| Target
Information |
| Name | D(4) dopamine receptor |
| Type of target | Clinical trial target |
| Synonyms | D(2C)D(4) dopamine receptor dopamine receptor |
| Dopamine D4 receptor |
| Disease | Parkinson's disease
[ICD9: 332 ICD10: F02.3, G20] | [1] |
| Psychiatric illness | [2] |
| Respiratory diseases | [3] |
| Drug(s) | NGD 94-1 |  | Phase I | Schizophrenia | [4] |
| Belaperidone | | Discontinued | Schizophrenia | [4] |
| Sarizotan | | Discontinued in Phase II | Parkinson¡¯s Disease | [5] |
| Sonepiprazole | | Discontinued | Schizophrenia | [4] |
| HMR-2934 | | No development reported | Schizophrenia | [4] |
| PD-165167 | | Preclinical | Schizophrenia | [4] |
| SPI-376 | | Preclinical | Schizophrenia | [4] |
| U-99363E | | Preclinical | Schizophrenia | [4] |
| BioChemical Class | G-protein coupled receptor (rhodopsin family) |
| Pathway | Neuroactive ligand-receptor interaction |
| UniProt ID | P21917 |
| Function | This is one of the five types (D1 to D5) of receptors for dopamine, and the activity of this receptor is mediated by g proteins which activate adenylyl cyclase. |
| Sequence | MGNRSTADADGLLAGRGPAAGASAGASAGLAGQGAAALVGGVLLIGAVLAGNSLVCVSVA
TERALQTPTNSFIVSLAAADLLLALLVLPLFVYSEVQGGAWLLSPRLCDALMAMDVMLCT
ASIFNLCAISVDRFVAVAVPLRYNRQGGSRRQLLLIGATWLLSAAVAAPVLCGLNDVRGR
DPAVCRLEDRDYVVYSSVCSFFLPCPLMLLLYWATFRGLQRWEVARRAKLHGRAPRRPSG
PGPPSPTPPAPRLPQDPCGPDCAPPAPGLPRGPCGPDCAPAAPGLPPDPCGPDCAPPAPG
LPQDPCGPDCAPPAPGLPRGPCGPDCAPPAPGLPQDPCGPDCAPPAPGLPPDPCGSNCAP
PDAVRAAALPPQTPPQTRRRRRAKITGRERKAMRVLPVVVGAFLLCWTPFFVVHITQALC
PACSVPPRLVSAVTWLGYVNSALNPVIYTVFNAEFRNVFRKALRACC
|
| Related US Patent | 6,479,491 |
| Target Validation | Click to Find Target Validation Information. |
| Inhibitor | (+/-)-nantenine | | [6] |
| (-)3- | | [7] |
| (4-Ethynyl-cyclohex-3-enyl)-dipropyl-amine | | [8] |
| (4-Phenylethynyl-cyclohex-3-enyl)-dipropyl-amine | | [8] |
| 1- (4- | | [9] |
| 1-Benzyl-4- (2-ethynyl-pyrrol-1-yl)-piperidine | | [10] |
| 1-Benzyl-4- (2-iodo-pyrrol-1-yl)-piperidine | | [10] |
| 1-Benzyl-4- (2-oxazol-5-yl-pyrrol-1-yl)-piperidine | | [10] |
| 1-Benzyl-4- (3-oxazol-5-yl-pyrrol-1-yl)-piperidine | | [10] |
| 1-Benzyl-4-pyrrol-1-yl-piperidine | | [10] |
| 1-Dibenzo[b,f]oxepin-10-yl-4-methyl-piperazine | | [11] |
| 1-[2- (2-Benzyl-phenoxy)-ethyl]-piperidine | | [12] |
| 1-[2- (2-Benzyl-phenoxy)-ethyl]-pyrrolidine | | [12] |
| 1-[3- (2-Benzyl-phenoxy)-propyl]-pyrrolidine | | [12] |
| 3- (1-Propyl-piperidin-3-yl)-phenol | | [13] |
| 3- (2-Benzylamino-ethoxy)-phenol | | [14] |
| 3- (4-Methyl-piperidin-1-ylmethyl)-1H-indole | | [15] |
| 3- (4-Phenyl-piperazin-1-ylmethyl)-1H-indole | | [15] |
| 3- (4-Phenyl-piperidin-1-ylmethyl)-1H-indole | | [15] |
| 4- (2-Benzylamino-ethoxy)-1,3-dihydro-indol-2-one | | [14] |
| 4- (4-Benzyl-piperazin-1-yl)-1H-benzoimidazole | | [16] |
| 4- (4-Benzyl-piperazin-1-yl)-1H-indole | | [16] |
| 4- (4-Benzyl-piperazin-1-yl)-5-chloro-1H-indole | | [16] |
| 4- (4-Benzyl-piperazin-1-yl)-7-bromo-1H-indole | | [16] |
| 4-[2- (2-Benzyl-phenoxy)-ethyl]-morpholine | | [12] |
| A-425444 | | [17] |
| A-80426 | | [18] |
| ABT-670 | | [17] |
| BP-897 | | [19] |
| Benzyl-[2- (1H-indazol-4-yloxy)-ethyl]-amine | | [14] |
| Benzyl-[2- (1H-indol-4-yloxy)-ethyl]-amine | | [14] |
| DIHYDREXIDINE | | [20] |
| FLUMEZAPINE | | [21] |
| FLUTROLINE | | [22] |
| ISOCLOZAPINE | | [11] |
| ISOLOXAPINE | | [23] |
| JL-18, NCGC00094013-01 | | [24] |
| L-741626 | | [25] |
| L-741742 | | [26] |
| L-745870 | | [27] |
| N- (4-Dipropylaminobutyl)-4-biphenylcarboxamide | | [28] |
| N- (4-Propylaminobutyl)-4-biphenylcarboxamide | | [28] |
| PG-01037 | | [29] |
| Phenyltoloxamine | | [12] |
| QUINPIROLE | | [30] |
| SB-271046 | | [31] |
| SPIPERONE | | [32] |
| STEPHOLIDINE | | [20] |
| UH-232 | | [33] |
| [2- (1H-Benzoimidazol-4-yloxy)-ethyl]-benzyl-amine | | [14] |
| Agonist | Sarizotan | | [5] |
| Antagonist | A-381393 | | [34][35] |
| Belaperidone | | [4] |
| FAUC 113 | | [35] |
| HMR-2934 | | [4] |
| L-745,870 | | [34][35] |
| NGD 94-1 | | [4] |
| PD-165167 | | [4] |
| Binder | SPI-376 | | [4] |
| Sonepiprazole | | [4] |
| U-99363E | | [4] |
| Multitarget | HMR-2934 | | [4] |
| Sarizotan | | [5] |
| Cross References |
3D Structure
Related Literature
On-Line
Medical Dictionary |
| Ref 1 | Tolerance to some behavioural effects of lisuride, a dopamine receptor agonist, and reverse tolerance to others, after repeated administration. Neuropharmacology. 1985 Mar;24(3):199-206. To Reference |
| Ref 2 | Dopamine D4 receptors and development of newer antipsychotic drugs. Fundam Clin Pharmacol. 2000 Nov-Dec;14(6):529-39. To Reference |
| Ref 3 | Effect of dopamine receptor agonists on sensory nerve activity: possible therapeutic targets for the treatment of asthma and COPD. Br J Pharmacol. 2002 Jun;136(4):620-8. To Reference |
| Ref 4 | The pipeline and future of drug development in schizophrenia. Mol Psychiatry. 2007 Oct;12(10):904-22. Epub 2007 Jul 31. To Reference |
| Ref 5 | Drugs used to treat Parkinson's disease, present status and future directions. CNS Neurol Disord Drug Targets. 2008 Oct;7(4):321-42. To Reference |
| Ref 6 | 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. To Reference |
| Ref 7 | J Med Chem. 1993 Oct 15;36(21):3188-96.Substituted 3-phenylpiperidines: new centrally acting dopamine autoreceptor antagonists. To Reference |
| Ref 8 | 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. To Reference |
| Ref 9 | 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. To Reference |
| Ref 10 | 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. To Reference |
| Ref 11 | 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. To Reference |
| Ref 12 | 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. To Reference |
| Ref 13 | J Med Chem. 1988 Aug;31(8):1621-5.Dopamine autoreceptor agonists as potential antipsychotics. 1. (Aminoalkoxy)anilines. To Reference |
| Ref 14 | 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. To Reference |
| Ref 15 | 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. To Reference |
| Ref 16 | 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. To Reference |
| Ref 17 | 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. To Reference |
| Ref 18 | 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. To Reference |
| Ref 19 | J Med Chem. 2005 May 5;48(9):3171-81.Enantiomerically pure hexahydropyrazinoquinolines as potent and selective dopamine 3 subtype receptor ligands. To Reference |
| Ref 20 | 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? To Reference |
| Ref 21 | J Med Chem. 1982 Oct;25(10):1133-40.Effects of conformationally restricted 4-piperazinyl-10H-thienobenzodiazepine neuroleptics on central dopaminergic and cholinergic systems. To Reference |
| Ref 22 | J Med Chem. 1980 Jun;23(6):635-43.Neuroleptic activity in 5-aryltetrahydro-gamma-carbolines. To Reference |
| Ref 23 | 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. To Reference |
| Ref 24 | 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. To Reference |
| Ref 25 | Bioorg. Med. Chem. 18(14):5291-5300 (2010) To Reference |
| Ref 26 | 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. To Reference |
| Ref 27 | Bioorg Med Chem. 2009 Feb 15;17(4):1716-23. Epub 2008 Dec 31.Synthesis and evaluation of ligands for D2-like receptors: the role of common pharmacophoric groups. To Reference |
| Ref 28 | 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. To Reference |
| Ref 29 | 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. To Reference |
| Ref 30 | 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. To Reference |
| Ref 31 | 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. To Reference |
| Ref 32 | 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. To Reference |
| Ref 33 | Bioorg. Med. Chem. Lett. 7(21):2759-2764 (1997) To Reference |
| Ref 34 | 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. To Reference |
| Ref 35 | 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. To Reference |
