Target Validation Information
TTD ID T24983
Target Name Dopamine D4 receptor (D4R)
Type of Target
Successful
Drug Potency against Target PD-165167 Drug Info IC50 = 1.3 nM
Sarizotan Drug Info Ki = 2.4 nM [24]
(+/-)-nantenine Drug Info Ki = 262 nM [15]
(4-Ethynyl-cyclohex-3-enyl)-dipropyl-amine Drug Info Ki = 22 nM [3]
(4-Phenylethynyl-cyclohex-3-enyl)-dipropyl-amine Drug Info Ki = 16000 nM [3]
1-(4-(1H-pyrazol-1-yl)benzyl)-4-phenylpiperazine Drug Info Ki = 20 nM [9]
1-Benzyl-4-(2-ethynyl-pyrrol-1-yl)-piperidine Drug Info Ki = 940 nM [2]
1-Benzyl-4-(2-iodo-pyrrol-1-yl)-piperidine Drug Info Ki = 1500 nM [2]
1-Benzyl-4-(2-oxazol-5-yl-pyrrol-1-yl)-piperidine Drug Info Ki = 63 nM [2]
1-Benzyl-4-(3-oxazol-5-yl-pyrrol-1-yl)-piperidine Drug Info Ki = 130 nM [2]
1-Benzyl-4-pyrrol-1-yl-piperidine Drug Info Ki = 1100 nM [2]
1-Dibenzo[b,f]oxepin-10-yl-4-methyl-piperazine Drug Info IC50 = 1500 nM [18]
1-[2-(2-Benzyl-phenoxy)-ethyl]-piperidine Drug Info Ki = 4476 nM [4]
1-[2-(2-Benzyl-phenoxy)-ethyl]-pyrrolidine Drug Info Ki = 1428 nM [4]
1-[3-(2-Benzyl-phenoxy)-propyl]-pyrrolidine Drug Info Ki = 1261 nM [4]
3-(2-Benzylamino-ethoxy)-phenol Drug Info Ki = 80.6 nM [1]
3-(4-Methyl-piperidin-1-ylmethyl)-1H-indole Drug Info Ki = 570 nM [20]
3-(4-Phenyl-piperazin-1-ylmethyl)-1H-indole Drug Info Ki = 8 nM [20]
3-(4-Phenyl-piperidin-1-ylmethyl)-1H-indole Drug Info Ki = 25 nM [20]
4-(2-Benzylamino-ethoxy)-1,3-dihydro-indol-2-one Drug Info Ki = 10 nM [1]
4-(4-Benzyl-piperazin-1-yl)-1H-benzoimidazole Drug Info Ki = 47 nM [23]
4-(4-Benzyl-piperazin-1-yl)-1H-indole Drug Info Ki = 14.7 nM [23]
4-(4-Benzyl-piperazin-1-yl)-5-chloro-1H-indole Drug Info Ki = 1.7 nM [23]
4-(4-Benzyl-piperazin-1-yl)-7-bromo-1H-indole Drug Info Ki = 2.6 nM [23]
4-[2-(2-Benzyl-phenoxy)-ethyl]-morpholine Drug Info Ki = 6484 nM [4]
A-425444 Drug Info Ki = 17 nM [10]
A-80426 Drug Info Ki = 234 nM [6]
ABT-670 Drug Info Ki = 1445 nM [10]
Benzyl-[2-(1H-indazol-4-yloxy)-ethyl]-amine Drug Info Ki = 315.5 nM [1]
Benzyl-[2-(1H-indol-4-yloxy)-ethyl]-amine Drug Info Ki = 230.2 nM [1]
BP-897 Drug Info Ki = 162 nM [7]
FLUMEZAPINE Drug Info IC50 = 20 nM [17]
FLUTROLINE Drug Info IC50 = 14 nM [16]
ISOCLOZAPINE Drug Info IC50 = 758 nM [18]
ISOLOXAPINE Drug Info IC50 = 2480 nM [19]
JL-18 Drug Info Ki = 21 nM [22]
L-741626 Drug Info Ki = 449 nM
L-741742 Drug Info Ki = 3.5 nM [21]
N-(4-Dipropylaminobutyl)-4-biphenylcarboxamide Drug Info Ki = 1400 nM [13]
N-(4-Propylaminobutyl)-4-biphenylcarboxamide Drug Info Ki = 6100 nM [13]
PG-01037 Drug Info Ki = 375 nM [11]
Phenyltoloxamine Drug Info Ki = 2765 nM [4]
QUINPIROLE Drug Info Ki = 1.8 nM [8]
SB-271046 Drug Info Ki = 130 nM [12]
STEPHOLIDINE Drug Info Ki = 3748 nM [14]
UH-232 Drug Info Ki = 48 nM
[2-(1H-Benzoimidazol-4-yloxy)-ethyl]-benzyl-amine Drug Info Ki = 51.6 nM [1]
[3H]spiperone Drug Info Ki = 0.33 nM [5]
Action against Disease Model Sonepiprazole Drug Info U-101387 displayed moderately high affinity (Ki = 10 nM) and selectivity for the dopamine D4.2 receptor expressed in clonal cell lines. It fully and dose-dependently antagonizedquinpirole-induced cAMP inhibition (without producing any effect by itself) in stably transfected cells. U-101387 potently induced c-fos mRNA expression in the infralimbic/ventral prelimbic cortex toa level similar to that produced by the atypical antipsychotic, clozapine. [25]
References
REF 1 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 2 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 3 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 4 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 5 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.
REF 6 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 7 Enantiomerically pure hexahydropyrazinoquinolines as potent and selective dopamine 3 subtype receptor ligands. J Med Chem. 2005 May 5;48(9):3171-81.
REF 8 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 9 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 10 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 11 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 12 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 13 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 14 Dibenzazecine scaffold rebuilding--is the flexibility always essential for high dopamine receptor affinities Bioorg Med Chem. 2009 Oct 1;17(19):6898-907.
REF 15 Synthetic studies and pharmacological evaluations on the MDMA ('Ecstasy') antagonist nantenine. Bioorg Med Chem Lett. 2010 Jan 15;20(2):628-31.
REF 16 Neuroleptic activity in 5-aryltetrahydro-gamma-carbolines. J Med Chem. 1980 Jun;23(6):635-43.
REF 17 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 18 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 19 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 20 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 21 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 22 (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 23 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 24 Sarizotan, a serotonin 5-HT1A receptor agonist and dopamine receptor ligand. 1. Neurochemical profile. J Neural Transm (Vienna). 2004 Feb;111(2):113-26.
REF 25 Pharmacological characterization of U-101387, a dopamine D4 receptor selective antagonist. J Pharmacol Exp Ther. 1996 Dec;279(3):1392-403.

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