Target Information

Target General Infomation
Target ID
T24983
Former ID
TTDC00291
Target Name
D(4) dopamine receptor
Gene Name
DRD4
Synonyms
D(2C)D(4) dopamine receptor dopamine receptor; Dopamine D4 receptor; DRD4
Target Type
Successful
Disease Allergy [ICD9: 995.3; ICD10: T78.4]
Erectile dysfunction [ICD9: 302.72, 607.84; ICD10: F52.2, N48.4]
Psychotic disorders [ICD9: 290-299; ICD10: F20-F29]
Schizophrenia [ICD9: 295; ICD10: F20]
Sexual dysfunction [ICD9: 302.7; ICD10: F52]
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 (By similarity).
BioChemical Class
GPCR rhodopsin
Target Validation
T24983
UniProt ID
P21917
Sequence
MGNRSTADADGLLAGRGPAAGASAGASAGLAGQGAAALVGGVLLIGAVLAGNSLVCVSVA
TERALQTPTNSFIVSLAAADLLLALLVLPLFVYSEVQGGAWLLSPRLCDALMAMDVMLCT
ASIFNLCAISVDRFVAVAVPLRYNRQGGSRRQLLLIGATWLLSAAVAAPVLCGLNDVRGR
DPAVCRLEDRDYVVYSSVCSFFLPCPLMLLLYWATFRGLQRWEVARRAKLHGRAPRRPSG
PGPPSPTPPAPRLPQDPCGPDCAPPAPGLPRGPCGPDCAPAAPGLPPDPCGPDCAPPAPG
LPQDPCGPDCAPPAPGLPRGPCGPDCAPPAPGLPQDPCGPDCAPPAPGLPPDPCGSNCAP
PDAVRAAALPPQTPPQTRRRRRAKITGRERKAMRVLPVVVGAFLLCWTPFFVVHITQALC
PACSVPPRLVSAVTWLGYVNSALNPVIYTVFNAEFRNVFRKALRACC
Drugs and Mode of Action
Drug(s) Clozapine Drug Info Approved Schizophrenia [536463], [540514]
Phenyltoloxamine Drug Info Approved Allergy [551871]
CM-2395 Drug Info Phase 3 Schizophrenia [551513]
Intranasal apomorphine Drug Info Phase 2 Sexual dysfunction [527086]
L-745,870 Drug Info Phase 2 Psychotic disorders [540265]
NGD 94-1 Drug Info Phase 1 Schizophrenia [536463], [543342]
PD-165167 Drug Info Preclinical Schizophrenia [536463]
SPI-376 Drug Info Preclinical Schizophrenia [536463]
U-99363E Drug Info Preclinical Schizophrenia [536463]
ABT-724 Drug Info Discontinued in Phase 2 Erectile dysfunction [547821]
Lu-35138 Drug Info Discontinued in Phase 2 Psychotic disorders [547224]
NGD-94-4 Drug Info Discontinued in Phase 1 Schizophrenia [546508]
A-80426 Drug Info Terminated Discovery agent [546043]
Belaperidone Drug Info Terminated Schizophrenia [536463]
BIMG80 Drug Info Terminated Psychotic disorders [546146]
HMR-2934 Drug Info Terminated Schizophrenia [536463]
Sonepiprazole Drug Info Terminated Schizophrenia [536463], [543344]
YM-43611 Drug Info Terminated Psychotic disorders [546030]
Inhibitor (+)-3-(1-Propyl-piperidin-3-yl)-phenol Drug Info [533938]
(+/-)-nantenine Drug Info [530558]
(4-Ethynyl-cyclohex-3-enyl)-dipropyl-amine Drug Info [525701]
(4-Phenylethynyl-cyclohex-3-enyl)-dipropyl-amine Drug Info [525701]
1-(4-(1H-pyrazol-1-yl)benzyl)-4-phenylpiperazine Drug Info [528099]
1-Benzyl-4-(2-ethynyl-pyrrol-1-yl)-piperidine Drug Info [525629]
1-Benzyl-4-(2-iodo-pyrrol-1-yl)-piperidine Drug Info [525629]
1-Benzyl-4-(2-oxazol-5-yl-pyrrol-1-yl)-piperidine Drug Info [525629]
1-Benzyl-4-(3-oxazol-5-yl-pyrrol-1-yl)-piperidine Drug Info [525629]
1-Benzyl-4-pyrrol-1-yl-piperidine Drug Info [525629]
1-Dibenzo[b,f]oxepin-10-yl-4-methyl-piperazine Drug Info [533570]
1-[2-(2-Benzyl-phenoxy)-ethyl]-piperidine Drug Info [527160]
1-[2-(2-Benzyl-phenoxy)-ethyl]-pyrrolidine Drug Info [527160]
1-[3-(2-Benzyl-phenoxy)-propyl]-pyrrolidine Drug Info [527160]
3-(2-Benzylamino-ethoxy)-phenol Drug Info [525599]
3-(4-Methyl-piperidin-1-ylmethyl)-1H-indole Drug Info [534131]
3-(4-Phenyl-piperazin-1-ylmethyl)-1H-indole Drug Info [534131]
3-(4-Phenyl-piperidin-1-ylmethyl)-1H-indole Drug Info [534131]
4-(2-Benzylamino-ethoxy)-1,3-dihydro-indol-2-one Drug Info [525599]
4-(4-Benzyl-piperazin-1-yl)-1H-benzoimidazole Drug Info [534802]
4-(4-Benzyl-piperazin-1-yl)-1H-indole Drug Info [534802]
4-(4-Benzyl-piperazin-1-yl)-5-chloro-1H-indole Drug Info [534802]
4-(4-Benzyl-piperazin-1-yl)-7-bromo-1H-indole Drug Info [534802]
4-[2-(2-Benzyl-phenoxy)-ethyl]-morpholine Drug Info [527160]
A-425444 Drug Info [528561]
A-80426 Drug Info [527481]
ABT-670 Drug Info [528561]
Benzyl-[2-(1H-indazol-4-yloxy)-ethyl]-amine Drug Info [525599]
Benzyl-[2-(1H-indol-4-yloxy)-ethyl]-amine Drug Info [525599]
FLUMEZAPINE Drug Info [533515]
FLUTROLINE Drug Info [533512]
ISOCLOZAPINE Drug Info [533570]
ISOLOXAPINE Drug Info [533577]
JL-18 Drug Info [534146]
L-741626 Drug Info [551224]
L-741742 Drug Info [534132]
N-(4-Dipropylaminobutyl)-4-biphenylcarboxamide Drug Info [529734]
N-(4-Propylaminobutyl)-4-biphenylcarboxamide Drug Info [529734]
PG-01037 Drug Info [528974]
Phenyltoloxamine Drug Info [527160]
QUINPIROLE Drug Info [527714]
SB-271046 Drug Info [529191]
SPIPERONE Drug Info [527420]
STEPHOLIDINE Drug Info [530374]
UH-232 Drug Info [551330]
[2-(1H-Benzoimidazol-4-yloxy)-ethyl]-benzyl-amine Drug Info [525599]
Antagonist A-381393 Drug Info [535158], [536766]
Belaperidone Drug Info [536463]
FAUC 113 Drug Info [535158]
HMR-2934 Drug Info [536463]
L-745,870 Drug Info [535158], [536766]
L-750,667 Drug Info [525665]
Lu-35138 Drug Info [547225]
ML398 Drug Info [532957]
nafadotride Drug Info [525665]
NGD 94-1 Drug Info [536463]
PD-165167 Drug Info [536463]
piribedil Drug Info [526443]
RBI257 Drug Info [527225]
Ro 10-4548 Drug Info [527225]
U101958 Drug Info [534357]
[125I]L750667 Drug Info [534293]
[3H]N-methylspiperone Drug Info [525665]
[3H]NGD941 Drug Info [534445]
[3H]spiperone Drug Info [533735]
Agonist A412997 Drug Info [527731]
ABT-724 Drug Info [544413]
CM-2395 Drug Info [548980]
CP-226269 Drug Info [527225]
FAUC213 Drug Info [527225]
Intranasal apomorphine Drug Info [534578]
PF-592379 Drug Info [531866]
Modulator BIMG80 Drug Info [534408]
Clozapine Drug Info [556264]
E-1455 Drug Info [543567]
NGD-94-4 Drug Info [534444]
TKP-1002 Drug Info [543567]
YM-43611 Drug Info
Binder Sonepiprazole Drug Info [536463]
SPI-376 Drug Info [536463]
U-99363E Drug Info [536463]
Target Expression Profile (TEP) and Drug Resistance Mutation (DRM)
TEP EXP Info
Pathways
KEGG Pathway Neuroactive ligand-receptor interaction
Dopaminergic synapse
PANTHER Pathway 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 Dopamine receptors
G alpha (i) signalling events
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
References
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Ref 540265(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: 3303).
Ref 540514(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 543342(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: 979).
Ref 543344(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: 980).
Ref 546030Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800005975)
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Ref 547821Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800019657)
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Ref 525629Bioorg Med Chem Lett. 1999 Nov 1;9(21):3143-6.Piperidinylpyrroles: design, synthesis and binding properties of novel and selective dopamine D4 receptor ligands.
Ref 525665Nonconserved 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 525701J Med Chem. 2000 Feb 24;43(4):756-62.Conjugated enynes as nonaromatic catechol bioisosteres: synthesis, binding experiments, and computational studies of novel dopamine receptor agonists recognizing preferentially the D(3) subtype.
Ref 526443Differential 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 527160J Med Chem. 2004 Aug 12;47(17):4155-8.Dopamine/serotonin receptor ligands. 9. Oxygen-containing midsized heterocyclic ring systems and nonrigidized analogues. A step toward dopamine D5 receptor selectivity.
Ref 527225Certain 1,4-disubstituted aromatic piperidines and piperazines with extreme selectivity for the dopamine D4 receptor interact with a common receptor microdomain. Mol Pharmacol. 2004 Dec;66(6):1491-9.Epub 2004 Sep 24.
Ref 527420J Med Chem. 2005 Feb 10;48(3):694-709.Modeling the similarity and divergence of dopamine D2-like receptors and identification of validated ligand-receptor complexes.
Ref 527481J Med Chem. 2005 Mar 24;48(6):2054-71.Discovery of a new series of centrally active tricyclic isoxazoles combining serotonin (5-HT) reuptake inhibition with alpha2-adrenoceptor blocking activity.
Ref 527714J Med Chem. 2005 Sep 8;48(18):5771-9.Pharmacophore-guided drug discovery investigations leading to bioactive 5-aminotetrahydropyrazolopyridines. Implications for the binding mode of heterocyclic dopamine D3 receptor agonists.
Ref 527731A-412997 is a selective dopamine D4 receptor agonist in rats. Pharmacol Biochem Behav. 2005 Sep;82(1):140-7. Epub 2005 Sep 8.
Ref 528099Bioorg Med Chem Lett. 2006 Jun 1;16(11):2955-9. Epub 2006 Mar 24.Synthesis and biological investigations of dopaminergic partial agonists preferentially recognizing the D4 receptor subtype.
Ref 528561J Med Chem. 2006 Dec 14;49(25):7450-65.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.
Ref 528974J Med Chem. 2007 Aug 23;50(17):4135-46. Epub 2007 Aug 2.Heterocyclic analogues of N-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butyl)arylcarboxamides with functionalized linking chains as novel dopamine D3 receptor ligands: potential substance abuse therapeutic agents.
Ref 529191Bioorg Med Chem Lett. 2008 Jan 15;18(2):738-43. Epub 2007 Nov 17.Discovery of 3-aryl-3-methyl-1H-quinoline-2,4-diones as a new class of selective 5-HT6 receptor antagonists.
Ref 529734J Med Chem. 2008 Nov 13;51(21):6829-38. Epub 2008 Oct 4.Novel D3 selective dopaminergics incorporating enyne units as nonaromatic catechol bioisosteres: synthesis, bioactivity, and mutagenesis studies.
Ref 530374Bioorg Med Chem. 2009 Oct 1;17(19):6898-907. Epub 2009 Aug 20.Dibenzazecine scaffold rebuilding--is the flexibility always essential for high dopamine receptor affinities?.
Ref 530558Bioorg Med Chem Lett. 2010 Jan 15;20(2):628-31. Epub 2009 Nov 20.Synthetic studies and pharmacological evaluations on the MDMA ('Ecstasy') antagonist nantenine.
Ref 531866Lack 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 532957Discovery 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 533512J Med Chem. 1980 Jun;23(6):635-43.Neuroleptic activity in 5-aryltetrahydro-gamma-carbolines.
Ref 533515J Med Chem. 1982 Oct;25(10):1133-40.Effects of conformationally restricted 4-piperazinyl-10H-thienobenzodiazepine neuroleptics on central dopaminergic and cholinergic systems.
Ref 533570J Med Chem. 1982 Jul;25(7):855-8.Affinity of 10-(4-methylpiperazino)dibenz[b,f]oxepins for clozapine and spiroperidol binding sites in rat brain.
Ref 533577J Med Chem. 1981 Sep;24(9):1021-6.Synthesis of clozapine analogues and their affinity for clozapine and spiroperidol binding sites in rat brain.
Ref 533735Differential effects of [3H]nemonapride and [3H]spiperone binding on human dopamine D4 receptors. Neurosci Lett. 1995 Feb 17;186(2-3):145-8.
Ref 533938J Med Chem. 1993 Oct 15;36(21):3188-96.Substituted 3-phenylpiperidines: new centrally acting dopamine autoreceptor antagonists.
Ref 534131J Med Chem. 1996 May 10;39(10):1941-2.3-((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.
Ref 534132J Med Chem. 1996 May 10;39(10):1943-5.5-(4-Chlorophenyl)-4-methyl-3-(1-(2-phenylethyl)piperidin-4-yl)isoxazole: a potent, selective antagonist at human cloned dopamine D4 receptors.
Ref 534146J Med Chem. 1996 Jun 21;39(13):2435-7.(S)-(-)-4-[4-[2-(isochroman-1-yl)ethyl]-piperazin-1-yl] benzenesulfonamide, a selective dopamine D4 antagonist.
Ref 534293Identification 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 534357Substituted 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 534408BIMG 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 534444I. 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 534445II. 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 534578Selective dopamine D4 receptor antagonists reverse apomorphine-induced blockade of prepulse inhibition. Psychopharmacology (Berl). 1998 Jan;135(2):194-200.
Ref 534802Bioorg Med Chem Lett. 1998 Oct 6;8(19):2675-80.New generation dopaminergic agents. 5. Heterocyclic bioisosteres that exploit the 3-OH-N1-phenylpiperazine dopaminergic template.
Ref 535158Comparative 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 536463The pipeline and future of drug development in schizophrenia. Mol Psychiatry. 2007 Oct;12(10):904-22. Epub 2007 Jul 31.
Ref 536766Dopamine 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. Epub 2008 Jul 6.
Ref 543567(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. (Target id: 217).
Ref 544413Activation 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 547225Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800014237)
Ref 548980Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800031127)
Ref 551224Synthesis 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. doi: 10.1016/j.bmc.2010.05.052. Epub 2010 May 24.
Ref 551330(Dipropylamino)-tetrahydronaphthofurans: centrally acting serotonin agonists and dopamine agonists-antagonists, Bioorg. Med. Chem. Lett. 7(21):2759-2764 (1997).
Ref 556264Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.

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