Target Information

Target General Information

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Target ID

T24983 (Former ID: TTDC00291)

Target Name

Dopamine D4 receptor (D4R)

Synonyms

DRD4; D(2C)D(4) dopamine receptor dopamine receptor

Gene Name

DRD4

Target Type

Successful target

[1]

Disease

[+] 2 Target-related Diseases

Allergic/hypersensitivity disorder [ICD-11: 4A80-4A8Z]

Schizophrenia [ICD-11: 6A20]

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. Its activity is mediated by G proteins which inhibit adenylyl cyclase. Modulates the circadian rhythm of contrast sensitivity by regulating the rhythmic expression of NPAS2 in the retinal ganglion cells.

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BioChemical Class

GPCR rhodopsin

UniProt ID

DRD4_HUMAN

Sequence

MGNRSTADADGLLAGRGPAAGASAGASAGLAGQGAAALVGGVLLIGAVLAGNSLVCVSVA
TERALQTPTNSFIVSLAAADLLLALLVLPLFVYSEVQGGAWLLSPRLCDALMAMDVMLCT
ASIFNLCAISVDRFVAVAVPLRYNRQGGSRRQLLLIGATWLLSAAVAAPVLCGLNDVRGR
DPAVCRLEDRDYVVYSSVCSFFLPCPLMLLLYWATFRGLQRWEVARRAKLHGRAPRRPSG
PGPPSPTPPAPRLPQDPCGPDCAPPAPGLPRGPCGPDCAPAAPSLPQDPCGPDCAPPAPG
LPPDPCGSNCAPPDAVRAAALPPQTPPQTRRRRRAKITGRERKAMRVLPVVVGAFLLCWT
PFFVVHITQALCPACSVPPRLVSAVTWLGYVNSALNPVIYTVFNAEFRNVFRKALRACC

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3D Structure

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AlphaFold

ADReCS ID

BADD_A04234

HIT2.0 ID

T49IR9

Drugs and Modes of Action

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Approved Drug(s)

[+] 2 Approved Drugs

Clozapine

Drug Info

Approved

Schizophrenia

[2], [3]

Phenyltoloxamine

Drug Info

Approved

Allergy

[4]

Clinical Trial Drug(s)

[+] 4 Clinical Trial Drugs

CM-2395

Drug Info

Phase 3

Schizophrenia

[5]

L-745,870

Drug Info

Phase 2

Psychotic disorder

[6]

RP5063

Drug Info

Phase 2

Schizophrenia

[7]

NGD 94-1

Drug Info

Phase 1

Schizophrenia

[3], [8]

Discontinued Drug(s)

[+] 7 Discontinued Drugs

ABT-724

Drug Info

Discontinued in Phase 2

Erectile dysfunction

[9]

Lu-35138

Drug Info

Discontinued in Phase 2

Psychotic disorder

[10]

NGD-94-4

Drug Info

Discontinued in Phase 1

Schizophrenia

[11]

Belaperidone

Drug Info

Terminated

Schizophrenia

[3]

BIMG80

Drug Info

Terminated

Psychotic disorder

[12]

Sonepiprazole

Drug Info

Terminated

Schizophrenia

[3], [13]

YM-43611

Drug Info

Terminated

Psychotic disorder

[14]

Preclinical Drug(s)

[+] 3 Preclinical Drugs

PD-165167

Drug Info

Preclinical

Schizophrenia

[3]

SPI-376

Drug Info

Preclinical

Schizophrenia

[3]

U-99363E

Drug Info

Preclinical

Schizophrenia

[3]

Mode of Action

[+] 6 Modes of Action

Modulator

[+] 6 Modulator drugs

Clozapine

Drug Info

[15]

NGD-94-4

Drug Info

[23]

BIMG80

Drug Info

[25]

YM-43611

Drug Info

[26]

E-1455

Drug Info

[38]

TKP-1002

Drug Info

[38]

Inhibitor

[+] 44 Inhibitor drugs

Phenyltoloxamine

Drug Info

[1]

A-80426

Drug Info

[24]

(+/-)-nantenine

Drug Info

[27]

(4-Ethynyl-cyclohex-3-enyl)-dipropyl-amine

Drug Info

[28]

(4-Phenylethynyl-cyclohex-3-enyl)-dipropyl-amine

Drug Info

[28]

1-(4-(1H-pyrazol-1-yl)benzyl)-4-phenylpiperazine

Drug Info

[29]

1-Benzyl-4-(2-ethynyl-pyrrol-1-yl)-piperidine

Drug Info

[30]

1-Benzyl-4-(2-iodo-pyrrol-1-yl)-piperidine

Drug Info

[30]

1-Benzyl-4-(2-oxazol-5-yl-pyrrol-1-yl)-piperidine

Drug Info

[30]

1-Benzyl-4-(3-oxazol-5-yl-pyrrol-1-yl)-piperidine

Drug Info

[30]

1-Benzyl-4-pyrrol-1-yl-piperidine

Drug Info

[30]

1-Dibenzo[b,f]oxepin-10-yl-4-methyl-piperazine

Drug Info

[31]

1-[2-(2-Benzyl-phenoxy)-ethyl]-piperidine

Drug Info

[1]

1-[2-(2-Benzyl-phenoxy)-ethyl]-pyrrolidine

Drug Info

[1]

1-[3-(2-Benzyl-phenoxy)-propyl]-pyrrolidine

Drug Info

[1]

3-(2-Benzylamino-ethoxy)-phenol

Drug Info

[32]

3-(4-Methyl-piperidin-1-ylmethyl)-1H-indole

Drug Info

[33]

3-(4-Phenyl-piperazin-1-ylmethyl)-1H-indole

Drug Info

[33]

3-(4-Phenyl-piperidin-1-ylmethyl)-1H-indole

Drug Info

[33]

4-(2-Benzylamino-ethoxy)-1,3-dihydro-indol-2-one

Drug Info

[32]

4-(4-Benzyl-piperazin-1-yl)-1H-benzoimidazole

Drug Info

[34]

4-(4-Benzyl-piperazin-1-yl)-1H-indole

Drug Info

[34]

4-(4-Benzyl-piperazin-1-yl)-5-chloro-1H-indole

Drug Info

[34]

4-(4-Benzyl-piperazin-1-yl)-7-bromo-1H-indole

Drug Info

[34]

4-[2-(2-Benzyl-phenoxy)-ethyl]-morpholine

Drug Info

[1]

A-425444

Drug Info

[35]

ABT-670

Drug Info

[35]

Benzyl-[2-(1H-indazol-4-yloxy)-ethyl]-amine

Drug Info

[32]

Benzyl-[2-(1H-indol-4-yloxy)-ethyl]-amine

Drug Info

[32]

FLUMEZAPINE

Drug Info

[39]

FLUTROLINE

Drug Info

[40]

ISOCLOZAPINE

Drug Info

[31]

ISOLOXAPINE

Drug Info

[41]

JL-18

Drug Info

[42]

L-741626

Drug Info

[43]

L-741742

Drug Info

[44]

N-(4-Dipropylaminobutyl)-4-biphenylcarboxamide

Drug Info

[47]

N-(4-Propylaminobutyl)-4-biphenylcarboxamide

Drug Info

[47]

PG-01037

Drug Info

[49]

QUINPIROLE

Drug Info

[51]

SB-271046

Drug Info

[52]

STEPHOLIDINE

Drug Info

[53]

UH-232

Drug Info

[55]

[2-(1H-Benzoimidazol-4-yloxy)-ethyl]-benzyl-amine

Drug Info

[32]

Agonist

[+] 6 Agonist drugs

CM-2395

Drug Info

[16]

ABT-724

Drug Info

[21]

A412997

Drug Info

[36]

CP-226269

Drug Info

[37]

FAUC213

Drug Info

[37]

PF-592379

Drug Info

[48]

Antagonist

[+] 17 Antagonist drugs

L-745,870

Drug Info

[17], [18]

NGD 94-1

Drug Info

[3], [20]

Lu-35138

Drug Info

[22]

PD-165167

Drug Info

[3]

Belaperidone

Drug Info

[3]

A-381393

Drug Info

[17], [18]

FAUC 113

Drug Info

[18]

L-750,667

Drug Info

[45]

ML398

Drug Info

[46]

nafadotride

Drug Info

[45]

piribedil

Drug Info

[50]

RBI257

Drug Info

[37]

Ro 10-4548

Drug Info

[37]

U101958

Drug Info

[54]

[125I]L750667

Drug Info

[56]

[3H]N-methylspiperone

Drug Info

[45]

[3H]spiperone

Drug Info

[57], [58]

Partial agonist

[+] 1 Partial agonist drugs

RP5063

Drug Info

[19]

Binder

[+] 3 Binder drugs

SPI-376

Drug Info

[3]

U-99363E

Drug Info

[3]

Sonepiprazole

Drug Info

[3]

Chemical Structure based Activity Landscape of Target

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Drug Property Profile of Target

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(1) Molecular Weight (mw) based Drug Clustering

(2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering

(3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering

(4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering

(5) Rotatable Bond Count (rotbonds) based Drug Clustering

(6) Topological Polar Surface Area (polararea) based Drug Clustering

"RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five

Co-Targets

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Co-Targets

Co-Targets Info

Target Poor or Non Binders

Top

Target Poor or Non Binders

Target Poor or Non Binders Info

Target Profiles in Patients

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Target Expression
Profile (TEP)

Target Expression Profile Info

Target Affiliated Biological Pathways

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KEGG Pathway

[+] 2 KEGG Pathways

Neuroactive ligand-receptor interaction

Dopaminergic synapse

Panther Pathway

[+] 4 Panther Pathways

Heterotrimeric G-protein signaling pathway-Gi alpha and Gs alpha mediated pathway

Heterotrimeric G-protein signaling pathway-Gq alpha and Go alpha mediated pathway

Dopamine receptor mediated signaling pathway

Nicotine pharmacodynamics pathway

Reactome

[+] 2 Reactome Pathways

Dopamine receptors

G alpha (i) signalling events

WikiPathways

[+] 8 WikiPathways

Hypothetical Network for Drug Addiction

Monoamine GPCRs

GPCRs, Class A Rhodopsin-like

Genes and (Common) Pathways Underlying Drug Addiction

GPCR ligand binding

GPCR downstream signaling

Nicotine Activity on Dopaminergic Neurons

GPCRs, Other

Target-Related Models and Studies

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Target Validation

Target Validation Info

References

Top

REF 1

Dopamine/serotonin receptor ligands. 9. Oxygen-containing midsized heterocyclic ring systems and nonrigidized analogues. A step toward dopamine D5 ... J Med Chem. 2004 Aug 12;47(17):4155-8.

REF 2

URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 38).

REF 3

The pipeline and future of drug development in schizophrenia. Mol Psychiatry. 2007 Oct;12(10):904-22.

REF 4

Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015

REF 5

Pharmaceutical Research Companies Are Developing More Than 300 Medicines to Treat Mental Illnesses. Pharmaceutical Research and Manufacturers of America report.2010.

REF 6

REF 7

ClinicalTrials.gov (NCT01490086) RP5063 in Subjects With Schizophrenia or Schizoaffective Disorder. U.S. National Institutes of Health.

REF 8

REF 9

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800019657)

REF 10

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800014237)

REF 11

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800008657)

REF 12

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800006596)

REF 13

REF 14

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800005975)

REF 15

Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.

REF 16

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800031127)

REF 17

Dopamine D4 receptor involvement in the discriminative stimulus effects in rats of LSD, but not the phenethylamine hallucinogen DOI. Psychopharmacology (Berl). 2009 Apr;203(2):265-77.

REF 18

Comparative molecular field analysis of dopamine D4 receptor antagonists including 3-[4-(4-chlorophenyl)piperazin-1-ylmethyl]pyrazolo[1,5-a]pyridine (FAUC 113), 3-[4-(4-chlorophenyl)piperazin-1-ylmethyl]-1H-pyrrolo-[2,3-b]pyridine (L-745,870), and clozapine. J Med Chem. 2001 Apr 12;44(8):1151-7.

REF 19

Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)

REF 20

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. 1997 Aug;282(2):1020-7.

REF 21

Activation of dopamine D4 receptors by ABT-724 induces penile erection in rats. Proc Natl Acad Sci U S A. 2004 April 27; 101(17): 6758-6763.

REF 22

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800014237)

REF 23

I. NGD 94-1: identification of a novel, high-affinity antagonist at the human dopamine D4 receptor. J Pharmacol Exp Ther. 1997 Aug;282(2):1011-9.

REF 24

Discovery of a new series of centrally active tricyclic isoxazoles combining serotonin (5-HT) reuptake inhibition with alpha2-adrenoceptor blocking... J Med Chem. 2005 Mar 24;48(6):2054-71.

REF 25

BIMG 80, a novel potential antipsychotic drug: evidence for multireceptor actions and preferential release of dopamine in prefrontal cortex. J Neurochem. 1997 Jul;69(1):182-90.

REF 26

Effects of YM-43611, a novel dopamine D2-like receptor antagonist, on immediate early gene expression in the rat forebrain. Neuropsychopharmacology. 1997 Jul;17(1):27-33.

REF 27

Synthetic studies and pharmacological evaluations on the MDMA ('Ecstasy') antagonist nantenine. Bioorg Med Chem Lett. 2010 Jan 15;20(2):628-31.

REF 28

Conjugated enynes as nonaromatic catechol bioisosteres: synthesis, binding experiments, and computational studies of novel dopamine receptor agonis... J Med Chem. 2000 Feb 24;43(4):756-62.

REF 29

Synthesis and biological investigations of dopaminergic partial agonists preferentially recognizing the D4 receptor subtype. Bioorg Med Chem Lett. 2006 Jun 1;16(11):2955-9.

REF 30

Piperidinylpyrroles: design, synthesis and binding properties of novel and selective dopamine D4 receptor ligands. Bioorg Med Chem Lett. 1999 Nov 1;9(21):3143-6.

REF 31

Affinity of 10-(4-methylpiperazino)dibenz[b,f]oxepins for clozapine and spiroperidol binding sites in rat brain. J Med Chem. 1982 Jul;25(7):855-8.

REF 32

New generation dopaminergic agents. 7. Heterocyclic bioisosteres that exploit the 3-OH-phenoxyethylamine D2 template. Bioorg Med Chem Lett. 1999 Sep 6;9(17):2593-8.

REF 33

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... J Med Chem. 1996 May 10;39(10):1941-2.

REF 34

New generation dopaminergic agents. 5. Heterocyclic bioisosteres that exploit the 3-OH-N1-phenylpiperazine dopaminergic template. Bioorg Med Chem Lett. 1998 Oct 6;8(19):2675-80.

REF 35

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 ago... J Med Chem. 2006 Dec 14;49(25):7450-65.

REF 36

A-412997 is a selective dopamine D4 receptor agonist in rats. Pharmacol Biochem Behav. 2005 Sep;82(1):140-7.

REF 37

Certain 1,4-disubstituted aromatic piperidines and piperazines with extreme selectivity for the dopamine D4 receptor interact with a common recepto... Mol Pharmacol. 2004 Dec;66(6):1491-9.

REF 38

REF 39

Effects of conformationally restricted 4-piperazinyl-10H-thienobenzodiazepine neuroleptics on central dopaminergic and cholinergic systems. J Med Chem. 1982 Oct;25(10):1133-40.

REF 40

Neuroleptic activity in 5-aryltetrahydro-gamma-carbolines. J Med Chem. 1980 Jun;23(6):635-43.

REF 41

Synthesis of clozapine analogues and their affinity for clozapine and spiroperidol binding sites in rat brain. J Med Chem. 1981 Sep;24(9):1021-6.

REF 42

(S)-(-)-4-[4-[2-(isochroman-1-yl)ethyl]-piperazin-1-yl] benzenesulfonamide, a selective dopamine D4 antagonist. J Med Chem. 1996 Jun 21;39(13):2435-7.

REF 43

Synthesis and characterization of selective dopamine D2 receptor antagonists. 2. Azaindole, benzofuran, and benzothiophene analogs of L-741,626. Bioorg Med Chem. 2010 Jul 15;18(14):5291-300.

REF 44

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. 1996 May 10;39(10):1943-5.

REF 45

Nonconserved residues in the second transmembrane-spanning domain of the D(4) dopamine receptor are molecular determinants of D(4)-selective pharmacology. Mol Pharmacol. 2000 Jan;57(1):144-52.

REF 46

Discovery and Characterization of ML398, a Potent and Selective Antagonist of the D4 Receptor with in Vivo Activity. ACS Med Chem Lett. 2014 Jul 9;5(9):1060-4.

REF 47

Novel D3 selective dopaminergics incorporating enyne units as nonaromatic catechol bioisosteres: synthesis, bioactivity, and mutagenesis studies. J Med Chem. 2008 Nov 13;51(21):6829-38.

REF 48

Lack of abuse potential in a highly selective dopamine D3 agonist, PF-592,379, in drug self-administration and drug discrimination in rats. Behav Pharmacol. 2012 Jun;23(3):280-91.

REF 49

Heterocyclic analogues of N-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butyl)arylcarboxamides with functionalized linking chains as novel dopamine D3... J Med Chem. 2007 Aug 23;50(17):4135-46.

REF 50

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 Ther. 2002 Nov;303(2):791-804.

REF 51

Pharmacophore-guided drug discovery investigations leading to bioactive 5-aminotetrahydropyrazolopyridines. Implications for the binding mode of he... J Med Chem. 2005 Sep 8;48(18):5771-9.

REF 52

Discovery of 3-aryl-3-methyl-1H-quinoline-2,4-diones as a new class of selective 5-HT6 receptor antagonists. Bioorg Med Chem Lett. 2008 Jan 15;18(2):738-43.

REF 53

Dibenzazecine scaffold rebuilding--is the flexibility always essential for high dopamine receptor affinities Bioorg Med Chem. 2009 Oct 1;17(19):6898-907.

REF 54

Substituted 4-aminopiperidines having high in vitro affinity and selectivity for the cloned human dopamine D4 receptor. Eur J Pharmacol. 1997 Mar 19;322(2-3):283-6.

REF 55

(Dipropylamino)-tetrahydronaphthofurans: centrally acting serotonin agonists and dopamine agonists-antagonists, Bioorg. Med. Chem. Lett. 7(21):2759-2764 (1997).

REF 56

Identification and pharmacological characterization of [125I]L-750,667, a novel radioligand for the dopamine D4 receptor. Mol Pharmacol. 1996 Dec;50(6):1658-64.

REF 57

Differential effects of [3H]nemonapride and [3H]spiperone binding on human dopamine D4 receptors. Neurosci Lett. 1995 Feb 17;186(2-3):145-8.

REF 58

Modeling the similarity and divergence of dopamine D2-like receptors and identification of validated ligand-receptor complexes. J Med Chem. 2005 Feb 10;48(3):694-709.

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