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
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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.
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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 525599Bioorg 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.
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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 533512J Med Chem. 1980 Jun;23(6):635-43.Neuroleptic activity in 5-aryltetrahydro-gamma-carbolines.
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Ref 533938J Med Chem. 1993 Oct 15;36(21):3188-96.Substituted 3-phenylpiperidines: new centrally acting dopamine autoreceptor antagonists.
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 525599Bioorg 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 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 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.
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