D4 receptor

Target id: 217

Nomenclature: D4 receptor

Family: Dopamine receptors

Annotation status:  image of a green circle Annotated and expert reviewed. Please contact us if you can help with updates.  » Email us

Gene and Protein Information
class A G protein-coupled receptor
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 7 467 11p15.5 DRD4 dopamine receptor D4 73
Mouse 7 387 7 F5 Drd4 dopamine receptor D4 40
Rat 7 387 1q41 Drd4 dopamine receptor D4 16
Previous and Unofficial Names
d(2C) dopamine receptor
dopamine receptor 4
D4R
Database Links
Specialist databases
GPCRDB P21917 (Hs), P51436 (Mm), P30729 (Rn)
Other databases
ChEMBL Target
DrugBank Target
Ensembl Gene
Entrez Gene
GeneCards
GenitoUrinary Development Molecular Anatomy Project
HomoloGene
Human Protein Reference Database
InterPro
KEGG Gene
NeXtProt
OMIM
PharmGKB Gene
PhosphoSitePlus
Protein Ontology (PRO)
RefSeq Nucleotide
RefSeq Protein
TreeFam
UniGene Hs.
UniProtKB
Wikipedia
Natural/Endogenous Ligands
dopamine

Download all structure-activity data for this target as a CSV file

Agonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
CP-226269 Rn Partial agonist 9.4 pKi 25
pKi 9.4 [25]
FAUC213 Rn Partial agonist 9.0 pKi 25
pKi 9.0 [25]
PD168,077 Rn Partial agonist 8.8 pKi 25
pKi 8.8 (Ki 1.58x10-9 M) [25]
apomorphine Hs Partial agonist 8.4 pKi 35
pKi 8.4 [35]
lisuride Hs Partial agonist 8.3 pKi 35
pKi 8.3 [35]
roxindole Hs Partial agonist 8.2 pKi 35
pKi 8.2 [35]
A412997 Rn Agonist 8.1 pKi 36
pKi 8.1 (Ki 7.9x10-9 M) [36]
A412997 Hs Full agonist 8.1 pKi 36
pKi 8.1 (Ki 7.9x10-9 M) [36]
WAY-100635 Hs Full agonist 7.8 pKi
pKi 7.8 (Ki 1.6x10-8 M)
dopamine Hs Full agonist 7.6 pKi 73
pKi 7.6 [73]
quinpirole Hs Full agonist 7.5 pKi 35,43,73
pKi 7.5 [35,43,73]
dopamine Rn Full agonist 7.4 pKi 52
pKi 7.4 [52]
cabergoline Hs Partial agonist 7.3 pKi 35
pKi 7.3 [35]
rotigotine Hs Agonist 7.3 pKi 75
pKi 7.3 (Ki 5.5x10-8 M) [75]
pergolide Hs Partial agonist 7.2 pKi 35
pKi 7.2 [35]
fenoldopam Hs Full agonist 6.5 pKi 73
pKi 6.5 [73]
ABT-670 Hs Full agonist 5.8 pKi 41
pKi 5.8 (Ki 1.445x10-6 M) [41]
PF-592379 Hs Agonist 5.4 pIC50 11
pIC50 5.4 (IC50 4.165x10-6 M) [11]
View species-specific agonist tables
Antagonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
nemonapride Hs Antagonist 10.0 pKd 58
pKd 10.0 [58]
[125I]L750667 Hs Antagonist 9.8 pKd 43
pKd 9.8 (Kd 1.6x10-10 M) [43]
[3H]spiperone Hs Antagonist 9.5 pKd 23,73
pKd 9.5 (Kd 3x10-10 M) [23,73]
[3H]NGD941 Hs Antagonist 8.3 pKd 46
pKd 8.3 (Kd 5x10-9 M) [46]
perospirone Hs Antagonist 10.1 pKi 59
pKi 10.1 (Ki 9x10-11 M) [59]
L-750,667 Rn Antagonist 10.0 pKi 52
pKi 10.0 [52]
RBI257 Rn Antagonist 9.6 pKi 25
pKi 9.6 [25]
[3H]N-methylspiperone Rn Antagonist 9.5 pKi 52
pKi 9.5 [52]
CP-293019 Rn Antagonist 9.5 pKi 25
pKi 9.5 [25]
NGD 94-1 Rn Antagonist 9.5 pKi 25
pKi 9.5 [25]
L745870 Hs Antagonist 9.4 pKi 27
pKi 9.4 (Ki 3.9x10-10 M) [27]
spiperone Hs Antagonist 9.3 pKi 13
pKi 9.3 [13]
FAUC213 Rn Antagonist 9.0 pKi 25
pKi 9.0 [25]
sonepiprazole Hs Antagonist 8.9 pKi 53
pKi 8.9 (Ki 1.4x10-9 M) [53]
U101958 Hs Antagonist 8.9 pKi 53
pKi 8.9 (Ki 1.4x10-9 M) [53]
A-381393 Hs Antagonist 8.8 pKi 38
pKi 8.8 (Ki 1.5x10-9 M) [38]
haloperidol Hs Antagonist 8.7 – 8.8 pKi 28,60,72
pKi 8.7 – 8.8 [28,60,72]
sonepiprazole Rn Antagonist 8.7 pKi 25
pKi 8.7 [25]
L741742 Hs Antagonist 8.5 pKi 50
pKi 8.5 (Ki 3.16x10-9 M) [50]
sertindole Hs Antagonist 7.8 – 9.1 pKi 6,56-57,59
pKi 7.8 – 9.1 (Ki 1.6x10-8 – 8.5x10-10 M) [6,56-57,59]
loxapine Hs Antagonist 8.1 pKi 57
pKi 8.1 (Ki 7.8x10-9 M) [57]
terguride Hs Antagonist 8.1 pKi 35
pKi 8.1 [35]
chlorpromazine Hs Antagonist 7.8 pKi 28
pKi 7.8 [28]
Ro 10-4548 Rn Antagonist 7.8 pKi 25
pKi 7.8 [25]
clozapine Hs Antagonist 7.5 pKi 28
pKi 7.5 [28]
ML398 Hs Antagonist 7.4 pKi 5
pKi 7.4 (Ki 3.6x10-8 M) [5]
zotepine Hs Antagonist 7.4 pKi 55
pKi 7.4 (Ki 3.9x10-8 M) [55]
trifluoperazine Hs Antagonist 7.4 pKi 57
pKi 7.4 (Ki 4.4x10-8 M) [57]
aripiprazole Rn Antagonist 7.3 pKi 52
pKi 7.3 [52]
eticlopride Hs Antagonist 7.0 pKi 13
pKi 7.0 [13]
(-)-sulpiride Hs Antagonist 5.7 – 7.7 pKi 43,69
pKi 5.7 – 7.7 (Ki 1.9x10-6 – 2x10-8 M) [43,69]
piribedil Hs Antagonist 6.5 pKi 35
pKi 6.5 [35]
bromocriptine Hs Antagonist 6.4 pKi 35
pKi 6.4 [35]
nafadotride Rn Antagonist 6.4 pKi 52
pKi 6.4 [52]
(+)-butaclamol Hs Antagonist 6.3 pKi 43
pKi 6.3 [43]
prochlorperazine Hs Antagonist 6.1 pKi 2
pKi 6.1 (Ki 8.1x10-7 M) [2]
raclopride Rn Antagonist 5.7 pKi 52
pKi 5.7 [52]
(+)-sulpiride Hs Antagonist 5.7 pKi 43
pKi 5.7 (Ki 2.2x10-6 M) [43]
View species-specific antagonist tables
Primary Transduction Mechanisms
Transducer Effector/Response
Gi/Go family Adenylate cyclase inhibition
References:  44
Tissue Distribution
Brain: Occipital lobe, cerebellum, hippocampus, middle frontal gyrus of temporal lobe, middle frontal gyrus of frontal lobe, cingulate gyrus of frontal lobe, amygdala > superior temporal gyrus of temporal lobe, superior frontal gyrus of frontal lobe, thalamus, septal nuclei, hypothalamus > substantia nigra, caudate nucleus, globus pallidus, superior parietal lobe.
Species:  Human
Technique:  RT-PCR
References:  37
Brain: Pre-frontal cortex, temporal neocortex > occipital cortex.
Species:  Human
Technique:  in situ hybridization.
References:  33
Aortic endothelium, umbilical vein endothelium.
Species:  Human
Technique:  RT-PCR
References:  78
Pulmonary artery.
Species:  Human
Technique:  Western Blot and Immunohistochemistry.
References:  47
Brain (especially cerebellum), eye, adrenal gland, testes, superior cervical ganglion, submaxillary gland, pancreas.
Species:  Mouse
Technique:  RT-PCR
References:  66
Retina, photoreceptor cell layer and inner nuclear and ganglion cell layers.
Species:  Mouse
Technique:  RT-PCR and in situ hybridization.
References:  10
Motor, somatosensory, visual, auditory, temporal association, cingulate, retrosplenial and granular insular cortices.
Species:  Rat
Technique:  Immunohistochemistry.
References:  48
Kidney: Cortex > inner medulla.
Species:  Rat
Technique:  Western Blot and Immunocytochemistry.
References:  62
Striatum, substantia nigra pars reticulata, entopeduncular nucleus, globus pallidus.
Species:  Rat
Technique:  Immunohistochemistry.
References:  49
Nucleus accumbens shell.
Species:  Rat
Technique:  immunocytochemistry.
References:  67
Pineal gland.
Species:  Rat
Technique:  RT-PCR.
References:  24
Kidney: Cortical collecting duct.
Species:  Rat
Technique:  RT-PCR
References:  64
Expression Datasets

Show »

Log average relative transcript abundance in mouse tissues measured by qPCR from Regard, J.B., Sato, I.T., and Coughlin, S.R. (2008). Anatomical profiling of G protein-coupled receptor expression. Cell, 135(3): 561-71. [PMID:18984166] [Raw data: website]

There should be a chart of expression data here, you may need to enable JavaScript!
Functional Assays
Measurement of cAMP levels in HEK 293 cells transfected with the human D4 receptor.
Species:  Human
Tissue:  HEK 293 cells.
Response measured:  Inhibition of cAMP accumulation.
References:  7,17,31
Measurement of cAMP levels in CHO cells transfected with the human D4 receptor.
Species:  Human
Tissue:  CHO cells.
Response measured:  Inhibition of cAMP accumulation.
References:  1,9,29,42,61,68
Measurement of cAMP levels in COS-7 cells transfected with the human D4 receptor.
Species:  Human
Tissue:  COS-7 cells.
Response measured:  Inhibition of cAMP accumulation.
References:  1
Measurement of cAMP levels in Chinese hamster lung fibroblast CCL39 cells transfected with the rat D4 receptor.
Species:  Rat
Tissue:  Chinese hamster lung fibroblast CCL39 cells.
Response measured:  Inhibition of cAMP accumulation.
References:  19
Measurement of high-voltage Ca2+ current in cultured granule cells from neonatal rat cerebellum endogenously expressing the D4 receptor.
Species:  Rat
Tissue:  Granule cells.
Response measured:  Inhibition of L-type Ca2+ current.
References:  34
Measurement of mitogenesis in CHO cells transfected with the human D4 receptor.
Species:  Human
Tissue:  CHO cells.
Response measured:  Mitogenesis.
References:  53
Measurement of Cl- currents in Xenopus oocytes transfected with murine D2L and D2S receptors.
Species:  Mouse
Tissue:  Xenopus oocytes.
Response measured:  Stimulation of Cl- influx.
References:  63
Measurement of inwardly rectifying K+ currents in Xenopus oocytes transfected with the human D4 receptor.
Species:  Human
Tissue:  Xenopus oocytes.
Response measured:  Activation of GIRK1 channels.
References:  45,76
Recruitment of beta-arrestin.
Species:  Human
Tissue:  Transfected CHO and HEK293 cells.
Response measured: 
References:  4,26,32
Physiological Functions
Modulation of the dark level of light-sensitive cAMP in photoreceptors.
Species:  Mouse
Tissue:  Retina.
References:  10
Regulation of electrolyte and water transport.
Species:  Rat
Tissue:  Kidney.
References:  62,64
Modulation of von Willebrand factor secretion in endothelial cells.
Species:  Human
Tissue:  Endothelium.
References:  78
Modulation of gastric acid secretion.
Species:  Rat
Tissue:  In vivo.
References:  20
Modulation of GABAA receptor functions.
Species:  Rat
Tissue:  Prefrontal cortex primary neurons.
References:  22
Modulation of angiotensin II type 1 receptor expression.
Species:  Rat
Tissue:  Kidney.
References:  8
Modulation of neuronal electrophysiological properties.
Species:  Mouse
Tissue:  Prefrontal cortex.
References:  79
Modulation of AMPA receptor trafficking and functions.
Species:  Rat
Tissue:  Prefrontal cortex.
References:  77
Physiological Consequences of Altering Gene Expression
D4 receptor knockout mice exhibit an increased sensitivity to ethanol, cocaine and methamphetamine.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  51
D4 receptor knockout mice exhibit a decrease in novelty-related exploration.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  12
D4 receptor knockout mice exhibit increased avoidance behaviour to unconditioned stimuli.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  15
D4 receptor knockout mice exhibit dysfunctional light-evoked regulation of cAMP in photoreceptors and abnormal retinal adaptation.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  39
D4 receptor knockout mice exhibit increased co-ordination.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  51
D4 receptor knockout mice exhibit an increase in blood pressure.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells and genotype polymorphism.
References:  3
D4 receptor knockout mice exhibit reduced longevity.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells and genotype polymorphism.
References:  21
D4 receptor knockout mice exhibit an increase in glutamate extracellular levels.
Species:  Mouse
Tissue:  Striatum.
Technique:  Gene targeting in embryonic stem cells and genotype polymorphism.
References:  70
D4 receptor knockout mice exhibit a decrease in dopamine release.
Species:  Mouse
Tissue:  Striatum.
Technique:  Gene targeting in embryonic stem cells and genotype polymorphism.
References:  71
GPCRDB Experimental Mutation Data
Species Residue# Wild-type Mutant GPCRDB# Segment PMID
Human (drd4_human) 119 CYS SER 3.36 TM3 9831905
Human (drd4_human) 194 VAL GLY 5.41 TM5 8741875
Species Residue# Wild-type Mutant GPCRDB# Segment PMID
Rat (drd4_rat) 87 LEU TRP 2.59 TM2 10617689
Rat (drd4_rat) 88 PHE VAL 2.60 TM2 10617689
Rat (drd4_rat) 91 SER LEU 2.63 TM2 10617689
Phenotypes, Alleles and Disease Models Mouse data from MGI

Show »

Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
Drd4tm1(IL2RA)Tao Drd4tm1(IL2RA)Tao/Drd4tm1(IL2RA)Tao
involves: C57BL/6J
MGI:94926  MP:0003463 abnormal single cell response PMID: 14684868 
Drd4tm1Dkg Drd4tm1Dkg/Drd4tm1Dkg
involves: 129P2/OlaHsd * C57BL/6J
MGI:94926  MP:0001417 decreased exploration in new environment PMID: 10531457 
Drd4tm1Dkg Drd4tm1Dkg/Drd4tm1Dkg
involves: 129P2/OlaHsd * C57BL/6J
MGI:94926  MP:0002757 decreased vertical activity PMID: 9323127 
Drd4tm1Dkg Drd4tm1Dkg/Drd4tm1Dkg
involves: 129P2/OlaHsd * C57BL/6J
MGI:94926  MP:0009754 enhanced behavioral response to cocaine PMID: 9323127 
Drd4tm1Dkg Drd4tm1Dkg/Drd4tm1Dkg
involves: 129P2/OlaHsd * C57BL/6J
MGI:94926  MP:0003858 enhanced coordination PMID: 9323127 
Drd4tm1Dkg Drd4tm1Dkg/Drd4tm1Dkg
involves: 129P2/OlaHsd * C57BL/6J
MGI:94926  MP:0002629 hyperactivity elicited by ethanol administration PMID: 9323127 
Drd4tm1Dkg Drd4tm1Dkg/Drd4tm1Dkg
involves: 129P2/OlaHsd * C57BL/6J
MGI:94926  MP:0001402 hypoactivity PMID: 9323127 
Drd4tm1Dkg Drd4tm1Dkg/Drd4tm1Dkg
involves: 129P2/OlaHsd * C57BL/6J
MGI:94926  MP:0009750 impaired behavioral response to addictive substance PMID: 9323127 
Drd4tm1Dkg Drd4tm1Dkg/Drd4tm1Dkg
involves: 129P2/OlaHsd * C57BL/6J
MGI:94926  MP:0001906 increased dopamine level PMID: 9323127 
Biologically Significant Variants
Type:  Repeat polymorphism of Exon III
Species:  Human
Description:  DRD4 7-repeat allele may increase likelihood of ADHD.
References:  14,65
General Comments
Human and primate receptors have a variable number (2-10) of imperfect 48 bp repeats in exon 3 [30,74]. This leads to a highly variable length and amino acid composition of the putative third cytoplasmic loop, apparently not associated with any marked variation in pharmacology. In humans the D4.2, D4.4 and D4.7 variants are the predominant variants [54].

Most D4 receptor-antagonists display agonistic activities in some heterologous expression systems [17-18].
Available Assays
DiscoveRx PathHunter® CHO-K1 DRD4 β-Arrestin Cell Line (Cat no. 93-0690C2)
PathHunter® eXpress DRD4 CHO-K1 β-Arrestin GPCR Assay (Cat no. 93-0690E2CP0M)
more info

References

Show »

1. Asghari V, Sanyal S, Buchwaldt S, Paterson A, Jovanovic V, Van Tol HH. (1995) Modulation of intracellular cyclic AMP levels by different human dopamine D4 receptor variants. J Neurochem65: 1157-1165. [PMID:7643093]

2. Auerbach SS, DrugMatrix® and ToxFX® Coordinator National Toxicology Program. National Toxicology Program: Dept of Health and Human Services. Accessed on 02/05/2014. Modified on 02/05/2014. DrugMatrix, https://ntp.niehs.nih.gov/drugmatrix/index.html

3. Bek MJ, Wang X, Asico LD, Jones JE, Zheng S, Li X, Eisner GM, Grandy DK, Carey RM, Soares-da-Silva P et al.. (2006) Angiotensin-II type 1 receptor-mediated hypertension in D4 dopamine receptor-deficient mice. Hypertension47 (2): 288-95. [PMID:16380537]

4. Bergman J, Roof RA, Furman CA, Conroy JL, Mello NK, Sibley DR, Skolnick P. (2013) Modification of cocaine self-administration by buspirone (buspar®): potential involvement of D3 and D4 dopamine receptors. Int. J. Neuropsychopharmacol.16 (2): 445-58. [PMID:22827916]

5. Berry CB, Bubser M, Jones CK, Hayes JP, Wepy JA, Locuson CW, Daniels JS, Lindsley CW, Hopkins CR. (2014) Discovery and Characterization of ML398, a Potent and Selective Antagonist of the D4 Receptor with in Vivo Activity. ACS Med Chem Lett5 (9): 1060-4. [PMID:25221667]

6. Burstein ES, Ma J, Wong S, Gao Y, Pham E, Knapp AE, Nash NR, Olsson R, Davis RE, Hacksell U et al.. (2005) Intrinsic efficacy of antipsychotics at human D2, D3, and D4 dopamine receptors: identification of the clozapine metabolite N-desmethylclozapine as a D2/D3 partial agonist. J. Pharmacol. Exp. Ther.315 (3): 1278-87. [PMID:16135699]

7. Chemel BR, Roth BL, Armbruster B, Watts VJ, Nichols DE. (2006) WAY-100635 is a potent dopamine D4 receptor agonist. Psychopharmacology (Berl)188: 244-251. [PMID:16915381]

8. Chen K, Deng K, Wang X, Wang Z, Zheng S, Ren H, He D, Han Y, Asico LD, Jose PA et al.. (2015) Activation of D4 dopamine receptor decreases angiotensin II type 1 receptor expression in rat renal proximal tubule cells. Hypertension65 (1): 153-60. [PMID:25368031]

9. Chio CL, Drong RF, Riley DT, Gill GS, Slighton JL, Huff RM. (1994) D4 dopamine receptor-mediated signalling events determined in transfected Chinese hamster ovary cells. J. Biol. Chem.269: 11813-11819. [PMID:7512953]

10. Cohen AI, Todd RD, Harmon S, O'Malley KL. (1992) Photoreceptors of mouse retinas possess D4 receptors coupled to adenylate cyclase. Proc Natl Acad Sci U S A89: 12093-12097. [PMID:1334557]

11. Collins GT, Butler P, Wayman C, Ratcliffe S, Gupta P, Oberhofer G, Caine SB. (2012) Lack of abuse potential in a highly selective dopamine D3 agonist, PF-592,379, in drug self-administration and drug discrimination in rats. Behav Pharmacol23 (3): 280-91. [PMID:22470105]

12. Dulawa SC, Grandy DK, Low MJ, Paulus MP, Geyer MA. (1999) Dopamine D4 receptor-knock-out mice exhibit reduced exploration of novel stimuli. J. Neurosci.19: 9550-9556. [PMID:10531457]

13. Durcan MJ, Rigdon GC, Norman MH, Morgan PF. (1995) Is clozapine selective for the dopamine D4 receptor?. Life Sci57: PL275-PL283. [PMID:7475902]

14. El-Faddagh M, Laucht M, Maras A, Vöhringer L, Schmidt MH. (2004) Association of dopamine D4 receptor (DRD4) gene with attention-deficit/hyperactivity disorder (ADHD) in a high-risk community sample: a longitudinal study from birth to 11 years of age. J Neural Transm111: 883-889. [PMID:15206004]

15. Falzone TL, Gelman DM, Young JI, Grandy DK, Low MJ, Rubinstein M. (2002) Absence of dopamine D4 receptors results in enhanced reactivity to unconditioned, but not conditioned, fear. Eur J Neurosci15: 158-164. [PMID:11860516]

16. Fishburn CS, Carmon S, Fuchs S. (1995) Molecular cloning and characterisation of the gene encoding the murine D4 dopamine receptor. FEBS Lett.361: 215-219. [PMID:7698326]

17. Gazi L, Bobirnac I, Danzeisen M, Schüpbach E, Bruinvels AT, Geisse S, Sommer B, Hoyer D, Tricklebank M, Schoeffter P. (1998) The agonist activities of the putative antipsychotic agents, L-745,870 and U-101958 in HEK293 cells expressing the human dopamine D4.4 receptor. Br. J. Pharmacol.124: 889-896. [PMID:9692773]

18. Gazi L, Bobirnac I, Danzeisen M, Schüpbach E, Langenegger D, Sommer B, Hoyer D, Tricklebank M, Schoeffter P. (1999) Receptor density as a factor governing the efficacy of the dopamine D4 receptor ligands, L-745,870 and U-101958 at human recombinant D4.4 receptors expressed in CHO cells. Br. J. Pharmacol.128: 613-620. [PMID:10516640]

19. Gazi L, Schoeffter P, Nunn C, Croskery K, Hoyer D, Feuerbach D. (2000) Cloning, expression, functional coupling and pharmacological characterization of the rat dopamine D4 receptor. Naunyn Schmiedebergs Arch Pharmacol361: 555-564. [PMID:10832611]

20. Glavin GB, Hall AM. (1994) Clozapine, a dopamine DA4 receptor antagonist, reduces gastric acid secretion and stress-induced gastric mucosal injury. Life Sci54: PL261-PL264. [PMID:8152334]

21. Grady DL, Thanos PK, Corrada MM, Barnett Jr JC, Ciobanu V, Shustarovich D, Napoli A, Moyzis AG, Grandy D, Rubinstein M et al.. (2013) DRD4 genotype predicts longevity in mouse and human. J. Neurosci.33 (1): 286-91. [PMID:23283341]

22. Graziane NM, Yuen EY, Yan Z. (2009) Dopamine D4 Receptors Regulate GABAA Receptor Trafficking via an Actin/Cofilin/Myosin-dependent Mechanism. J. Biol. Chem.284 (13): 8329-36. [PMID:19179335]

23. Hidaka K, Matsumoto M, Tada S, Tasaki Y, Yamaguchi T. (1995) Differential effects of [3H]nemonapride and [3H]spiperone binding on human dopamine D4 receptors. Neurosci. Lett.186 (2-3): 145-8. [PMID:7777184]

24. Kim JS, Bailey MJ, Weller JL, Sugden D, Rath MF, Møller M, Klein DC. (2010) Thyroid hormone and adrenergic signaling interact to control pineal expression of the dopamine receptor D4 gene (Drd4). Mol. Cell. Endocrinol.314 (1): 128-35. [PMID:19482058]

25. Kortagere S, Gmeiner P, Weinstein H, Schetz JA. (2004) Certain 1,4-disubstituted aromatic piperidines and piperazines with extreme selectivity for the dopamine D4 receptor interact with a common receptor microdomain. Mol Pharmacol66: 1491-1499. [PMID:15448188]

26. Kroeze WK, Sassano MF, Huang XP, Lansu K, McCorvy JD, Giguère PM, Sciaky N, Roth BL. (2015) PRESTO-Tango as an open-source resource for interrogation of the druggable human GPCRome. Nat. Struct. Mol. Biol.22 (5): 362-9. [PMID:25895059]

27. Kulagowski JJ, Broughton HB, Curtis NR, Mawer IM, Ridgill MP, Baker R, Emms F, Freedman SB, Marwood R, Patel S et al.. (1996) 3-((4-(4-Chlorophenyl)piperazin-1-yl)-methyl)-1H-pyrrolo-2,3-b-pyridine: an antagonist with high affinity and selectivity for the human dopamine D4 receptor. J. Med. Chem.39 (10): 1941-2. [PMID:8642550]

28. Lahti RA, Evans DL, Stratman NC, Figur LM. (1993) Dopamine D4 versus D2 receptor selectivity of dopamine receptor antagonists: possible therapeutic implications. Eur J Pharmacol236: 483-486. [PMID:8102973]

29. Lanau F, Zenner MT, Civelli O, Hartman DS. (1997) Epinephrine and norepinephrine act as potent agonists at the recombinant human dopamine D4 receptor. J Neurochem68: 804-812. [PMID:9003072]

30. Livak KJ, Rogers J, Lichter JB. (1995) Variability of dopamine D4 receptor (DRD4) gene sequence within and among nonhuman primate species. Proc. Natl. Acad. Sci. U.S.A.92: 427-431. [PMID:7831304]

31. McAllister G, Knowles MR, Ward-Booth SM, Sinclair HA, Patel S, Marwood R, Emms F, Patel S, Smith A, Seabrook GR. (1995) Functional coupling of human D2, D3, and D4 dopamine receptors in HEK293 cells. J Recept Signal Transduct Res15: 267-281. [PMID:8903944]

32. Meade JA, Free RB, Miller NR, Chun LS, Doyle TB, Moritz AE, Conroy JL, Watts VJ, Sibley DR. (2014) (-)-Stepholidine is a potent pan-dopamine receptor antagonist of both G protein- and β-arrestin-mediated signaling. Psychopharmacology (Berl.),  [Epub ahead of print]. [PMID:25231919]

33. Meador-Woodruff JH, Damask SP, Wang J, Haroutunian V, Davis KL, Watson SJ. (1996) Dopamine receptor mRNA expression in human striatum and neocortex. Neuropsychopharmacology15: 17-29. [PMID:8797188]

34. Mei YA, Griffon N, Buquet C, Martres MP, Vaudry H, Schwartz JC, Sokoloff P, Cazin L. (1995) Activation of dopamine D4 receptor inhibits an L-type calcium current in cerebellar granule cells. Neuroscience68: 107-116. [PMID:7477916]

35. Millan MJ, Maiofiss L, Cussac D, Audinot V, Boutin JA, Newman-Tancredi A. (2002) Differential actions of antiparkinson agents at multiple classes of monoaminergic receptor. I. A multivariate analysis of the binding profiles of 14 drugs at 21 native and cloned human receptor subtypes. J Pharmacol Exp Ther303: 791-804. [PMID:12388666]

36. Moreland RB, Patel M, Hsieh GC, Wetter JM, Marsh K, Brioni JD. (2005) A-412997 is a selective dopamine D4 receptor agonist in rats. Pharmacol Biochem Behav82: 140-147. [PMID:16153699]

37. Mulcrone J, Kerwin RW. (1997) The regional pattern of D4 gene expression in human brain. Neurosci Lett234: 147-150. [PMID:9364519]

38. Nakane M, Cowart MD, Hsieh GC, Miller L, Uchic ME, Chang R, Terranova MA, Donnelly-Roberts DL, Namovic MT, Miller TR et al.. (2005) 2-[4-(3,4-Dimethylphenyl)piperazin-1-ylmethyl]-1H benzoimidazole (A-381393), a selective dopamine D4 receptor antagonist. Neuropharmacology49 (1): 112-21. [PMID:15992586]

39. Nir I, Harrison JM, Haque R, Low MJ, Grandy DK, Rubinstein M, Iuvone PM. (2002) Dysfunctional light-evoked regulation of cAMP in photoreceptors and abnormal retinal adaptation in mice lacking dopamine D4 receptors. J Neurosci22: 2063-2073. [PMID:11896146]

40. O'Malley KL, Harmon S, Tang L, Todd RD. (1992) The rat dopamine D4 receptor sequence, gene structure, and demonstration of expression in the cardiovascular system. New Biol.2: 137-146. [PMID:1554689]

41. Patel MV, Kolasa T, Mortell K, Matulenko MA, Hakeem AA, Rohde JJ, Nelson SL, Cowart MD, Nakane M, Miller LN et al.. (2006) Discovery of 3-methyl-N-(1-oxy-3',4',5',6'-tetrahydro-2'H-[2,4'-bipyridine]-1'-ylmethyl)benzamide (ABT-670), an orally bioavailable dopamine D4 agonist for the treatment of erectile dysfunction. J. Med. Chem.49 (25): 7450-65. [PMID:17149874]

42. Patel S, Freedman S, Chapman KL, Emms F, Fletcher AE, Knowles M, Marwood R, McAllister G, Myers J, Curtis N, Kulagowski JJ, Leeson PD, Ridgill M, Graham M, Matheson S, Rathbone D, Watt AP, Bristow LJ, Rupniak NM, Baskin E, Lynch JJ, Ragan CI. (1997) Biological profile of L-745,870, a selective antagonist with high affinity for the dopamine D4 receptor. J Pharmacol Exp Ther283: 636-647. [PMID:9353380]

43. Patel S, Patel S, Marwood R, Emms F, Marston D, Leeson PD, Curtis NR, Kulagowski JJ, Freedman SB. (1996) Identification and pharmacological characterization of [125I]L-750,667, a novel radioligand for the dopamine D4 receptor. Mol Pharmacol50: 1658-1664. [PMID:8967990]

44. Pilla M, Perachon S, Sautel F, Garrido F, Mann A, Wermuth CG, Schwartz JC, Everitt BJ, Sokoloff P. (1999) Selective inhibition of cocaine-seeking behaviour by a partial dopamine D3 receptor agonist. Nature400: 371-375. [PMID:10432116]

45. Pillai G, Brown NA, McAllister G, Milligan G, Seabrook GR. (1998) Human D2 and D4 dopamine receptors couple through betagamma G-protein subunits to inwardly rectifying K+ channels (GIRK1) in a Xenopus oocyte expression system: selective antagonism by L-741,626 and L-745,870 respectively. Neuropharmacology37: 983-987. [PMID:9833627]

46. Primus RJ, Thurkauf A, Xu J, Yevich E, McInerney S, Shaw K, Tallman JF, Gallagher DW. (1997) II. Localization and characterization of dopamine D4 binding sites in rat and human brain by use of the novel, D4 receptor-selective ligand [3H]NGD 94-1. J. Pharmacol. Exp. Ther.282 (2): 1020-7. [PMID:9262371]

47. Ricci A, Mignini F, Tomassoni D, Amenta F. (2006) Dopamine receptor subtypes in the human pulmonary arterial tree. Auton Autacoid Pharmacol26: 361-369. [PMID:16968475]

48. Rivera A, Peñafiel A, Megías M, Agnati LF, López-Téllez JF, Gago B, Gutiérrez A, de la Calle A, Fuxe K. (2008) Cellular localization and distribution of dopamine D(4) receptors in the rat cerebral cortex and their relationship with the cortical dopaminergic and noradrenergic nerve terminal networks. Neuroscience155 (3): 997-1010. [PMID:18620029]

49. Rivera A, Trías S, Penafiel A, Angel Narváez J, Díaz-Cabiale Z, Moratalla R, de la Calle A. (2003) Expression of D4 dopamine receptors in striatonigral and striatopallidal neurons in the rat striatum. Brain Res989: 35-41. [PMID:14519509]

50. Rowley M, Broughton HB, Collins I, Baker R, Emms F, Marwood R, Patel S, Patel S, Ragan CI, Freedman SB et al.. (1996) 5-(4-Chlorophenyl)-4-methyl-3-(1-(2-phenylethyl)piperidin-4-yl)isoxazole: a potent, selective antagonist at human cloned dopamine D4 receptors. J. Med. Chem.39 (10): 1943-5. [PMID:8642551]

51. Rubinstein M, Phillips TJ, Bunzow JR, Falzone TL, Dziewczapolski G, Zhang G, Fang Y, Larson JL, McDougall JA, Chester JA, Saez C, Pugsley TA, Gershanik O, Low MJ, Grandy DK. (1997) Mice lacking dopamine D4 receptors are supersensitive to ethanol, cocaine, and methamphetamine. Cell90: 991-1001. [PMID:9323127]

52. Schetz JA, Benjamin PS, Sibley DR. (2000) Nonconserved residues in the second transmembrane-spanning domain of the D(4) dopamine receptor are molecular determinants of D(4)-selective pharmacology. Mol Pharmacol57: 144-152. [PMID:10617689]

53. Schlachter SK, Poel TJ, Lawson CF, Dinh DM, Lajiness ME, Romero AG, Rees SA, Duncan JN, Smith MW. (1997) Substituted 4-aminopiperidines having high in vitro affinity and selectivity for the cloned human dopamine D4 receptor. Eur J Pharmacol322: 283-286. [PMID:9098699]

54. Schoots O, Van Tol HH. (2003) The human dopamine D4 receptor repeat sequences modulate expression. Pharmacogenomics J.3 (6): 343-8. [PMID:14581929]

55. Schotte A, Janssen PF, Gommeren W, Luyten WH, Van Gompel P, Lesage AS, De Loore K, Leysen JE. (1996) Risperidone compared with new and reference antipsychotic drugs: in vitro and in vivo receptor binding. Psychopharmacology (Berl)124: 57-73. [PMID:8935801]

56. Seeman P. (2001) Antipsychotic drugs, dopamine receptors, and schizophrenia. Clinical Neuroscience Research1 (1-2): 53-60.

57. Seeman P, Corbett R, Van Tol HH. (1997) Atypical neuroleptics have low affinity for dopamine D2 receptors or are selective for D4 receptors. Neuropsychopharmacology16 (2): 93-110; discussion 111-35. [PMID:9015795]

58. Seeman P, Guan HC, Van Tol HH, Niznik HB. (1993) Low density of dopamine D4 receptors in Parkinson's, schizophrenia, and control brain striata. Synapse14: 247-253. [PMID:8248849]

59. Seeman P, Tallerico T. (1998) Antipsychotic drugs which elicit little or no parkinsonism bind more loosely than dopamine to brain D2 receptors, yet occupy high levels of these receptors. Mol. Psychiatry3 (2): 123-34. [PMID:9577836]

60. Shahid M, Walker GB, Zorn SH, Wong EH. (2009) Asenapine: a novel psychopharmacologic agent with a unique human receptor signature. J. Psychopharmacol. (Oxford)23 (1): 65-73. [PMID:18308814]

61. Shih YH, Chung FZ, Pugsley TA. (1997) Cloning, expression and characterization of a human dopamine D4.2 receptor (CHO K1 cells) and various D4.2/D2L chimeras (COS-7 cells). Prog Neuropsychopharmacol Biol Psychiatry21: 153-167. [PMID:9075264]

62. Shin Y, Kumar U, Patel Y, Patel SC, Sidhu A. (2003) Differential expression of D2-like dopamine receptors in the kidney of the spontaneously hypertensive rat. J Hypertens21: 199-207. [PMID:12544452]

63. Skaaning Jensen B, Levavi-Sivan B, Fishburn CS, Fuchs S. (1997) Functional expression of the murine D2, D3, and D4 dopamine receptors in Xenopus laevis oocytes. FEBS Lett420: 191-195. [PMID:9459308]

64. Sun D, Wilborn TW, Schafer JA. (1998) Dopamine D4 receptor isoform mRNA and protein are expressed in the rat cortical collecting duct. Am J Physiol275: F742-F751. [PMID:9815131]

65. Sunohara GA, Roberts W, Malone M, Schachar RJ, Tannock R, Basile VS, Wigal T, Wigal SB, Schuck S, Moriarty J, Swanson JM, Kennedy JL, Barr CL. (2000) Linkage of the dopamine D4 receptor gene and attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry39: 1537-1542. [PMID:11128331]

66. Suzuki T, Kobayashi K, Nagatsu T. (1995) Genomic structure and tissue distribution of the mouse dopamine D4 receptor. Neurosci Lett199: 69-72. [PMID:8584230]

67. Svingos AL, Periasamy S, Pickel VM. (2000) Presynaptic dopamine D(4) receptor localization in the rat nucleus accumbens shell. Synapse36: 222-232. [PMID:10819901]

68. Tallman JF, Primus RJ, Brodbeck R, Cornfield L, Meade R, Woodruff K, Ross P, Thurkauf A, Gallager DW. (1997) I. NGD 94-1: identification of a novel, high-affinity antagonist at the human dopamine D4receptor. J. Pharmacol. Exp. Ther.282: 1011-1019. [PMID:9262370]

69. Tang L, Todd RD, Heller A, O'Malley KL. (1994) Pharmacological and functional characterization of D2, D3 and D4 dopamine receptors in fibroblast and dopaminergic cell lines. J Pharmacol Exp Ther268: 495-502. [PMID:8301592]

70. Thomas TC, Grandy DK, Gerhardt GA, Glaser PE. (2009) Decreased dopamine D4 receptor expression increases extracellular glutamate and alters its regulation in mouse striatum. Neuropsychopharmacology34 (2): 436-45. [PMID:18536704]

71. Thomas TC, Kruzich PJ, Joyce BM, Gash CR, Suchland K, Surgener SP, Rutherford EC, Grandy DK, Gerhardt GA, Glaser PE. (2007) Dopamine D4 receptor knockout mice exhibit neurochemical changes consistent with decreased dopamine release. J. Neurosci. Methods166 (2): 306-14. [PMID:17449106]

72. Tice MA, Hashemi T, Taylor LA, Duffy RA, McQuade RD. (1994) Characterization of the binding of SCH 39166 to the five cloned dopamine receptor subtypes. Pharmacol. Biochem. Behav.49 (3): 567-71. [PMID:7862709]

73. Van Tol HHM, Bunzow JR, Guan HC, Sunahara RK, Seeman P, Niznik HB, Civelli O. (1991) Cloning of the gene for a human dopamine D4 receptor with high affinity for the antipsychotic clozapine. Nature350: 610-614. [PMID:1840645]

74. Van Tol HHM, Wu CM, Guan HC, Ohara K, Bunzow JR, Civelli O, Kennedy J, Seeman P, Niznik HB, Jovanovic V. (1992) Multiple dopamine D4 receptor variants in the human population. Nature358: 149-152. [PMID:1319557]

75. van Vliet LA, Tepper PG, Dijkstra D, Damsma G, Wikström H, Pugsley TA, Akunne HC, Heffner TG, Glase SA, Wise LD. (1996) Affinity for dopamine D2, D3, and D4 receptors of 2-aminotetralins. Relevance of D2 agonist binding for determination of receptor subtype selectivity. J. Med. Chem.39 (21): 4233-7. [PMID:8863800]

76. Wedemeyer C, Goutman JD, Avale ME, Franchini LF, Rubinstein M, Calvo DJ. (2007) Functional activation by central monoamines of human dopamine D(4) receptor polymorphic variants coupled to GIRK channels in Xenopus oocytes. Eur. J. Pharmacol.562 (3): 165-73. [PMID:17350612]

77. Yuen EY, Zhong P, Yan Z. (2010) Homeostatic regulation of glutamatergic transmission by dopamine D4 receptors. Proc. Natl. Acad. Sci. U.S.A.107 (51): 22308-13. [PMID:21135234]

78. Zarei S, Frieden M, Rubi B, Villemin P, Gauthier BR, Maechler P, Vischer UM. (2006) Dopamine modulates von Willebrand factor secretion in endothelial cells via D2-D4 receptors. J Thromb Haemost4: 1588-1595. [PMID:16839358]

79. Zhong P, Yan Z. (2014) Distinct Physiological Effects of Dopamine D4 Receptors on Prefrontal Cortical Pyramidal Neurons and Fast-Spiking Interneurons. Cereb. Cortex,  [Epub ahead of print]. [PMID:25146372]

How to cite this page

Raul R. Gainetdinov, Jean-Martin Beaulieu, Emiliana Borrelli, Arvid Carlsson, Marc G. Caron, Stefano Espinoza, Gilberto Fisone, David K. Grandy, Maria Cristina Missale, Kim A. Neve, David R. Sibley, Pierre Sokoloff.
Dopamine receptors: D4 receptor. Last modified on 15/07/2015. Accessed on 31/08/2015. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=217.