DRD4

Summary

DRD4 (dopamine receptor D4, HGNC:3025) is a protein-coding gene on chromosome 11p15.5, encoding D(4) dopamine receptor (P21917). Dopamine receptor responsible for neuronal signaling in the mesolimbic system of the brain, an area of the brain that regulates emotion and complex behavior.

This gene encodes the D4 subtype of the dopamine receptor. The D4 subtype is a G-protein coupled receptor which inhibits adenylyl cyclase. It is a target for drugs which treat schizophrenia and Parkinson disease. Mutations in this gene have been associated with various behavioral phenotypes, including autonomic nervous system dysfunction, attention deficit/hyperactivity disorder, and the personality trait of novelty seeking. This gene contains a polymorphic number (2-10 copies) of tandem 48 nt repeats; the sequence shown contains four repeats.

Source: NCBI Gene 1815 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 214 total — 1 likely-pathogenic
• GTEx eGene: eQTL in 41 tissues, sQTL in 1 (q < 0.05)
• Phenotypes (HPO): 3
• Drug target: yes — 2 curated mechanism-of-action drugs, 19 via a complex or family; 119 molecules with ChEMBL bioactivity (top 1% of genes corpus-wide)
• Approved drugs acting on a complex or family including it: 19 — Amoxapine, Apomorphine Hydrochloride, Bromocriptine Mesylate, +16 more (Dopamine receptor; D2-like dopamine receptor)
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 1.95 (unconstrained)
• MANE Select transcript: NM_000797
• Notable: 214 clinical variants but no curated precision-oncology (CIViC) evidence yet

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3025
Approved symbol	DRD4
Name	dopamine receptor D4
Location	11p15.5
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000069696
Ensembl biotype	protein_coding
OMIM	126452
Entrez	1815

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 1 protein_coding, 1 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

MANE Select: ENST00000176183

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 1, TSL 3: 1

ENST00000176183, ENST00000528733, ENST00001064212

RefSeq mRNA: 1 — MANE Select: NM_000797 NM_000797

CCDS: CCDS7710

Canonical transcript exons

ENST00000176183 — 4 exons

Exon	Start	End
ENSE00000438635	637269	637589
ENSE00001318101	640401	640706
ENSE00001325621	639648	640306
ENSE00003462140	639433	639545

Expression profiles

Bgee: expression breadth ubiquitous, 130 present calls, max score 82.96.

FANTOM5 (CAGE): breadth broad, TPM avg 3.7003 / max 368.9632, expressed in 257 samples.

Highest expression (Bgee): male germ line stem cell (sensu Vertebrata) in testis, lower esophagus mucosa, uterine tube, pituitary gland, hemisphere of cerebellum.

Genetic regulation across tissues (GTEx eQTL / sQTL)

DRD4 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 41 tissues and its splicing (sQTL) in 1 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 42 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Testis	eqtl	6.9e-17	-0.41	11:612148:T:C
Esophagus Mucosa	eqtl	1.0e-16	-0.33	11:571568:A:G
Nerve Tibial	eqtl	2.0e-15	-0.31	11:601785:T:C
Skin Not Sun Exposed Suprapubic	eqtl	2.5e-15	-0.51	11:604941:G:A
Brain Cortex	eqtl	1.2e-11	-0.40	11:590648:A:G
Skin Sun Exposed Lower leg	eqtl	1.9e-10	-0.40	11:604941:G:A
Thyroid	eqtl	4.7e-10	-0.26	11:612355:T:C
Brain Anterior cingulate cortex BA24	eqtl	4.1e-09	-0.42	11:621795:G:A
Cells Cultured fibroblasts	eqtl	4.2e-09	-0.46	11:604941:G:A
Brain Frontal Cortex BA9	eqtl	5.0e-09	-0.34	11:599313:T:C
Brain Cerebellum	eqtl	1.4e-08	-0.62	11:595168:A:T
Adipose Subcutaneous	eqtl	2.7e-08	-0.43	11:583156:T:C
Brain Cerebellar Hemisphere	eqtl	1.5e-07	-0.35	11:621634:G:A
Prostate	eqtl	2.0e-07	-0.48	11:583156:T:C
Stomach	eqtl	2.7e-07	-0.40	11:621634:G:A
Esophagus Muscularis	eqtl	4.6e-07	-0.21	11:601785:T:C
Artery Aorta	eqtl	4.6e-07	-0.21	11:613757:A:G
Esophagus Gastroesophageal Junction	eqtl	6.9e-07	-0.38	11:497039:C:T
Artery Tibial	eqtl	1.1e-06	-0.38	11:583158:G:A
Colon Sigmoid	eqtl	2.2e-06	-0.37	11:604941:G:A

FANTOM5 promoters

4 alternative TSS:

Promoter ID	TPM avg	Samples expressed
112224	3.3669	251
112227	0.1486	44
112226	0.1185	41
112225	0.0664	31

Top tissues by expression

showing 100 of 135 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	82.96	gold quality
lower esophagus mucosa	UBERON:0035834	76.73	gold quality
right uterine tube	UBERON:0001302	75.62	gold quality
pituitary gland	UBERON:0000007	74.89	gold quality
right hemisphere of cerebellum	UBERON:0014890	74.69	gold quality
left ovary	UBERON:0002119	74.46	gold quality
cerebellum	UBERON:0002037	73.80	gold quality
cerebellar hemisphere	UBERON:0002245	73.65	gold quality
adenohypophysis	UBERON:0002196	73.64	gold quality
cerebellar cortex	UBERON:0002129	73.63	gold quality
right ovary	UBERON:0002118	72.95	gold quality
primary visual cortex	UBERON:0002436	72.50	gold quality
sural nerve	UBERON:0015488	71.98	gold quality
lower esophagus	UBERON:0013473	71.75	gold quality
lower esophagus muscularis layer	UBERON:0035833	71.74	gold quality
ovary	UBERON:0000992	71.71	gold quality
body of uterus	UBERON:0009853	71.18	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	70.94	gold quality
endocervix	UBERON:0000458	70.91	gold quality
right frontal lobe	UBERON:0002810	70.61	gold quality
muscle layer of sigmoid colon	UBERON:0035805	70.53	gold quality
tibial nerve	UBERON:0001323	70.28	gold quality
ectocervix	UBERON:0012249	69.96	gold quality
putamen	UBERON:0001874	69.58	gold quality
myometrium	UBERON:0001296	69.36	gold quality
skin of abdomen	UBERON:0001416	69.11	gold quality
right lobe of liver	UBERON:0001114	69.03	gold quality
Ammon’s horn	UBERON:0001954	69.02	gold quality
nucleus accumbens	UBERON:0001882	68.88	gold quality
uterine cervix	UBERON:0000002	68.45	gold quality
hindlimb stylopod muscle	UBERON:0004252	68.44	gold quality
tibial artery	UBERON:0007610	68.39	gold quality
popliteal artery	UBERON:0002250	68.38	gold quality
skin of leg	UBERON:0001511	68.33	gold quality
zone of skin	UBERON:0000014	68.20	gold quality
temporal lobe	UBERON:0001871	68.14	gold quality
vagina	UBERON:0000996	67.88	gold quality
mucosa of transverse colon	UBERON:0004991	67.87	gold quality
amygdala	UBERON:0001876	67.84	gold quality
caudate nucleus	UBERON:0001873	67.80	gold quality
esophagus	UBERON:0001043	67.07	gold quality
substantia nigra	UBERON:0002038	66.93	gold quality
hypothalamus	UBERON:0001898	66.87	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	66.85	gold quality
brain	UBERON:0000955	66.69	gold quality
prostate gland	UBERON:0002367	66.52	gold quality
anterior cingulate cortex	UBERON:0009835	66.47	gold quality
ascending aorta	UBERON:0001496	66.40	gold quality
left lobe of thyroid gland	UBERON:0001120	66.31	gold quality
right coronary artery	UBERON:0001625	66.28	gold quality
thoracic aorta	UBERON:0001515	66.20	gold quality
descending thoracic aorta	UBERON:0002345	66.07	gold quality
granulocyte	CL:0000094	65.91	gold quality
subcutaneous adipose tissue	UBERON:0002190	65.84	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	65.68	gold quality
mucosa of stomach	UBERON:0001199	65.66	gold quality
thyroid gland	UBERON:0002046	65.38	gold quality
gastrocnemius	UBERON:0001388	65.32	gold quality
fundus of stomach	UBERON:0001160	65.29	gold quality
Brodmann (1909) area 9	UBERON:0013540	65.17	gold quality
stromal cell of endometrium	CL:0002255	65.14	gold quality
left coronary artery	UBERON:0001626	65.00	gold quality
small intestine Peyer’s patch	UBERON:0003454	64.96	gold quality
body of pancreas	UBERON:0001150	64.85	gold quality
superior frontal gyrus	UBERON:0002661	64.85	gold quality
colon	UBERON:0001155	64.73	gold quality
adipose tissue	UBERON:0001013	64.68	gold quality
right lobe of thyroid gland	UBERON:0001119	64.47	gold quality
right lung	UBERON:0002167	64.36	gold quality
left uterine tube	UBERON:0001303	64.18	gold quality
esophagus mucosa	UBERON:0002469	64.14	gold quality
multicellular organism	UBERON:0000468	63.92	gold quality
small intestine	UBERON:0002108	63.80	gold quality
omental fat pad	UBERON:0010414	63.78	gold quality
intestine	UBERON:0000160	63.43	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	63.35	gold quality
cortex of kidney	UBERON:0001225	63.19	gold quality
right adrenal gland	UBERON:0001233	63.16	gold quality
left testis	UBERON:0004533	63.08	gold quality
transverse colon	UBERON:0001157	63.06	gold quality
muscle of leg	UBERON:0001383	63.00	gold quality
body of stomach	UBERON:0001161	62.90	gold quality
right testis	UBERON:0004534	62.67	gold quality
metanephros cortex	UBERON:0010533	62.64	gold quality
cerebral cortex	UBERON:0000956	62.44	gold quality
adult mammalian kidney	UBERON:0000082	62.28	gold quality
thoracic mammary gland	UBERON:0005200	61.91	gold quality
left adrenal gland cortex	UBERON:0035825	61.88	gold quality
left adrenal gland	UBERON:0001234	61.74	gold quality
right adrenal gland cortex	UBERON:0035827	61.71	gold quality
testis	UBERON:0000473	61.14	gold quality
liver	UBERON:0002107	61.14	gold quality
cortical plate	UBERON:0005343	59.70	gold quality
skeletal muscle tissue	UBERON:0001134	59.60	gold quality
minor salivary gland	UBERON:0001830	59.57	gold quality
kidney	UBERON:0002113	59.52	gold quality
stomach	UBERON:0000945	59.50	gold quality
spleen	UBERON:0002106	59.24	gold quality
upper lobe of left lung	UBERON:0008952	59.21	gold quality
blood	UBERON:0000178	58.89	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	1.15
E-CURD-10	no	0.64

HPA expression

RNA tissue specificity: Low tissue specificity

19 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM
Pituitary gland	tissue	3.9
Hippocampus	tissue	2.5
Nucleus accumbens	tissue	2.4
Postcentral gyrus	tissue	2.3
Locus coeruleus	tissue	2.2
Choroid plexus	tissue	1.8
Vagina	tissue	1.6
Superior colliculi	tissue	0.4
Cerebral cortex	tissue	0.1
Adipose tissue	tissue	0.1
Putamen	tissue	0.1
Hypothalamus	tissue	0.1
Substantia nigra	tissue	0.1
Hippocampal formation	tissue	0.1
Ventral forebrain	tissue	0.1
Olfactory bulb	tissue	0.1
Septum	tissue	0.1
Somatosensory cortex	tissue	0.1
Temporal cortex	tissue	0.1

Brain sub-regions (HPA Brain Atlas): detected in 184; highest nTPM — Flocculonodular lobe (5.3), Vermis (4.5), Cerebellar cortex (4.1), Area striata (white matter) (3.9), Kolliker-Fuse nucleus (3.7).

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

Targeting DRD4 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

4 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-1252-5P	100.00	69.80	2774

Functional genomics

gnomAD constraint: pLI 7.17e-14, LOEUF 1.95, missense Z -6.32 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000176183 — one region, missense o/e 1.44.

Literature-anchored findings (GeneRIF, showing 40)

• we propose that this allele originated as a rare mutational event that nevertheless increased to high frequency in human populations by positive selection. (PMID:11756666)
• No association between dopamine D4 receptor gene variants and novelty seeking was found in Swedish adults. (PMID:11803441)
• The DRD4 gene plays a role in the development of attachment behavior in low-risk, non-clinical populations. (PMID:11803443)
• no association of polymorphism and methampheteamine abuse in Chinese males (PMID:11901357)
• DRD4 VNTR polymorphism moderates craving after alcohol comsumption (PMID:11950104)
• The dopamine D4 receptor and the hyperactivity phenotype: no evidence to support this association. (PMID:11986982)
• study did not support the involvement of 5-HTTLPR, TPH, MAO-A, or DRD4 polymorphisms in mood disorders (PMID:11992558)
• possible influence of monoamine oxydase A (MAO-A), catechol-O-methyltransferase (COMT), serotonin receptor 2A (5-HT2A), dopamine receptor D2 (DRD2), and dopamine receptor D4 (DRD4) gene variants on timing of recurrence in mood disorders (PMID:11992560)
• no association between gene exon III and -521C/T polymorphism and novelty seeking (PMID:12140774)
• on average, there is no association between DRD4 polymorphism and novelty seeking (PMID:12192615)
• genetic variation within the DRD4 promoter and gender differences contribute to variation in Novelty Seeking behaviors such as Extraversion. (PMID:12192624)
• the relationship between the DRD4 receptor and ADHD is complex and may be reflecting linkage disequilibrium between the 7 or long DRD4 exon III repeats and a ’true’ risk allele in this gene or a neighboring locus. (PMID:12192625)
• Ethnic heterogeneity in allele variation in the DRD4 gene in schizophrenia in Asians and Caucasians (PMID:12223255)
• the fact that DRD4 exhibit parent of orgin effect and is located in close proximity to a cluster of imprinted genes, suggests that genomic imprinting may be operating in bipolar disorder. (PMID:12232779)
• dopamine receptor D4 mRNA levels were significantly decreased in untreated depressed patients as compared to controls (PMID:12452539)
• Significant age-related decline was observed for dopamine receptor mRNAs in the hippocampus and entorhinal cortex (PMID:12509874)
• both temperament and attachment behavior were affected by the DRD4 repeat polymorphism (PMID:12556912)
• An association analysis for dopamine D4 receptor polymorphism and p300 component in normal young women is negative. (PMID:12605102)
• link between the DRD4 gene and human temperament in 3 year old infants. (PMID:12687422)
• no significant association was found between the DRD4 genotype and clinical response to risperidone in schizophrenics (PMID:12729944)
• variation in exon III in novelty seeking behavior (PMID:12740593)
• A 48-bp repeat polymorphism in the DRD4 gene was studied. The odds ratios for any 2- or 5-repeat allele vs. 0 was 2.41 for total novelty-seeking, 2.94 for exploratory excitability & 2.74 for impulsiveness but not for other components. of novelty seeking. (PMID:12764221)
• genotyped 16 subjects for the DRD4 and MAOA genes who had been scanned during the Attention Network Test (PMID:12773616)
• allelic heterogeneity at the DRD4 locus may also contribute to the observed association with attention deficit disorder with hyperactivity (PMID:12808433)
• a haplotype of markers in the 5’ promoter region of the dopamine D4 receptor gene may confer susceptibility to attention-deficit hyperactivity disorder (PMID:12960764)
• 7-repeat allele (7R) of the dopamine-4 receptor gene (DRD4) carriers reported significantly greater inattention and dysphoria in childhood (p=0.01 and 0.001, respectively) and a higher maximal lifetime BMI (p=0.007) than did probands without this allele. (PMID:14560322)
• Participants carrying any two- or five-repeat alleles of the DRD4 gene had a significantly greater risk of exhibiting novelty seeking bsehaviors. (PMID:14569271)
• Placement of the three repeat variants of dopamine D4 receptor downstream from the luciferase gene in the expression vector, shows that the D4.7 repeat sequence has significantly suppressed expression of the reporter compared to the D4.2 and D4.4 repeats. (PMID:14581929)
• Schizophrenia and polymorphisms including -616C>G, -603T>del, -602G>del, 600G>C, -521C>T, -376C>T and a 120 bp tandem duplication polymorphism (120 bp repeat) in 1.2 kb upstream from the initiation codon in the promoter region of the DRD4 gene. (PMID:14623368)
• DRD5 146-bp (DRD5.146) allele and the DRD4 240-bp (DRD4.240) allele of the promoter polymorphism emerge as the two DNA variants showing a significant association in this large sample of predominantly multiplex families with attention deficit disorder (PMID:14699430)
• drd4 gene is associated with neuropsychological test performance in children with ADHD (PMID:14702261)
• Polymorphisms (-C616G, -C521T, and 48 bp repeat) at the DRD4 gene do not have a minor effect in the susceptibility to schizophrenia (PMID:14755438)
• the associations between DRD4 duplication genotype and novelty seeking were not significant in these groups. (PMID:15048656)
• The personality dimension of persistence is associated with the third-exon VNTR of the DRD4 gene among Caucasian males. (PMID:15048658)
• Association of ADHD to genetic variation in or near to DRD4 and replicate the previously reported association between ADHD and the 7R allele. (PMID:15094785)
• Findings provide additional evidence for the role of the dopamine D4 receptor in attention-deficit/hyperactivity disorder during the course of child development. (PMID:15206004)
• long-repeat alleles of DRD4 (ranging from 4 to 6 repeats) and DAT1 (ranging from 11 to 12 repeats), were present more frequently in attention deficit hyperactivity disorder probands than controls (PMID:15211638)
• no association was demonstrated between this dopamine receptor D4 polymorphism and novelty seeking in our young Chinese female sample population (PMID:15292670)
• The “Social Problem” scale was weakly associated with the number of risk alleles of DRD2 and DRD4. (PMID:15319572)
• An association between DRD4 exon 3 long allele variants and delusional symptomatology could not be confirmed in an independent sample from Germany. (PMID:15364409)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	drd4b	ENSDARG00000035820
danio_rerio	drd4a	ENSDARG00000038363
mus_musculus	Drd4	ENSMUSG00000025496
rattus_norvegicus	Drd4	ENSRNOG00000017927

Paralogs (25): HRH3 (ENSG00000101180), HRH2 (ENSG00000113749), CHRM3 (ENSG00000133019), HRH4 (ENSG00000134489), TAAR5 (ENSG00000135569), GPR84 (ENSG00000139572), GPR161 (ENSG00000143147), TAAR2 (ENSG00000146378), TAAR6 (ENSG00000146383), TAAR8 (ENSG00000146385), TAAR1 (ENSG00000146399), DRD3 (ENSG00000151577), HTR4 (ENSG00000164270), CHRM1 (ENSG00000168539), DRD5 (ENSG00000169676), HTR1A (ENSG00000178394), HTR1D (ENSG00000179546), CHRM4 (ENSG00000180720), CHRM2 (ENSG00000181072), DRD1 (ENSG00000184845), CHRM5 (ENSG00000184984), GPR21 (ENSG00000188394), HRH1 (ENSG00000196639), GPR52 (ENSG00000203737), TAAR9 (ENSG00000237110)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:94926) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 11 distinct phenotype terms.

Mouse phenotype (MP)	Records
decreased locomotor activity	1
decreased exploration in new environment	1
increased dopamine level	1
abnormal vision	1
hyperactivity elicited by ethanol administration	1
decreased vertical activity	1
abnormal single cell response	1
enhanced coordination	1
abnormal eye electrophysiology	1
impaired behavioral response to addictive substance	1
enhanced behavioral response to cocaine	1

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Pan troglodytes	P60026	100.0%	Diamond
Sus scrofa	Q29005	100.0%	Diamond
Chlorocebus aethiops	P52702	99.1%	Diamond
Microtus montanus	Q9WTV8	99.0%	Diamond
Microtus ochrogaster	Q9WTV9	99.0%	Diamond
Xenopus laevis	Q9PU16	98.4%	Diamond
Macaca mulatta	F7EQ49	98.1%	Diamond
Ovis aries	P46628	97.8%	Diamond
Bos taurus	Q28031	97.8%	Diamond
Mustela putorius furo	Q6TLI9	97.3%	Diamond
Canis lupus familiaris	Q9GJU1	97.3%	Diamond
Oryctolagus cuniculus	A5A4K9	95.1%	Diamond
Dugong dugon	O77713	91.3%	Diamond
Procavia capensis habessinica	O19054	90.7%	Diamond
Caenorhabditis briggsae	Q61H86	89.1%	Diamond
Caenorhabditis elegans	Q6RYS9	89.1%	Diamond
Cavia porcellus	Q60475	87.8%	Diamond
Gallus gallus	P49288	85.3%	Diamond
Talpa europaea	O19091	84.6%	Diamond
Meleagris gallopavo	O73810	79.6%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
TMEM80	protein-coding	283232
SCT	protein-coding	6343
EPS8L2	protein-coding	64787
TALDO1	protein-coding	6888
DEAF1	protein-coding	10522
IRF7	protein-coding	3665
CDHR5	protein-coding	53841
PHRF1	protein-coding	57661

Protein

Protein identifiers

D(4) dopamine receptor — P21917 (reviewed: P21917)

Alternative names: D(2C) dopamine receptor, Dopamine D4 receptor

All UniProt accessions (1): P21917

UniProt curated annotations — full annotation on UniProt →

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.

Subunit / interactions. Forms homo- and heterooligomers with DRD2. D4.7 allele exhibits higher affinity for homodimers compared to DRD2 heterodimers, while alleles D42. and 4.4 have similar affinities for both. The interaction with DRD2 may modulate agonist-induced downstream signaling. Interacts with CLIC6. Interacts with GPRASP1. May interact with ADORA2A. Interacts with KLHL12.

Subcellular location. Cell membrane.

Tissue specificity. Highly expressed in retina. Detected at much lower levels in brain, in amygdala, thalamus, hypothalamus, cerebellum and pituitary.

Post-translational modifications. Polyubiquitinated by the BCR(KLHL12) E3 ubiquitin ligase complex: polyubiquitination does not lead to degradation of DRD4 protein. Palmitoylated. Palmitoylation of the C-terminal Cys is important for normal expression at the cell membrane.

Activity regulation. Signaling in response to agonists such as dopamine, epinephrine and norepinephrine is modulated by Na(+); lower Na(+) levels result in higher receptor activity (in vitro).

Polymorphism. The number of repeats of 16 amino acids in the third cytoplasmic loop is highly polymorphic and varies among different alleles. Alleles corresponding in size to a 2 (D4.2), 3 (D4.3), 4 (D4.4), 5 (D4.5), 6 (D4.6), 7 (D4.7) and 9 (D4.9) repeats have been described. The sequence shown is that of allele D4.4. The polymorphic repeat sequence has little influence on DRD4-binding profiles and might not be essential for G protein interaction.

Similarity. Belongs to the G protein-coupled receptor 1 family.

RefSeq proteins (1): NP_000788* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000276	GPCR_Rhodpsn	Family
IPR000929	Dopamine_rcpt	Family
IPR002185	Dopamine_D4_rcpt	Family
IPR017452	GPCR_Rhodpsn_7TM	Domain

Pfam: PF00001

UniProt features (55 total): helix 14, topological domain 8, transmembrane region 7, repeat 4, binding site 4, region of interest 3, sequence variant 3, mutagenesis site 3, disulfide bond 2, chain 1, compositionally biased region 1, lipid moiety-binding region 1, glycosylation site 1, sequence conflict 1, turn 1, strand 1

Structure

Experimental structures (PDB)

2 structures by resolution:

PDB	Title	Method	Resolution (Å)
5WIU	Structure of the human D4 Dopamine receptor in complex with Nemonapride	X-RAY DIFFRACTION	1.96
5WIV	Structure of the sodium-bound human D4 Dopamine receptor in complex with Nemonapride	X-RAY DIFFRACTION	2.14

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P21917-F1	78.06	0.47

Human Protein Atlas

Protein class: G-protein coupled receptors, GPCRs excl olfactory receptors, Predicted membrane proteins, GPCRHMM predicted membrane proteins, FDA approved drug targets, Small molecule drugs, Human disease related genes, Mental and behavioural disorders

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): plasma membrane; centrosome

Antibody reliability (HPA): IF uncertain

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (4)

Position	Role
80	Na(+)
115	(2R,3R)-nemonapride
122	Na(+)
196	(2R,3R)-nemonapride

Post-translational modifications (1)

Type	Positions
S-palmitoyl cysteine	419

Disulfide bonds (2)

Type	Positions
Disulfide bond	108–185, 372–375

Glycosylation sites (1)

Type	Positions
N-linked (glcnac…) asparagine	3

Mutagenesis-validated functional residues (3)

Position	Phenotype
382	increased basal level of g protein-mediated signaling.
418	no effect on palmitoylation.
419	loss of palmitoylation.

Function

Pathways and Gene Ontology

Reactome pathways

2 curated (TAS) of 8; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

8 pathways:

ID	Pathway	Evidence
R-HSA-390651	Dopamine receptors	curated
R-HSA-418594	G alpha (i) signalling events	curated
R-HSA-375280	Amine ligand-binding receptors	—
R-HSA-373076	Class A/1 (Rhodopsin-like receptors)	—
R-HSA-388396	GPCR downstream signalling	—
R-HSA-500792	GPCR ligand binding	—
R-HSA-162582	Signal Transduction	—
R-HSA-372790	Signaling by GPCR	—

MSigDB gene sets: 210 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_MCMV_INFECTION_UP, GSE45365_NK_CELL_VS_CD11B_DC_UP, GOBP_CIRCADIAN_RHYTHM, GOBP_PHENOL_CONTAINING_COMPOUND_METABOLIC_PROCESS, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_RESPONSE_TO_ETHANOL, GOMF_G_PROTEIN_COUPLED_SEROTONIN_RECEPTOR_ACTIVITY, BENPORATH_ES_WITH_H3K27ME3, MODULE_274, GOBP_BEHAVIOR, GOBP_RESPONSE_TO_COCAINE, GOBP_RESPONSE_TO_AMINE, GOBP_NEUROTRANSMITTER_UPTAKE, GOBP_ADULT_BEHAVIOR, GOBP_POSITIVE_REGULATION_OF_MAPK_CASCADE

GO Biological Process (30): behavioral fear response (GO:0001662), response to amphetamine (GO:0001975), intracellular calcium ion homeostasis (GO:0006874), G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger (GO:0007187), adenylate cyclase-modulating G protein-coupled receptor signaling pathway (GO:0007188), adenylate cyclase-inhibiting dopamine receptor signaling pathway (GO:0007195), chemical synaptic transmission (GO:0007268), adult locomotory behavior (GO:0008344), response to histamine (GO:0034776), social behavior (GO:0035176), regulation of dopamine metabolic process (GO:0042053), fear response (GO:0042596), regulation of circadian rhythm (GO:0042752), positive regulation of MAPK cascade (GO:0043410), behavioral response to cocaine (GO:0048148), behavioral response to ethanol (GO:0048149), rhythmic process (GO:0048511), arachidonate secretion (GO:0050482), negative regulation of protein secretion (GO:0050709), positive regulation of dopamine uptake involved in synaptic transmission (GO:0051586), inhibitory postsynaptic potential (GO:0060080), phospholipase C-activating dopamine receptor signaling pathway (GO:0060158), regulation of postsynaptic neurotransmitter receptor internalization (GO:0099149), synaptic transmission, dopaminergic (GO:0001963), signal transduction (GO:0007165), G protein-coupled receptor signaling pathway (GO:0007186), adult behavior (GO:0030534), regulation of transport (GO:0051049), regulation of primary metabolic process (GO:0080090), G protein-coupled serotonin receptor signaling pathway (GO:0098664)

GO Molecular Function (13): dopamine neurotransmitter receptor activity, coupled via Gi/Go (GO:0001591), dopamine neurotransmitter receptor activity (GO:0004952), G protein-coupled serotonin receptor activity (GO:0004993), potassium channel regulator activity (GO:0015459), SH3 domain binding (GO:0017124), neurotransmitter receptor activity (GO:0030594), dopamine binding (GO:0035240), identical protein binding (GO:0042802), metal ion binding (GO:0046872), epinephrine binding (GO:0051379), norepinephrine binding (GO:0051380), G protein-coupled receptor activity (GO:0004930), protein binding (GO:0005515)

GO Cellular Component (5): plasma membrane (GO:0005886), membrane (GO:0016020), dendrite (GO:0030425), postsynapse (GO:0098794), glutamatergic synapse (GO:0098978)

Reactome top-level categories

6 top-level categories:

Category	Pathways
Signaling by GPCR	2
Amine ligand-binding receptors	1
GPCR downstream signalling	1
Signal Transduction	1
GPCR ligand binding	1
Class A/1 (Rhodopsin-like receptors)	1

GO top-level categories

58 GO namespaces:

Category	Terms
cation binding	4
G protein-coupled receptor signaling pathway	3
adult behavior	3
catecholamine binding	3
G protein-coupled dopamine receptor signaling pathway	2
cellular anatomical structure	2
synapse	2
behavioral defense response	1
fear response	1
response to amine	1
intracellular monoatomic cation homeostasis	1
calcium ion homeostasis	1
adenylate cyclase activity	1
adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway	1
anterograde trans-synaptic signaling	1
locomotory behavior	1
response to nitrogen compound	1
behavior	1
biological process involved in intraspecies interaction between organisms	1
regulation of catecholamine metabolic process	1
dopamine metabolic process	1
multicellular organismal response to stress	1
circadian rhythm	1
regulation of biological process	1
MAPK cascade	1
regulation of MAPK cascade	1
positive regulation of intracellular signal transduction	1
response to cocaine	1
response to ethanol	1
biological_process	1
icosanoid secretion	1
arachidonate transport	1
protein secretion	1
regulation of protein secretion	1
negative regulation of protein transport	1
negative regulation of secretion by cell	1
positive regulation of neurotransmitter uptake	1
dopamine uptake involved in synaptic transmission	1
regulation of dopamine uptake involved in synaptic transmission	1
dopamine neurotransmitter receptor activity	1
synaptic transmission, dopaminergic	1
dopamine binding	1
postsynaptic neurotransmitter receptor activity	1
G protein-coupled amine receptor activity	1
serotonin binding	1
G protein-coupled serotonin receptor signaling pathway	1
potassium channel activity	1
ion channel regulator activity	1
protein domain specific binding	1
signaling receptor activity	1
protein binding	1
hormone binding	1
transmembrane signaling receptor activity	1
binding	1
membrane	1
cell periphery	1
neuron projection	1
dendritic tree	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 16 of 48 annotations. The rest are phylogenetic / computational / electronic (IEA).

16 experimentally-supported GO terms:

GO term	NS	Evidence
adenylate cyclase-inhibiting dopamine receptor signaling pathway	BP	direct assay
arachidonate secretion	BP	direct assay
intracellular calcium ion homeostasis	BP	direct assay
negative regulation of protein secretion	BP	direct assay
phospholipase C-activating dopamine receptor signaling pathway	BP	direct assay
positive regulation of MAPK cascade	BP	direct assay
response to histamine	BP	direct assay
membrane	CC	direct assay
plasma membrane	CC	direct assay
SH3 domain binding	MF	direct assay
dopamine binding	MF	direct assay
dopamine neurotransmitter receptor activity	MF	direct assay
dopamine neurotransmitter receptor activity, coupled via Gi/Go	MF	direct assay
epinephrine binding	MF	direct assay
identical protein binding	MF	physical interaction
norepinephrine binding	MF	direct assay

Protein interactions and networks

STRING

showing 15 of 1,475 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DRD4	SLC6A4	P31645	964
DRD4	SLC6A3	Q01959	958
DRD4	COMT	P21964	942
DRD4	MAOA	P21397	872
DRD4	TPH1	P17752	784
DRD4	ANKK1	Q8NFD2	766
DRD4	MAOB	P27338	750
DRD4	DBH	P09172	741
DRD4	OXTR	P30559	712
DRD4	CHRNA4	P43681	699
DRD4	SNAP25	P13795	697
DRD4	BDNF	P23560	685
DRD4	TH	P07101	681
DRD4	TOMT	Q8WZ04	660
DRD4	TPH2	Q8IWU9	643

IntAct

Human interaction partners of DRD4 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

11 partners by confidence:

Partner	Interaction type	MIscore	Records
APP	physical association	0.560	6
GAP43	physical association	0.560	3
METAP2	physical association	0.560	3
NECAB3	physical association	0.560	3
STXBP1	physical association	0.560	3
ADRA1B	physical association	0.470	2
ADRB1	physical association	0.470	2
DRD2	physical association	0.400	5
RAMP2	physical association	0.400	1
RAMP3	physical association	0.400	1
TNPO2	association	0.350	1

BioGRID (33 interactions; top human partners by supporting records): KLHL12 (Affinity Capture-Western; 6 records), ADRB2 (Affinity Capture-Western; 3 records), ARRB2 (Affinity Capture-Western; 3 records), CUL3 (Affinity Capture-Western; 2 records), ADCY2 (FRET), ARL10 (Affinity Capture-MS), ARRB1 (Affinity Capture-Western), ATM (Affinity Capture-MS), CLIC6 (Two-hybrid), DPY19L3 (Affinity Capture-MS), GNAI1 (FRET), GRB2 (Reconstituted Complex), INTS1 (Affinity Capture-MS), KCNJ3 (Affinity Capture-Western), KCNJ5 (Affinity Capture-Western)

SIGNOR signaling

7 signaling interactions:

A	Effect	B	Mechanism
DRD4	“up-regulates activity”	GNAI1	binding
DRD4	“up-regulates activity”	GNAI3	binding
DRD4	“up-regulates activity”	GNAO1	binding
DRD4	“up-regulates activity”	GNAZ	binding
dopamine	“up-regulates activity”	DRD4	“chemical activation”
DRD4	“up-regulates activity”	GNB5	binding
zotepine	“down-regulates activity”	DRD4	“chemical inhibition”

Protein complexes (CORUM) (4)

Experimentally-characterized complexes this protein is a subunit of (★ = the complex contains a known drug target).

4 complexes by size:

Complex	Subunits	Members
CUL3-DRD4-KLHL12 complex	3	CUL3, DRD4, KLHL12
★ ADRA1B-DRD4 complex	2	ADRA1B, DRD4
★ ADRB1-DRD4 complex	2	ADRB1, DRD4
★ DRD2(short)-DRD4 complex	2	DRD2, DRD4

Ligand–receptor pairs (CellPhoneDB) (4)

Curated ligand–receptor partners (cell-cell communication), distinct from the protein–protein interactions above.

4 ligand–receptor pairs:

Partner	This gene’s role	Signaling class
DDC;SLC6A3	receptor	Signaling by Serotonin/Dopamine
DDC;SLC18A1	receptor	Signaling by Serotonin/Dopamine
DDC;SLC18A2	receptor	Signaling by Serotonin/Dopamine
DDC	receptor	Signaling by Serotonin/Dopamine

Disease & clinical

Genetic variants

Variant evidence for DRD4: 214 ClinVar records (1 pathogenic / likely pathogenic). Per-variant detail is on Sugi Variant.

ClinVar

214 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	1
Uncertain significance	162
Likely benign	33
Benign	9

Top pathogenic / likely-pathogenic (1)

Showing all 1 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
3065214	NM_000797.4(DRD4):c.155dup (p.Asn52fs)	Likely pathogenic	criteria provided, single submitter	1

Per-variant reference — Sugi Variant

Explore DRD4’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 28 predictions of 264):

Position(s)	Effect	Δscore	Sites
11:637590–637591	donor_loss	1.0000	5
11:639916	donor_gain	0.9900
11:640399–640400	acceptor_loss	0.9900	6
11:639431–639432	acceptor_loss	0.9700	6
11:640307–640308	donor_loss	0.9600	5
11:638533	donor_gain	0.9500
11:640308	donor_loss	0.9400
11:638769	donor_gain	0.9300
11:639430	acceptor_loss	0.9300
11:638082	donor_gain	0.9000

AlphaMissense

899 missense substitutions predicted likely pathogenic (of 2,646 scored), across 214 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
D80	8	0.997	0.999
D115	8	0.992	0.996
F355	8	0.990	0.999
F363	8	0.988	0.998
N396	8	0.987	0.998
N52	8	0.977	0.996
F362	8	0.976	0.998
S393	8	0.972	0.998
D132	8	0.968	0.989
F201	8	0.967	0.997
N392	8	0.957	0.999
F407	8	0.956	0.997
F72	8	0.932	0.986
F411	8	0.928	0.980
S75	8	0.918	0.999
D109	8	0.902	0.975
F403	8	0.901	0.984
F202	8	0.879	0.967
S130	8	0.859	0.999
H366	8	0.838	0.971

HPA cancer prognostics

RNA cancer specificity: Cancer enhanced (Ovary Serous Cystadenocarcinoma)

Disease associations

OMIM: gene MIM:126452 | disease phenotypes: MIM:143465

GenCC curated gene-disease

Mondo (1): hereditary attention deficit-hyperactivity disorder (MONDO:0100518)

HPO phenotypes

3 phenotypes (HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000752	Hyperactivity
HP:0007018	Attention deficit hyperactivity disorder

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (5): CHEMBL2095396 (SELECTIVITY GROUP), CHEMBL2096905 (PROTEIN FAMILY), CHEMBL2097165 (SELECTIVITY GROUP), CHEMBL219 (SINGLE PROTEIN), CHEMBL2331075 (PROTEIN FAMILY)

Drugs by curated mechanism of action (ChEMBL)

Drugs whose curated ChEMBL mechanism of action targets the DRD4 protein itself — single-protein targets only (drugs acting on a protein family or complex that merely includes it are excluded). Includes antibodies and oligonucleotides that bioactivity screening does not capture.

2 curated-mechanism drugs:

Drug	Modality	Max phase
SARIZOTAN HYDROCHLORIDE	Small molecule	3
CLOTHIAPINE	Small molecule	2

Drugs acting on a complex or family that includes this protein

Curated ChEMBL mechanism-of-action drugs whose target is a protein complex or family of ≤10 members that includes DRD4 — the drug acts on the assembly or class, not necessarily on this subunit alone.

19 drugs via a complex or family:

Drug	Target (ChEMBL)	Members	Max phase
AMOXAPINE	Dopamine receptor	5	4
APOMORPHINE HYDROCHLORIDE	D2-like dopamine receptor	3	4
BROMOCRIPTINE MESYLATE	D2-like dopamine receptor	3	4
CHLORPROMAZINE	D2-like dopamine receptor	3	4
DROPERIDOL	D2-like dopamine receptor	3	4
ERGOLOID MESYLATES	Dopamine receptor	5	4
HALOPERIDOL	D2-like dopamine receptor	3	4
HALOPERIDOL DECANOATE	D2-like dopamine receptor	3	4
LEVOMEPROMAZINE	D2-like dopamine receptor	3	4
LOXAPINE	D2-like dopamine receptor	3	4
OLANZAPINE	D2-like dopamine receptor	3	4
PERGOLIDE MESYLATE	Dopamine receptor	5	4
PIMOZIDE	Dopamine receptor	5	4
PRAMIPEXOLE DIHYDROCHLORIDE	D2-like dopamine receptor	3	4
PROMAZINE HYDROCHLORIDE	D2-like dopamine receptor	3	4
ROPINIROLE HYDROCHLORIDE	D2-like dopamine receptor	3	4
ROTIGOTINE	D2-like dopamine receptor	3	4
THIORIDAZINE	D2-like dopamine receptor	3	4
TRIFLUOPERAZINE HYDROCHLORIDE	D2-like dopamine receptor	3	4

Molecules with ChEMBL bioactivity

Phase ≥1, by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 434,012 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

showing 60 of 119 molecules by phase:

Molecule	Name	Phase	Patents
CHEMBL633	AMIODARONE	4	30,023
CHEMBL629	AMITRIPTYLINE	4	53,007
CHEMBL1113	AMOXAPINE	4	20,303
CHEMBL53	APOMORPHINE	4	26,040
CHEMBL1112	ARIPIPRAZOLE	4	24,497
CHEMBL3187365	ASENAPINE	4	146
CHEMBL296419	ASTEMIZOLE	4	21,684
CHEMBL1366	AURANOFIN	4
CHEMBL297302	BENPERIDOL	4	3,436
CHEMBL2105760	BREXPIPRAZOLE	4	1,845
CHEMBL493	BROMOCRIPTINE	4	44,193
CHEMBL1201087	CABERGOLINE	4	12,895
CHEMBL2028019	CARIPRAZINE	4	1,672
CHEMBL2024517	CARIPRAZINE HYDROCHLORIDE	4	292
CHEMBL723	CARVEDILOL	4	30,479
CHEMBL71	CHLORPROMAZINE	4	46,206
CHEMBL104	CLOTRIMAZOLE	4	56,839
CHEMBL42	CLOZAPINE	4	37,868
CHEMBL1172	DESLORATADINE	4	19,866
CHEMBL1200517	DIHYDROERGOTAMINE MESYLATE	4	2,721
CHEMBL964	DISULFIRAM	4
CHEMBL926	DOBUTAMINE	4
CHEMBL502	DONEPEZIL	4
CHEMBL59	DOPAMINE	4
CHEMBL1557	DOPAMINE HYDROCHLORIDE	4
CHEMBL1628227	DOXEPIN	4
CHEMBL1201217	DYCLONINE	4
CHEMBL305660	EBASTINE	4
CHEMBL808	ECONAZOLE	4
CHEMBL596	FENTANYL	4
CHEMBL726	FLUPHENAZINE	4
CHEMBL2138684	FROVATRIPTAN SUCCINATE	4
CHEMBL54	HALOPERIDOL	4
CHEMBL1200986	HALOPERIDOL DECANOATE	4
CHEMBL896	HYDROXYZINE	4
CHEMBL14376	ILOPERIDONE	4
CHEMBL11	IMIPRAMINE	4
CHEMBL126224	IPRINDOLE	4
CHEMBL434	ISOPROTERENOL	4
CHEMBL51	KETANSERIN	4
CHEMBL480	LANSOPRAZOLE	4
CHEMBL841	LOPERAMIDE	4
CHEMBL1707	LOPERAMIDE HYDROCHLORIDE	4
CHEMBL831	LOXAPINE	4
CHEMBL3233142	LUMATEPERONE TOSYLATE	4
CHEMBL1623	MECLIZINE	4
CHEMBL651	METHADONE	4
CHEMBL86	METOCLOPRAMIDE	4
CHEMBL6437	MIANSERIN	4
CHEMBL91	MICONAZOLE	4
CHEMBL623	NEFAZODONE	4
CHEMBL1200492	NEFAZODONE HYDROCHLORIDE	4
CHEMBL715	OLANZAPINE	4
CHEMBL1621	PALIPERIDONE	4
CHEMBL531	PERGOLIDE	4
CHEMBL1423	PIMOZIDE	4
CHEMBL500	PINDOLOL	4
CHEMBL301265	PRAMIPEXOLE	4
CHEMBL3182733	PRAMIPEXOLE DIHYDROCHLORIDE	4
CHEMBL2	PRAZOSIN	4

PharmGKB: 1 entry (CPIC guideline: no)

PharmGKB variant annotations

Per-publication pharmacogenomic findings for this gene (significant associations).

5 published findings:

Variant	Drug(s)	Category	Finding	PMID
rs11246226	methylphenidate	Efficacy	Genotype AA is associated with increased response to methylphenidate in children with Autism Spectrum Disorder as compared to genotypes AC + CC.	PMID:23856854
rs1800955	methamphetamine	Toxicity	Genotypes CC + CT is associated with decreased likelihood of Paranoid psychosis NOS when exposed to methamphetamine in people with methamphetamine dependence as compared to genotype TT.	PMID:38151046
rs2133251840	clozapine	Efficacy	Allele del is associated with increased clinical benefit to clozapine in people with Schizophrenia or Psychotic Disorder as compared to allele GA.	PMID:40048458
rs762502	clozapine	Efficacy	Allele C is associated with increased clinical benefit to clozapine in people with Schizophrenia or Psychotic Disorder as compared to allele T.	PMID:40048458
rs747302		Other	Allele C is associated with increased likelihood of Substance-Related Disorders as compared to allele G.	PMID:40926693

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: gpcr — Dopamine receptors

Most potent curated ligand interactions (53 total), top 25:

Ligand	Action	Affinity	Parameter
benperidol	Antagonist	10.18	pKi
perospirone	Antagonist	10.05	pKi
L-750,667	Antagonist	10.0	pKi
nemonapride	Antagonist	10.0	pKd
[125I]L750667	Antagonist	9.8	pKd
RBI257	Antagonist	9.6	pKi
[3H]N-methylspiperone	Antagonist	9.5	pKi
[3H]spiperone	Antagonist	9.5	pKd
CP-293019	Antagonist	9.5	pKi
NGD 94-1	Antagonist	9.5	pKi
L745870	Antagonist	9.41	pKi
CP-226269	Partial agonist	9.4	pKi
spiperone	Antagonist	9.3	pKi
sertindole	Antagonist	9.07	pKi
FAUC213	Partial agonist	9.0	pKi
sonepiprazole	Antagonist	8.9	pKi
U101958	Antagonist	8.9	pKi
A-381393	Antagonist	8.82	pKi
haloperidol	Antagonist	8.8	pKi
PD168,077	Partial agonist	8.8	pKi
L741742	Antagonist	8.5	pKi
apomorphine	Partial agonist	8.4	pKi
[3H]NGD941	Antagonist	8.3	pKd
lisuride	Partial agonist	8.3	pKi
roxindole	Partial agonist	8.2	pKi

Binding affinities (BindingDB)

1971 measured of 2412 human assays (3056 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
[O-methyl-11C]2-{4-[4-(7-methoxynaphthalen-1-yl)piperazin-1-yl]butyl}-4-methyl-2H-[1,2,4]triazine-3,5-dione	EC50	0.01 nM
2-(8-Bromo-2,3,6,7-tetrahydro-benzo[1,2-b;4,5-b’]difuran-4-yl)-ethylamine	EC50	0.029 nM
Mosapramine	KI	0.03 nM
CHEMBL1813595	KI	0.07 nM
(Recemic)3-Propyl-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indol-9-ol	KI	0.1 nM
6-[Propyl-(2-thiophen-3-yl-ethyl)-amino]-5,6,7,8-tetrahydro-naphthalen-1-ol	KI	0.14 nM
CHEMBL1813594	KI	0.14 nM
3,3-diethyl-1-[(4R,7R)-6-methyl-6,11-diazatetracyclo[7.6.1.0^{2,7}.0^{12,16}]hexadeca-1(15),2,9,12(16),13-pentaen-4-yl]urea	KI	0.15 nM
4-[(R)-5-(4-Phenyl-3,6-dihydro-2H-pyridin-1-ylmethyl)-cyclohex-1-enyl]-phenol	KI	0.2 nM
(R)-N-(4-(7-chloro-8-hydroxy-3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)benzyl)-N-cyclobutylacetamide	KI	0.2 nM
11-chloro-12-hydroxy-7-methyl-6,6a,7,8,9,13b-hexahydro-5H-benzo[d]naphtho[2,1-b]azepine-4-carbaldehyde O-benzyl oxime	KI	0.2 nM
CAS_53772-85-3	KI	0.2 nM
CAS_163091	KI	0.21 nM
CHEMBL4083252	KI	0.22 nM
CHEMBL1813591	KI	0.26 nM
2-(4-(4-(3-methoxyphenyl)piperazin-1-yl)butyl)-4-methyl-1,2,4-triazine-3,5(2H,4H)-dione	EC50	0.3 nM
(6aS,13bS)-11-chloro-7-methyl-4-(pyridin-4-yl)-6,6a,7,8,9,13b-hexahydro-5H-benzo[d]naphtho[2,1-b]azepin-12-ol	KI	0.3 nM
7-methyl-5,6,7,8,9,14-hexahydrodibenzo[d,g]azecin-3-ol	KI	0.355 nM
1-(2-{4-[5-chloro-1-(4-fluorophenyl)-1H-indol-3-yl]piperidin-1-yl}ethyl)imidazolidin-2-one	KI	0.38 nM
ss-2c	KI	0.4 nM
PHNO,(+)	KI	0.45 nM
(2,4-Dimethyl-azetidin-1-yl)-(7-methyl-4,6,6a,7,8,9-hexahydro-indolo[4,3-fg]quinolin-9-yl)-methanone	KI	0.45 nM
4-chloro-7-methyl-5,6,7,8,9,14-hexahydrodibenzo[d,g]azecin-3-ol	KI	0.46 nM
2-(4-Ethylsulfanyl-2,5-dimethoxy-phenyl)-1-methyl-ethylamine	EC50	0.489 nM
6-Propylamino-5,6,7,8-tetrahydro-naphthalen-1-ol	KI	0.5 nM
N-{4-[4-(2-methoxyphenyl)piperazin-1-yl]butyl}-1-ferra-1,1’-spirobi[pentacyclo[2.2.0.0^{1,3}.0^{1,5}.0^{2,6}]hexane]-2,2’,4,4’-tetraene-6-carboxamide	KI	0.5 nM
(R)-N-(4-(7-chloro-8-hydroxy-3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)benzyl)-N-cyclobutylmethanesulfonamide	KI	0.5 nM
N-((6aS,13bR)-11-chloro-12-hydroxy-7-methyl-6,6a,7,8,9,13b-hexahydro-5H-benzo[d]naphtho[2,1-b]azepin-3-yl)methanesulfonamide	KI	0.5 nM
UNC10108016	EC50	0.5 nM	US-9156822: Functionally selective ligands of dopamine D2 receptors
N-[2-hydroxy-4-[4-(2-methoxyphenyl)piperazin-1-yl]butyl]-1H-indole-2-carboxamide	KI	0.5 nM	US-8748608: 4-phenylpiperazine derivatives with functionalized linkers as dopamine D3 receptor selective ligands and methods of use
CHEMBL2164354	KI	0.51 nM
(R)-N-(4-(7-chloro-8-hydroxy-3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)benzyl)-N-methylbenzenesulfonamide	KI	0.6 nM
(6aS,13bS)-11-chloro-7-methyl-6,6a,7,8,9,13b-hexahydro-5H-benzo[d]naphtho[2,1-b]azepine-4,12-diol	KI	0.6 nM
3-((6aS,13bS)-11-chloro-12-hydroxy-7-methyl-6,6a,7,8,9,13b-hexahydro-5H-benzo[d]naphtho[2,1-b]azepin-4-yl)benzonitrile	KI	0.6 nM
(6aS,13bS)-11-chloro-7-methyl-4-(3-nitrophenyl)-6,6a,7,8,9,13b-hexahydro-5H-benzo[d]naphtho[2,1-b]azepin-12-ol	KI	0.6 nM
CHEMBL4071929	KI	0.631 nM
CHEMBL2312227	KI	0.66 nM
7-(Methyl-propyl-amino)-5,6,7,8-tetrahydro-naphthalen-2-ol	KI	0.67 nM
CHEMBL4082195	KI	0.692 nM
N-((6aS,13bR)-11-chloro-12-hydroxy-7-methyl-6,6a,7,8,9,13b-hexahydro-5H-benzo[d]naphtho[2,1-b]azepin-3-yl)ethanesulfonamide	KI	0.7 nM
(6aS,13bS)-11-chloro-4-(4-methoxyphenyl)-7-methyl-6,6a,7,8,9,13b-hexahydro-5H-benzo[d]naphtho[2,1-b]azepin-12-ol	KI	0.7 nM
7-[Propyl-(2-thiophen-2-yl-ethyl)-amino]-5,6,7,8-tetrahydro-naphthalen-2-ol	KI	0.76 nM
N-{2-[4-(2,3-Dihydro-benzo[1,4]dioxin-5-yl)-piperazin-1-yl]-ethyl}-4-fluoro-benzamide	EC50	0.78 nM
roxindole	IC50	0.8 nM
7-(dipropylamino)-5,6,7,8-tetrahydronaphthalen-1-ol	KI	0.9 nM	US-10562853: Compounds for treating disorders sensitive to serotoninergic regulation controlled by the 5-HT1A receptors
2-amino-6-chloro-N-[8-chloro-11-(4-methyl-piperazin-1-yl)-dibenzo[b,e][1,4]diazepin-5-yl]-benzamide	KI	0.9 nM
(R)-8-chloro-5-(4-((cyclobutylamino)methyl)phenyl)-3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol	KI	0.9 nM
(6aS,13bS)-11-chloro-7-methyl-4-(thiophen-2-yl)-6,6a,7,8,9,13b-hexahydro-5H-benzo[d]naphtho[2,1-b]azepin-12-ol	KI	0.9 nM
4-(4-Iodophenyl)-1-((4-methoxy-1H-indol-3-yl)methyl)-piperidin-4-ol oxalate	KI	0.9 nM
4-(4-Iodophenyl)-1-((5-methoxy-1H-indol-3-yl)methyl)-piperidin-4-ol oxalate	KI	0.9 nM

ChEMBL bioactivities

4476 potent at pChembl≥5 of 4536 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.74	Ki	0.018	nM	CHEMBL156599
10.60	Ki	0.025	nM	CHEMBL156845
10.52	Ki	0.03	nM	CHEMBL2420894
10.52	Ki	0.03	nM	MOSAPRAMINE
10.40	Ki	0.04	nM	CHEMBL157322
10.40	Ki	0.04	nM	CHEMBL93403
10.24	IC50	0.057	nM	CHEMBL93403
10.18	Ki	0.066	nM	BENPERIDOL
10.11	Kd	0.078	nM	CHEMBL4860528
10.11	Kd	0.078	nM	CHEMBL5207281
10.11	Kd	0.078	nM	CHEMBL5206565
10.11	Kd	0.078	nM	CHEMBL5201074
9.80	EC50	0.1585	nM	CHEMBL4085780
9.78	EC50	0.166	nM	CHEMBL6167299
9.74	EC50	0.18	nM	CHEMBL5290993
9.70	Ki	0.2	nM	SPIPERONE
9.70	EC50	0.2	nM	UCSF924
9.70	Ki	0.2	nM	UCSF924
9.68	Kd	0.21	nM	NEMONAPRIDE
9.68	Ki	0.21	nM	CHEMBL345848
9.64	Ki	0.23	nM	CHEMBL326454
9.60	Ki	0.25	nM	CHEMBL211164
9.60	Ki	0.25	nM	CHEMBL4442460
9.59	Ki	0.26	nM	CHEMBL157388
9.55	Ki	0.28	nM	CHEMBL379602
9.51	Ki	0.309	nM	CHEMBL129534
9.51	Ki	0.31	nM	CHEMBL129534
9.48	Ki	0.33	nM	SPIPERONE
9.48	Ki	0.33	nM	CHEMBL379125
9.48	Ki	0.33	nM	CHEMBL4096543
9.48	Ki	0.3311	nM	CHEMBL4096543
9.48	Ki	0.33	nM	CHEMBL92859
9.46	Ki	0.3467	nM	CHEMBL129927
9.46	Ki	0.35	nM	CHEMBL129927
9.43	Ki	0.37	nM	N-{4-[4-(2-methoxyphenyl)piperazin-1-yl]butyl}-1-ruthena-1,1’-spirobi[pentacyclo[2.2.0.0^{1,3}.0^{1,5}.0^{2,6}]hexane]-2,2’,4,4’-tetraene-6-carboxamide
9.41	Ki	0.39	nM	CHEMBL279247
9.40	Ki	0.4	nM	CHEMBL2207643
9.40	Ki	0.4	nM	L-745870
9.39	Ki	0.4074	nM	CHEMBL5198170
9.37	Ki	0.43	nM	L-745870
9.37	Ki	0.43	nM	CHEMBL555670
9.36	Ki	0.44	nM	CHEMBL210404
9.36	Ki	0.4365	nM	CHEMBL210404
9.35	Ki	0.45	nM	SPIPERONE
9.35	Ki	0.45	nM	CHEMBL394473
9.34	Ki	0.4571	nM	CHEMBL128232
9.34	Ki	0.46	nM	CHEMBL128232
9.34	Ki	0.46	nM	CHEMBL93832
9.32	Kd	0.48	nM	MESPIPERONE
9.32	Kd	0.4786	nM	MESPIPERONE

PubChem BioAssay actives

3858 with measured affinity, of 6100 total; 50 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
N-[2-[4-(2-chlorophenyl)piperazin-1-yl]ethyl]-3-methoxybenzamide	63533: Binding affinity towards human Dopamine receptor D4 using [3H]spiroperidol as radioligand	ki	<0.0001	uM
3-methoxy-N-[2-[4-(4-methylphenyl)piperazin-1-yl]ethyl]benzamide	63533: Binding affinity towards human Dopamine receptor D4 using [3H]spiroperidol as radioligand	ki	<0.0001	uM
N-[2-[4-(2,3-dichlorophenyl)piperazin-1-yl]ethyl]-3-methoxybenzamide	63533: Binding affinity towards human Dopamine receptor D4 using [3H]spiroperidol as radioligand	ki	<0.0001	uM
3-[[4-(2-ethoxyphenyl)piperazin-1-yl]methyl]-1H-indole	767064: Binding affinity to human dopamine D4 receptor by radioligand binding assay	ki	<0.0001	uM
N-[2-[4-(4-chlorophenyl)piperazin-1-yl]ethyl]-3-methoxybenzamide	63533: Binding affinity towards human Dopamine receptor D4 using [3H]spiroperidol as radioligand	ki	<0.0001	uM
1’-[3-(2-chloro-5,6-dihydrobenzo[b][1]benzazepin-11-yl)propyl]spiro[1,5,6,7,8,8a-hexahydroimidazo[1,2-a]pyridine-3,4’-piperidine]-2-one	1615608: Agonist activity at dopamine D4 receptor (unknown origin)	ki	<0.0001	uM
3-[1-[4-(4-fluorophenyl)-4-oxobutyl]piperidin-4-yl]-1H-benzimidazol-2-one	1309485: Binding affinity to human dopamine D4 receptor by radioligand displacement assay	ki	0.0001	uM
1-[N’-[3-(2-amino-4-methyl-1,3-thiazol-5-yl)propyl]carbamimidoyl]-3-pentylurea	1895224: Displacement of [3H]N-methylspiperone from human D4.4 receptor stably expressed in HEK293T cells co-expressing ElucN-betaarr2 hD4.4R-ELuc incubated for 60 mins by scintillation counting analysis	kd	0.0001	uM
1-[(1R)-1-phenylethyl]-3-[N’-[3-(1H-1,2,4-triazol-5-yl)propyl]carbamimidoyl]urea;dihydrochloride	1895224: Displacement of [3H]N-methylspiperone from human D4.4 receptor stably expressed in HEK293T cells co-expressing ElucN-betaarr2 hD4.4R-ELuc incubated for 60 mins by scintillation counting analysis	kd	0.0001	uM
1-[N’-[3-(5-amino-1,3,4-thiadiazol-2-yl)propyl]carbamimidoyl]-3-pentylurea;bis(2,2,2-trifluoroacetic acid)	1895224: Displacement of [3H]N-methylspiperone from human D4.4 receptor stably expressed in HEK293T cells co-expressing ElucN-betaarr2 hD4.4R-ELuc incubated for 60 mins by scintillation counting analysis	kd	0.0001	uM
1-[N’-[3-(5-amino-1,3,4-thiadiazol-2-yl)propyl]carbamimidoyl]-3-benzylurea;bis(2,2,2-trifluoroacetic acid)	1895224: Displacement of [3H]N-methylspiperone from human D4.4 receptor stably expressed in HEK293T cells co-expressing ElucN-betaarr2 hD4.4R-ELuc incubated for 60 mins by scintillation counting analysis	kd	0.0001	uM
3-methoxy-N-[2-(4-naphthalen-1-ylpiperazin-1-yl)ethyl]benzamide	63533: Binding affinity towards human Dopamine receptor D4 using [3H]spiroperidol as radioligand	ki	0.0002	uM
1-[3-(4-phenylpiperazin-1-yl)propyl]-3,4-dihydroquinolin-2-one	1479887: Agonist activity at human SP/Myc epitope-tagged dopamine D4 receptor expressed in HEK293T cells assessed as RLuc8-fused Galphai1 activation after 2 mins by BRET assay	ec50	0.0002	uM
(1S)-1-methyl-N-[(3R,4S)-4-methyl-1-propan-2-ylpyrrolidin-3-yl]-1,3-dihydroisoindole-2-carboxamide	1932168: Agonist activity at D4R (unknown origin) by camp reporter assay	ec50	0.0002	uM
1-[3-(4-naphthalen-1-ylpiperazin-1-yl)propyl]-3,4-dihydroquinolin-2-one	2240048: Partial agonist activity at D4 receptor (unknown origin) transfected in HEK293 cells co-transfected with Galphai1-RLuc8/Gbeta1/Ggamma2-mVenus incubated for 30 mins by BRET assay	ec50	0.0002	uM
N-(1-benzyl-2-methylpyrrolidin-3-yl)-5-chloro-2-methoxy-4-(methylamino)benzamide	65945: Binding Affinity to Human Dopamine receptor D4 expressed in CHO cells was determined using [3H]- nemonapride as radioligand	kd	0.0002	uM
8-[4-(4-fluorophenyl)-4-oxobutyl]-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one	751684: Displacement of [3H]Spiperone from human recombinant dopamine D4 receptor expressed in CHOK1 cells after 2 hrs	ki	0.0002	uM
4-methyl-3-[1-[(3-methylphenyl)methyl]piperidin-4-yl]-5-phenyl-1H-imidazol-2-one	63511: Affinity to displace [3H]spiperone from cloned human Dopamine receptor D4 stably expressed in HEK393 cell lines	ki	0.0003	uM
N-[2-(3-chlorophenoxy)ethyl]-3-phenoxypropan-1-amine	243282: Binding affinity to displace [3H]spiperone from cloned human dopamine receptor D4 was determined	ki	0.0003	uM
N-[2-(3,4-dimethylphenoxy)ethyl]-3-phenoxypropan-1-amine	243282: Binding affinity to displace [3H]spiperone from cloned human dopamine receptor D4 was determined	ki	0.0003	uM
N-[2-[4-(3-chlorophenyl)piperazin-1-yl]ethyl]-3-methoxybenzamide	63533: Binding affinity towards human Dopamine receptor D4 using [3H]spiroperidol as radioligand	ki	0.0003	uM
6-bromo-2-[[4-(2-methoxyphenyl)piperazin-1-yl]methyl]imidazo[1,2-a]pyridine	1615608: Agonist activity at dopamine D4 receptor (unknown origin)	ki	0.0003	uM
6-iodo-2-[[4-(2-methoxyphenyl)piperazin-1-yl]methyl]imidazo[1,2-a]pyridine	1615608: Agonist activity at dopamine D4 receptor (unknown origin)	ki	0.0003	uM
1-(N-benzylanilino)-3-[3-[4-(2-methoxyphenyl)piperazin-1-yl]propyl]urea	1526878: Displacement of [3H] Spiperone from human D4.4 receptor expressed in CHO cells by competitive radioligand binding assay	ki	0.0003	uM
1-(2-methoxyphenyl)-4-[(1-phenylpyrazol-4-yl)methyl]piperazine	265126: Displacement of [3H]spiperone from human cloned dopamine D4 receptor expressed in CHO cells	ki	0.0003	uM
N-[1-[(4-iodophenyl)methyl]piperidin-4-yl]-N-methyl-3-propan-2-yloxypyridin-2-amine	1456755: Inhibition of human dopamine D4 receptor	ki	0.0003	uM
3-[[4-(4-chlorophenyl)piperazin-1-yl]methyl]-1H-pyrrolo[2,3-b]pyridine;hydrochloride	238524: Binding affinity for dopamine D4 receptor	ki	0.0004	uM
1-[3-[4-(2-nitrophenyl)piperazin-1-yl]propyl]-3,4-dihydroquinolin-2-one;oxalic acid	1851862: Displacement of [3H]N-methylspiperone from human D4.4 receptor expressed in HEK293T cell membrane incubated for 1 hr by MicroBeta scintillation counting method	ki	0.0004	uM
1-benzyl-4-(3-methyl-4-phenylpyrazol-1-yl)piperidine	63525: Binding affinity of compound towards human Dopamine receptor D4 by displacing [125I]-iodosulpiride expressed in CHO cells	ki	0.0004	uM
1-(azulen-1-ylmethyl)-4-(2-methoxyphenyl)piperazine	1932146: Displacement of [3H]-spiperone from human D4 receptor expressed in CHO cells assessed as inhibition constant	ki	0.0004	uM
1-(2-methoxyphenyl)-4-[(1-pyridin-2-ylpyrazol-4-yl)methyl]piperazine	265126: Displacement of [3H]spiperone from human cloned dopamine D4 receptor expressed in CHO cells	ki	0.0004	uM
N-[2-[4-(2,3-dichlorophenyl)piperazin-1-yl]ethyl]-3-ethynylbenzamide	301658: Displacement of [3H]spiperone from human cloned dopamine D4.4 receptor expressed in CHO cell membranes	ki	0.0004	uM
3-[[4-(4-chlorophenyl)piperazin-1-yl]methyl]-1H-pyrrolo[2,3-b]pyridine	1456755: Inhibition of human dopamine D4 receptor	ki	0.0004	uM
N-[2-(4-chlorophenoxy)ethyl]-3-phenoxypropan-1-amine	243282: Binding affinity to displace [3H]spiperone from cloned human dopamine receptor D4 was determined	ki	0.0005	uM
N-[2-(3-chloro-4-methylphenoxy)ethyl]-3-phenoxypropan-1-amine	243282: Binding affinity to displace [3H]spiperone from cloned human dopamine receptor D4 was determined	ki	0.0005	uM
N-[2-(3-methylphenoxy)ethyl]-3-phenoxypropan-1-amine	243282: Binding affinity to displace [3H]spiperone from cloned human dopamine receptor D4 was determined	ki	0.0005	uM
3-[1-[(3-chlorophenyl)methyl]piperidin-4-yl]-4-methyl-5-phenyl-1H-imidazol-2-one	63511: Affinity to displace [3H]spiperone from cloned human Dopamine receptor D4 stably expressed in HEK393 cell lines	ki	0.0005	uM
N-[2-(4-methylphenoxy)ethyl]-3-phenoxypropan-1-amine	243282: Binding affinity to displace [3H]spiperone from cloned human dopamine receptor D4 was determined	ki	0.0005	uM
8-iodo-2-[[4-(2-methoxyphenyl)piperazin-1-yl]methyl]-6-methylimidazo[1,2-a]pyridine	266776: Displacement of [3H]spiperone from human dopamine receptor D4.4 in CHO cell membrane	ki	0.0005	uM
8-[4-(4-fluorophenyl)-4-oxobutyl]-3-methyl-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one	2198856: Binding affinity to DRD4 in human HEK293T cells membrane assessed as dissociation constant incubated for 2 hrs by radioligand saturation assay	kd	0.0005	uM
Pramipexole	63685: in vitro high binding affinity was determined on human Dopamine receptor D4 expressed in chinese hamster ovary(CHO) K-1 cells using [3H]spiperone as radioligand.	ki	0.0005	uM
1-[3-[4-(2-chlorophenyl)piperazin-1-yl]propyl]-3,4-dihydroquinolin-2-one;oxalic acid	1851877: Displacement of [3H]7-OH-DPAT from human D4.4 receptor expressed in HEK293T cell membrane incubated for 1.5 hrs by MicroBeta scintillation counting method	ki	0.0005	uM
(NE)-N-[[2-[(4-phenylpiperazin-1-yl)methyl]-1H-indol-3-yl]methylidene]hydroxylamine	1932146: Displacement of [3H]-spiperone from human D4 receptor expressed in CHO cells assessed as inhibition constant	ki	0.0005	uM
1-[3-[4-(2-methoxyphenyl)piperazin-1-yl]propyl]-3-[(2-phenylphenyl)methyl]urea	1998321: Displacement of [3H]-N-methylspiperone from human dopmaine D4.4 receptor expressed in HEK293T cells assessed as inhibition constant by competition binding assay	ki	0.0005	uM
1-(3-chlorobenzo[b][1]benzoxepin-5-yl)-4-methylpiperazine	64202: Affinity was evaluated by inhibition of [3H]-spiperone binding to COS cells transfected with human dopamine D-4 receptor	ki	0.0005	uM
3-(1,3-dihydroisoindol-2-yl)-2-[4-(6-fluoro-1,2-benzoxazol-3-yl)piperidin-1-yl]propan-1-ol	1799610: Binding Assay from Article 10.1002/1439-7633(20021004)3:10: “Synthesis and structure-activity relationship of the isoindolinyl benzisoxazolpiperidines as potent, selective, and orally active human dopamine D4 receptor antagonists.”	ki	0.0005	uM
2-[4-(6-fluoro-1,2-benzoxazol-3-yl)piperidin-1-yl]-3-(4-fluoro-1,3-dihydroisoindol-2-yl)propan-1-ol	1799610: Binding Assay from Article 10.1002/1439-7633(20021004)3:10: “Synthesis and structure-activity relationship of the isoindolinyl benzisoxazolpiperidines as potent, selective, and orally active human dopamine D4 receptor antagonists.”	ki	0.0005	uM
3-[[4-(4-iodophenyl)piperazin-1-yl]methyl]-1H-pyrrolo[2,3-b]pyridine	63531: Binding affinity towards cloned human Dopamine receptor D4 stably expressed in CHO cells was evaluated using [3H]spiperone as radioligand	ki	0.0005	uM
4-methyl-5-phenyl-3-[1-(2-phenylethyl)piperidin-4-yl]-1H-imidazol-2-one	63511: Affinity to displace [3H]spiperone from cloned human Dopamine receptor D4 stably expressed in HEK393 cell lines	ki	0.0006	uM
3-[1-[(3-methoxyphenyl)methyl]piperidin-4-yl]-4-methyl-5-phenyl-1H-imidazol-2-one	63511: Affinity to displace [3H]spiperone from cloned human Dopamine receptor D4 stably expressed in HEK393 cell lines	ki	0.0006	uM

CTD chemical–gene interactions

44 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, decreases expression, increases methylation	7
trichostatin A	affects cotreatment, decreases expression	3
Clozapine	affects binding, decreases reaction, increases activity, affects response to substance	3
mercuric bromide	decreases expression, affects cotreatment	2
Benzo(a)pyrene	decreases expression, decreases methylation, increases methylation	2
Dopamine	affects binding, decreases reaction, increases activity	2
Methamphetamine	affects response to substance, increases response to substance	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Spiperone	affects binding, decreases reaction	2
aristolochic acid I	increases expression	1
GSK-J4	increases expression	1
methylmercuric chloride	decreases expression	1
dimethyl phosphate	affects response to substance	1
fucoxanthin	increases activity	1
nemonapride	affects binding	1
ropinirole	affects binding, increases activity	1
di-n-butylphosphoric acid	affects expression	1
A 86929	affects binding	1
NRA 0045	affects binding	1
NRA 0160	affects binding, decreases activity	1
7-methyl-6,7,8,9,14,15-hexahydro-5H-benz(d)indolo(2,3-g)azecine	affects binding, decreases activity	1
7-fluoro-2-oxo-4-(2-(4-(thieno(3,2-c)pyridin-4-yl)piperazin-1-yl)ethyl)-1,2-dihydroquinoline-1-acetamide	affects activity	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
bisphenol S	decreases expression	1
jinfukang	affects cotreatment, decreases expression	1
1-(2,3-dihydrobenzo(b)(1,4)dioxin-6-yl)-4-((6-fluoropyridin-3-yl)methyl)piperazine	affects binding	1
Resveratrol	affects cotreatment, decreases expression	1
Temozolomide	increases expression	1
Cisplatin	affects cotreatment, decreases expression	1

ChEMBL screening assays

951 unique, capped per target: 787 binding, 154 functional, 9 admet, 1 unclassified

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5232013	Binding	Binding affinity to human D2/D4 receptor assessed as inhibition constant	A review: Biologically active 3,4-heterocycle-fused coumarins. — *Eur J Med Chem*
CHEMBL661208	Functional	Antagonism of apomorphine induced inhibition of the tachycardia produced by stimulation of the right cardioaccelerator nerve in cat.	Assessment of a potential dopaminergic prodrug moiety in several ring systems. — *J Med Chem*
CHEMBL4048887	Unclassified	Selectivity ratio of Ki for human dopamine D3 receptor to Ki for human dopamine D4 receptor	1-[3-(4-Butylpiperidin-1-yl)propyl]-1,2,3,4-tetrahydroquinolin-2-one (77-LH-28-1) as a Model for the Rational Design of a Novel Class of Brain Penetrant Ligands with High Affinity and Selectivity for Dopamine D4 Receptor. — *J Med Chem*

Cellosaurus cell lines

5 cell lines: 2 transformed cell line, 2 spontaneously immortalized cell line, 1 undefined cell line type

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_E7HL	HEK293 hD4.4	Transformed cell line	Female
CVCL_H365	293 c18/DRD4	Transformed cell line	Female
CVCL_KS83	Chem-5 DRD4	Undefined cell line type
CVCL_KV09	cAMP Hunter CHO-K1 DRD4 Gi	Spontaneously immortalized cell line	Female
CVCL_KW89	PathHunter CHO-K1 DRD4 beta-arrestin	Spontaneously immortalized cell line	Female

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for DRD4 across ~30M SureChEMBL compounds — explore on Sugi Predict.