Identification of the dopamine autoreceptor in the guinea‐pig retina as D<sub>2</sub> receptor using novel subtype‐selective antagonists

Weber, Bernd; Schlicker, Eberhard; Sokoloff, Pierre; Stark, Holger

doi:10.1038/sj.bjp.0704192

Cited by 21 publications

(17 citation statements)

References 19 publications

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“…Substitution with electron donors on the aryl moiety of the 1,2,3,4-tetrahydroisoquinoline structure (16,18) led to slightly enhanced affinities for the D 3 receptor relative to that of compound 15 and a maintained preference for the D 3 receptor. In contrast, substitution with an electron-withdrawing nitro group (17) resulted in deteriorated affinity.…”

Section: Resultsmentioning

confidence: 96%

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Development of Novel 1,2,3,4‐Tetrahydroisoquinoline Derivatives and Closely Related Compounds as Potent and Selective Dopamine D₃ Receptor Ligands

et al. 2004

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Based on N-alkylated 1,2,3,4-tetrahydroisoquinoline derivatives, which are structurally related to the partial agonist BP 897, a series of novel, selective dopamine D3 receptor antagonists has been synthesised. Derivatisation included changes in the arylamide moiety and the tetrahydroisoquinoline substructure leading to compounds with markedly improved selectivities and affinities in the low nanomolar concentration range. From the 55 structures presented here, (E)-3-(4-iodophenyl)-N-(4-(1,2,3,4-tetrahydroisoquinolin-2-yl)butyl)acrylamide (51) has high affinity (Ki(hD3)=12 nM) and a 123-fold preference for the D3 receptor relative to the D2 receptor subtype. Its pharmacological profile offers the prospect of a novel radioligand as a tool for various dopamine D3-receptor-related in vitro and in vivo investigations.

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Section: Resultsmentioning

confidence: 96%

“…These compounds are suitable as pharmacological tools. [17,18] A new iodinated compound (51, ST 283) was developed and a convenient and facile method for its radiolabelling was applied. [23] Based on the lead structure 15…”

Section: Resultsmentioning

confidence: 99%

Development of Novel 1,2,3,4‐Tetrahydroisoquinoline Derivatives and Closely Related Compounds as Potent and Selective Dopamine D₃ Receptor Ligands

et al. 2004

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“…ST-148 is a D 2 dopamine receptor antagonist. Although there are no known effects of this compound on mitochondrial function, there is research indicating that antagonizing the dopamine receptors can result in mitochondrial toxicity 43 . ML-7 is a selective myosin light chain kinase inhibitor.…”

Section: Discussionmentioning

confidence: 99%

High-throughput respirometric assay identifies predictive toxicophore of mitochondrial injury

Wills¹,

Beeson²,

Trager³

et al. 2013

Toxicology and Applied Pharmacology

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Many environmental chemicals and drugs negatively affect human health through deleterious effects on mitochondrial function. Currently there is no chemical library of mitochondrial toxicants, and no reliable methods for predicting mitochondrial toxicity. We hypothesized that discrete toxicophores defined by distinct chemical entities can identify previously unidentified mitochondrial toxicants. We used a respirometric assay to screen 1760 compounds (5 μM) from the LOPAC and ChemBridge DIVERSet libraries. Thirty-one of the assayed compounds decreased uncoupled respiration, a stress test for mitochondrial dysfunction, prior to a decrease in cell viability and reduced the oxygen consumption rate in isolated mitochondria. The mitochondrial toxicants were grouped by chemical similarity and two clusters containing four compounds each were identified. Cheminformatic analysis of one of the clusters identified previously uncharacterized mitochondrial toxicants from the ChemBridge DIVERSet. This approach will enable the identification of mitochondrial toxicants and advance the prediction of mitochondrial toxicity for both drug discovery and risk assessment.

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“…Replacement of the naphthylamide residue of BP 897 by a cinnamoyl group and choosing 1,2,3,4-tetrahydroisoquinoline as basic residue has lead to the full antagonist ST 198 [10,11]. Antagonists also look promising in the treatment of Parkinson's disease and drug abuse [6,12,13].…”

Section: Introductionmentioning

confidence: 96%

N‐(4‐(4‐(2‐Halogenophenyl)piperazin‐1‐yl)butyl) Substituted Cinnamoyl Amide Derivatives as Dopamine D₂and D₃ Receptor Ligands

Saur

Hackling

Perachon

et al. 2007

Archiv der Pharmazie

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A series of eight substituted N-(4-(4-(2-halogenophenyl)piperazin-1-yl)butyl)-3-phenylacryl amide derivatives have been synthesized and screened for binding affinities at dopamine hD(2) and hD(3) receptors. All compounds have shown high to remarkable receptor affinities and some have led to distinct selectivity for D(3) receptors. Highest D(3)-receptor affinity has been observed for 3-(4-aminophenyl)-N-(4-(4-(2-fluorophenyl)piperazin-1-yl)butyl)acryl amide (hD(3) K(i) 0.9 nM; hD(2) K(i) 17.4 nM). Selectivity ratio has been best for 3-(4-chlorophenyl)-N-(4-(4-(2-fluorophenyl)piperazin-1-yl)butyl)acryl amide with a 56-fold preference for hD(3) versus hD(2). A functional activity test has been performed by a mitogenesis test for N-(4-(4-(2-fluorophenyl)piperazin-1-yl)butyl)-3,3-diphenylacryl amide, which, surprisingly, has shown full agonist properties.

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Identification of the dopamine autoreceptor in the guinea‐pig retina as D₂ receptor using novel subtype‐selective antagonists

Cited by 21 publications

References 19 publications

Development of Novel 1,2,3,4‐Tetrahydroisoquinoline Derivatives and Closely Related Compounds as Potent and Selective Dopamine D₃ Receptor Ligands

Development of Novel 1,2,3,4‐Tetrahydroisoquinoline Derivatives and Closely Related Compounds as Potent and Selective Dopamine D₃ Receptor Ligands

High-throughput respirometric assay identifies predictive toxicophore of mitochondrial injury

N‐(4‐(4‐(2‐Halogenophenyl)piperazin‐1‐yl)butyl) Substituted Cinnamoyl Amide Derivatives as Dopamine D₂and D₃ Receptor Ligands

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Identification of the dopamine autoreceptor in the guinea‐pig retina as D2 receptor using novel subtype‐selective antagonists

Cited by 21 publications

References 19 publications

Development of Novel 1,2,3,4‐Tetrahydroisoquinoline Derivatives and Closely Related Compounds as Potent and Selective Dopamine D3 Receptor Ligands

Development of Novel 1,2,3,4‐Tetrahydroisoquinoline Derivatives and Closely Related Compounds as Potent and Selective Dopamine D3 Receptor Ligands

High-throughput respirometric assay identifies predictive toxicophore of mitochondrial injury

N‐(4‐(4‐(2‐Halogenophenyl)piperazin‐1‐yl)butyl) Substituted Cinnamoyl Amide Derivatives as Dopamine D2 and D3 Receptor Ligands

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Identification of the dopamine autoreceptor in the guinea‐pig retina as D₂ receptor using novel subtype‐selective antagonists

Development of Novel 1,2,3,4‐Tetrahydroisoquinoline Derivatives and Closely Related Compounds as Potent and Selective Dopamine D₃ Receptor Ligands

Development of Novel 1,2,3,4‐Tetrahydroisoquinoline Derivatives and Closely Related Compounds as Potent and Selective Dopamine D₃ Receptor Ligands

N‐(4‐(4‐(2‐Halogenophenyl)piperazin‐1‐yl)butyl) Substituted Cinnamoyl Amide Derivatives as Dopamine D₂and D₃ Receptor Ligands