Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTAJTO7N)

• DOT Name: D(4) dopamine receptor (DRD4)
• Synonyms: D(2C) dopamine receptor; Dopamine D4 receptor
• Gene Name: DRD4
• UniProt ID: DRD4_HUMAN
• PDB ID: 5WIU; 5WIV
• Pfam ID: PF00001
• Sequence:
  MGNRSTADADGLLAGRGPAAGASAGASAGLAGQGAAALVGGVLLIGAVLAGNSLVCVSVA
  TERALQTPTNSFIVSLAAADLLLALLVLPLFVYSEVQGGAWLLSPRLCDALMAMDVMLCT
  ASIFNLCAISVDRFVAVAVPLRYNRQGGSRRQLLLIGATWLLSAAVAAPVLCGLNDVRGR
  DPAVCRLEDRDYVVYSSVCSFFLPCPLMLLLYWATFRGLQRWEVARRAKLHGRAPRRPSG
  PGPPSPTPPAPRLPQDPCGPDCAPPAPGLPRGPCGPDCAPAAPSLPQDPCGPDCAPPAPG
  LPPDPCGSNCAPPDAVRAAALPPQTPPQTRRRRRAKITGRERKAMRVLPVVVGAFLLCWT
  PFFVVHITQALCPACSVPPRLVSAVTWLGYVNSALNPVIYTVFNAEFRNVFRKALRACC
• Function: Dopamine receptor responsible for neuronal signaling in the mesolimbic system of the brain, an area of the brain that regulates emotion and complex behavior. Activated by dopamine, but also by epinephrine and norepinephrine, and by numerous synthetic agonists and drugs. Agonist binding triggers signaling via G proteins that inhibit adenylyl cyclase. Modulates the circadian rhythm of contrast sensitivity by regulating the rhythmic expression of NPAS2 in the retinal ganglion cells.
• Tissue Specificity: Highly expressed in retina. Detected at much lower levels in brain, in amygdala, thalamus, hypothalamus, cerebellum and pituitary.
• 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 12 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Clozapine	DMFC71L	Approved	D(4) dopamine receptor (DRD4) affects the response to substance of Clozapine.	[10]
Cocaine	DMSOX7I	Approved	D(4) dopamine receptor (DRD4) increases the response to substance of Cocaine.	[11]
Methamphetamine	DMPM4SK	Approved	D(4) dopamine receptor (DRD4) increases the response to substance of Methamphetamine.	[12]
Olanzapine	DMPFN6Y	Approved	D(4) dopamine receptor (DRD4) increases the Tardive dyskinesia ADR of Olanzapine.	[13]
Thioridazine	DM35M8J	Approved	D(4) dopamine receptor (DRD4) increases the Tardive dyskinesia ADR of Thioridazine.	[13]
Risperidone	DMN6DXL	Approved	D(4) dopamine receptor (DRD4) increases the Tardive dyskinesia ADR of Risperidone.	[13]
Trifluoperazine	DMKBYWI	Approved	D(4) dopamine receptor (DRD4) increases the Tardive dyskinesia ADR of Trifluoperazine.	[13]
Droperidol	DM0DXA8	Approved	D(4) dopamine receptor (DRD4) increases the Tardive dyskinesia ADR of Droperidol.	[13]
Zuclopenthixol	DMKYD5N	Approved	D(4) dopamine receptor (DRD4) increases the Tardive dyskinesia ADR of Zuclopenthixol.	[13]
Chlorpromazine	DMBGZI3	Phase 3 Trial	D(4) dopamine receptor (DRD4) increases the Tardive dyskinesia ADR of Chlorpromazine.	[13]
Flupenthixol	DMY9P37	Withdrawn from market	D(4) dopamine receptor (DRD4) increases the Tardive dyskinesia ADR of Flupenthixol.	[13]
Fluphenazine	DMIT8LX	Investigative	D(4) dopamine receptor (DRD4) increases the Tardive dyskinesia ADR of Fluphenazine.	[13]

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(4) dopamine receptor (DRD4).	[1]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of D(4) dopamine receptor (DRD4).	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of D(4) dopamine receptor (DRD4).	[2]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of D(4) dopamine receptor (DRD4).	[3]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of D(4) dopamine receptor (DRD4).	[4]
Haloperidol	DM96SE0	Approved	Haloperidol affects the activity of D(4) dopamine receptor (DRD4).	[5]
Fucoxanthin	DMPQFTA	Phase 2	Fucoxanthin increases the activity of D(4) dopamine receptor (DRD4).	[6]
SL65.0472	DMU5RKC	Discontinued in Phase 2	SL65.0472 affects the activity of D(4) dopamine receptor (DRD4).	[5]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of D(4) dopamine receptor (DRD4).	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
[3H]spiperone	DMWHEV8	Investigative	[3H]spiperone affects the binding of D(4) dopamine receptor (DRD4).	[9]

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] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [3] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [4] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [5] Profiling 976 ToxCast chemicals across 331 enzymatic and receptor signaling assays. Chem Res Toxicol. 2013 Jun 17;26(6):878-95.
• [6] 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.
• [7] 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.
• [8] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [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] Dopamine D4 receptor gene exon III polymorphism and interindividual variation in response to clozapine. Int J Neurosci. 2005 Nov;115(11):1539-47. doi: 10.1080/00207450590957863.
• [11] Polymorphisms TaqI A of the DRD2, BalI of the DRD3, exon III repeat of the DRD4, and 3' UTR VNTR of the DAT: association with childhood ADHD in male African-Caribbean cocaine dependents?. Am J Med Genet B Neuropsychiatr Genet. 2007 Dec 5;144B(8):1034-41. doi: 10.1002/ajmg.b.30540.
• [12] Association analysis of the DRD4 and COMT genes in methamphetamine abuse. Am J Med Genet B Neuropsychiatr Genet. 2004 Aug 15;129B(1):120-4. doi: 10.1002/ajmg.b.30024.
• [13] 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.