54(22):7911-9. doi: 10.1021/jm2009919. Epub 2011 Oct 31.
• [10] Effect of dopamine D3 receptor gene polymorphisms and clozapine treatment response: exploratory analysis of nine polymorphisms and meta-analysis of the Ser9Gly variant. Pharmacogenomics J. 2010 Jun;10(3):200-18. doi: 10.1038/tpj.2009.65. Epub 2009 Dec 22.
• [11] The acute EPS of haloperidol may be unrelated to its metabolic transformation to BCPP+. Bioorg Med Chem Lett. 2003 Nov 3;13(21):3779-82. doi: 10.1016/j.bmcl.2003.07.015.
• [12] 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.
• [13] A common variant in DRD3 gene is associated with risperidone-induced extrapyramidal symptoms. Pharmacogenomics J. 2009 Dec;9(6):404-10. doi: 10.1038/tpj.2009.26. Epub 2009 Jun 9.