Target Validation Information | |||||
---|---|---|---|---|---|
Target ID | T24983 | ||||
Target Name | D(4) dopamine receptor | ||||
Target Type | Successful |
||||
Drug Potency against Target | ABT-670 | Drug Info | Ki = 1445 nM | [528561] | |
(+/-)-nantenine | Drug Info | Ki = 262 nM | [530558] | ||
PD-165167 | Drug Info | IC50 = 1.3 nM | |||
JL-18 | Drug Info | Ki = 21 nM | [534146] | ||
FLUMEZAPINE | Drug Info | IC50 = 20 nM | [533515] | ||
STEPHOLIDINE | Drug Info | Ki = 3748 nM | [530374] | ||
Phenyltoloxamine | Drug Info | Ki = 2765 nM | [527160] | ||
1-[3-(2-Benzyl-phenoxy)-propyl]-pyrrolidine | Drug Info | Ki = 1261 nM | [527160] | ||
N-(4-Dipropylaminobutyl)-4-biphenylcarboxamide | Drug Info | Ki = 1400 nM | [529734] | ||
Sarizotan | Drug Info | Ki = 2.4 nM | [552412] | ||
A-80426 | Drug Info | Ki = 234 nM | [527481] | ||
PG-01037 | Drug Info | Ki = 375 nM | [528974] | ||
BP-897 | Drug Info | Ki = 162 nM | [527534] | ||
A-425444 | Drug Info | Ki = 17 nM | [528561] | ||
N-(4-Propylaminobutyl)-4-biphenylcarboxamide | Drug Info | Ki = 6100 nM | [529734] | ||
4-(4-Benzyl-piperazin-1-yl)-5-chloro-1H-indole | Drug Info | Ki = 1.7 nM | [534802] | ||
SPIPERONE | Drug Info | Ki = 0.33 nM | [527420] | ||
4-(2-Benzylamino-ethoxy)-1,3-dihydro-indol-2-one | Drug Info | Ki = 10 nM | [525599] | ||
4-(4-Benzyl-piperazin-1-yl)-7-bromo-1H-indole | Drug Info | Ki = 2.6 nM | [534802] | ||
[2-(1H-Benzoimidazol-4-yloxy)-ethyl]-benzyl-amine | Drug Info | Ki = 51.6 nM | [525599] | ||
1-[2-(2-Benzyl-phenoxy)-ethyl]-piperidine | Drug Info | Ki = 4476 nM | [527160] | ||
L-741742 | Drug Info | Ki = 3.5 nM | [534132] | ||
4-[2-(2-Benzyl-phenoxy)-ethyl]-morpholine | Drug Info | Ki = 6484 nM | [527160] | ||
3-(4-Methyl-piperidin-1-ylmethyl)-1H-indole | Drug Info | Ki = 570 nM | [534131] | ||
1-Benzyl-4-pyrrol-1-yl-piperidine | Drug Info | Ki = 1100 nM | [525629] | ||
3-(2-Benzylamino-ethoxy)-phenol | Drug Info | Ki = 80.6 nM | [525599] | ||
1-Benzyl-4-(3-oxazol-5-yl-pyrrol-1-yl)-piperidine | Drug Info | Ki = 130 nM | [525629] | ||
Benzyl-[2-(1H-indazol-4-yloxy)-ethyl]-amine | Drug Info | Ki = 315.5 nM | [525599] | ||
1-(4-(1H-pyrazol-1-yl)benzyl)-4-phenylpiperazine | Drug Info | Ki = 20 nM | [528099] | ||
1-Benzyl-4-(2-iodo-pyrrol-1-yl)-piperidine | Drug Info | Ki = 1500 nM | [525629] | ||
ISOLOXAPINE | Drug Info | IC50 = 2480 nM | [533577] | ||
UH-232 | Drug Info | Ki = 48 nM | |||
FLUTROLINE | Drug Info | IC50 = 14 nM | [533512] | ||
4-(4-Benzyl-piperazin-1-yl)-1H-indole | Drug Info | Ki = 14.7 nM | [534802] | ||
SB-271046 | Drug Info | Ki = 130 nM | [529191] | ||
ISOCLOZAPINE | Drug Info | IC50 = 758 nM | [533570] | ||
(+)-3-(1-Propyl-piperidin-3-yl)-phenol | Drug Info | Ki = 130 nM | [533938] | ||
(4-Phenylethynyl-cyclohex-3-enyl)-dipropyl-amine | Drug Info | Ki = 16000 nM | [525701] | ||
Benzyl-[2-(1H-indol-4-yloxy)-ethyl]-amine | Drug Info | Ki = 230.2 nM | [525599] | ||
3-(4-Phenyl-piperazin-1-ylmethyl)-1H-indole | Drug Info | Ki = 8 nM | [534131] | ||
3-(4-Phenyl-piperidin-1-ylmethyl)-1H-indole | Drug Info | Ki = 25 nM | [534131] | ||
1-[2-(2-Benzyl-phenoxy)-ethyl]-pyrrolidine | Drug Info | Ki = 1428 nM | [527160] | ||
1-Benzyl-4-(2-oxazol-5-yl-pyrrol-1-yl)-piperidine | Drug Info | Ki = 63 nM | [525629] | ||
4-(4-Benzyl-piperazin-1-yl)-1H-benzoimidazole | Drug Info | Ki = 47 nM | [534802] | ||
1-Dibenzo[b,f]oxepin-10-yl-4-methyl-piperazine | Drug Info | IC50 = 1500 nM | [533570] | ||
(4-Ethynyl-cyclohex-3-enyl)-dipropyl-amine | Drug Info | Ki = 22 nM | [525701] | ||
1-Benzyl-4-(2-ethynyl-pyrrol-1-yl)-piperidine | Drug Info | Ki = 940 nM | [525629] | ||
QUINPIROLE | Drug Info | Ki = 1.8 nM | [527714] | ||
L-741626 | Drug Info | Ki = 449 nM | |||
Action against Disease Model | Sonepiprazole | 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. | [553244] | Drug Info | |
The Effect of Target Knockout, Knockdown or Genetic Variations | The 5-choice continuous performance test (5C-CPT) in mice offers the opportunity to assess vigilance and two forms of impulsivity. Since reduced dopamine D4 receptor (DRD4) function is implicated in several disorders, DRD4 is a potential therapeutic target for cognition enhancement. We trained wildtype (WT), heterozygous (HT), and knockout (KO) mice of the murine Drd4 to perform the 5C-CPT under baseline and variable stimulus duration conditions. To dissect motor impulsivity (premature responding) from behavioral disinhibition (false alarms), we administered the 5-HT(2C)antagonist SB242084 during an extended inter-trial-interval session. We also examined the preattentive and exploratory profile of these mice in prepulse inhibition (PPI) and the Behavioral Pattern Monitor (BPM). Reduced Drd4 expression in HT mice, as confirmed by quantitative RT-PCR, resulted in response disinhibition and impaired 5C-CPT performance, while premature responding was unaffected. Conversely, SB242084 increased premature responding without affecting response inhibition or attentional measures. No genotypic differences were observed in PPI or BPM behavior. Thus, reduced Drd4 expression impairs attentional performance, but not other behaviors associated with neuropsychiatric disorders. | [553244] | |||
References | |||||
Ref 553244 | Pharmacological characterization of U-101387, a dopamine D4 receptor selective antagonist. J Pharmacol Exp Ther. 1996 Dec;279(3):1392-403. | ||||
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 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 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 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 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 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 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 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 552412 | Sarizotan, a serotonin 5-HT1A receptor agonist and dopamine receptor ligand. 1. Neurochemical profile. J Neural Transm (Vienna). 2004 Feb;111(2):113-26. Epub 2003 Dec 31. | ||||
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 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 527534 | J Med Chem. 2005 May 5;48(9):3171-81.Enantiomerically pure hexahydropyrazinoquinolines as potent and selective dopamine 3 subtype receptor ligands. | ||||
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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 533512 | J Med Chem. 1980 Jun;23(6):635-43.Neuroleptic activity in 5-aryltetrahydro-gamma-carbolines. | ||||
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 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 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 533938 | J Med Chem. 1993 Oct 15;36(21):3188-96.Substituted 3-phenylpiperidines: new centrally acting dopamine autoreceptor antagonists. | ||||
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 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 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 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 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 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 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 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 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 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 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. |
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