Target Information
Target General Infomation | |||||
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Target ID |
T24983
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Former ID |
TTDC00291
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Target Name |
D(4) dopamine receptor
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Gene Name |
DRD4
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Synonyms |
D(2C)D(4) dopamine receptor dopamine receptor; Dopamine D4 receptor; DRD4
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Target Type |
Successful
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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).
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BioChemical Class |
GPCR rhodopsin
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Target Validation |
T24983
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UniProt ID | |||||
Sequence |
MGNRSTADADGLLAGRGPAAGASAGASAGLAGQGAAALVGGVLLIGAVLAGNSLVCVSVA
TERALQTPTNSFIVSLAAADLLLALLVLPLFVYSEVQGGAWLLSPRLCDALMAMDVMLCT ASIFNLCAISVDRFVAVAVPLRYNRQGGSRRQLLLIGATWLLSAAVAAPVLCGLNDVRGR DPAVCRLEDRDYVVYSSVCSFFLPCPLMLLLYWATFRGLQRWEVARRAKLHGRAPRRPSG PGPPSPTPPAPRLPQDPCGPDCAPPAPGLPRGPCGPDCAPAAPGLPPDPCGPDCAPPAPG LPQDPCGPDCAPPAPGLPRGPCGPDCAPPAPGLPQDPCGPDCAPPAPGLPPDPCGSNCAP PDAVRAAALPPQTPPQTRRRRRAKITGRERKAMRVLPVVVGAFLLCWTPFFVVHITQALC PACSVPPRLVSAVTWLGYVNSALNPVIYTVFNAEFRNVFRKALRACC |
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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 | |||||
Ref 536463 | The pipeline and future of drug development in schizophrenia. Mol Psychiatry. 2007 Oct;12(10):904-22. Epub 2007 Jul 31. | ||||
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 546030 | 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 546043 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800006017) | ||||
Ref 546146 | 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 546508 | 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 547224 | 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 547821 | 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 525599 | Bioorg Med Chem Lett. 1999 Sep 6;9(17):2593-8.New generation dopaminergic agents. 7. Heterocyclic bioisosteres that exploit the 3-OH-phenoxyethylamine D2 template. | ||||
Ref 525629 | Bioorg 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 525665 | 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 525701 | J 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 526443 | 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 527160 | J 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 527225 | Certain 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 527420 | J 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 527481 | J 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 527714 | J 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 527731 | A-412997 is a selective dopamine D4 receptor agonist in rats. Pharmacol Biochem Behav. 2005 Sep;82(1):140-7. Epub 2005 Sep 8. | ||||
Ref 528099 | Bioorg 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 528561 | J 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 528974 | J 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 529191 | Bioorg 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 529734 | J 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 530374 | Bioorg 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 530558 | Bioorg 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 531866 | 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 532957 | 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 533512 | J Med Chem. 1980 Jun;23(6):635-43.Neuroleptic activity in 5-aryltetrahydro-gamma-carbolines. | ||||
Ref 533515 | J Med Chem. 1982 Oct;25(10):1133-40.Effects of conformationally restricted 4-piperazinyl-10H-thienobenzodiazepine neuroleptics on central dopaminergic and cholinergic systems. | ||||
Ref 533570 | J 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 533577 | J 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 533735 | 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 533938 | J Med Chem. 1993 Oct 15;36(21):3188-96.Substituted 3-phenylpiperidines: new centrally acting dopamine autoreceptor antagonists. | ||||
Ref 534131 | J 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 534132 | J 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 534146 | J 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 534293 | 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 534357 | 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 534408 | 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 534444 | 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 534445 | 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 534578 | Selective dopamine D4 receptor antagonists reverse apomorphine-induced blockade of prepulse inhibition. Psychopharmacology (Berl). 1998 Jan;135(2):194-200. | ||||
Ref 534802 | Bioorg 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 535158 | 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 536463 | The pipeline and future of drug development in schizophrenia. Mol Psychiatry. 2007 Oct;12(10):904-22. Epub 2007 Jul 31. | ||||
Ref 536766 | 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. 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 544413 | 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 547225 | 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 548980 | 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 551224 | 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. doi: 10.1016/j.bmc.2010.05.052. Epub 2010 May 24. |
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