Development of molecular tools based on the dopamine D3 receptor ligand FAUC 329 showing inhibiting effects on drug and food maintained behavior

Stößel, Anne; Brox, Regine; Purkayastha, Nirupam; Hübner, Harald; Hocke, Carsten; Prante, Olaf; Gmeiner, Peter

doi:10.1016/j.bmc.2017.04.036

Cited by 9 publications

(6 citation statements)

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“…Synthesis of the dansyl-labeled ligands started from the secondary amines N -propyl-2,3-dihydro-1 H -inden-2-amine, 2,3-dichlorophenylpiperazine, 2-methoxyphenylpiperazine or 2-( tert -butyl)-4-(piperazin-1-yl)-6-(trifluoromethyl)pyrimidine (Fig. 1 , building blocks A–D), that were reacted with 6-chlorohex-1-yne in a nucleophilic displacement reaction in analogy to previously described protocols 39 , 40 . The resulting terminal alkynes 1a - d were subjected to a copper(I)-catalyzed azide-alkyne cycloaddition with 4-azido-benzonitrile 14 , 41 , giving access to the 1,4-disubstituted triazoles 2a - d in excellent yield.…”

Section: Resultsmentioning

confidence: 99%

Fluorescent ligands for dopamine D2/D3 receptors

Allikalt

Purkayastha

Flad

et al. 2020

Sci Rep

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Fluorescent ligands are versatile tools for the study of G protein-coupled receptors. Depending on the fluorophore, they can be used for a range of different applications, including fluorescence microscopy and bioluminescence or fluorescence resonance energy transfer (BRET or FRET) assays. Starting from phenylpiperazines and indanylamines, privileged scaffolds for dopamine D2-like receptors, we developed dansyl-labeled fluorescent ligands that are well accommodated in the binding pockets of D2 and D3 receptors. These receptors are the target proteins for the therapy for several neurologic and psychiatric disorders, including Parkinson’s disease and schizophrenia. The dansyl-labeled ligands exhibit binding affinities up to 0.44 nM and 0.29 nM at D2R and D3R, respectively. When the dansyl label was exchanged for sterically more demanding xanthene or cyanine dyes, fluorescent ligands 10a-c retained excellent binding properties and, as expected from their indanylamine pharmacophore, acted as agonists at D2R. While the Cy3B-labeled ligand 10b was used to visualize D2R and D3R on the surface of living cells by total internal reflection microscopy, ligand 10a comprising a rhodamine label showed excellent properties in a NanoBRET binding assay at D3R.

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Section: Resultsmentioning

confidence: 99%

Fluorescent ligands for dopamine D2/D3 receptors

Allikalt

Purkayastha

Flad

et al. 2020

Sci Rep

Self Cite

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“…However, in vivo PET imaging revealed that it does not significantly accumulate in the CNS structures of rat brains, probably due to a low BBB penetration. Instead, a significant uptake occurred in the brain ventricular system, due to a significant penetration of this compound in the blood-liquor barrier and, more noticeable, in the pituitary gland, outside the BBB [53]. The results of PET studies also suggest that the main mode of action of FAUC 329, in vivo, could be due to binding to the dopamine receptors in the pituitary gland.…”

Section: Dopamine Receptors Ligandsmentioning

confidence: 93%

“…These results demonstrate that [ 18 F]FAUC F41 (24) represents a potential radioligand for studying the D4R in vivo by PET imaging. (Figure 10) [53]. In vitro AGR studies showed that 26 successfully visualized D3-rich brain regions, including the islands of Calleja.…”

Section: Dopamine Receptors Ligandsmentioning

confidence: 96%

“…Biodistribution and radiopharmacological studies with male Wistar rats revealed promising brain uptakes and low in vivo radiodefluorinations in comparison with other PET radioligands for brain GRs [55]. (Figure 10) [53]. In vitro AGR studies showed that 26 successfully visualized D 3 -rich brain regions, including the islands of Calleja.…”

Section: Glucocorticoid Receptor Ligandsmentioning

confidence: 99%

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Pyrazoles as Key Scaffolds for the Development of Fluorine-18-Labeled Radiotracers for Positron Emission Tomography (PET)

Gomes

Silva

2020

Molecules

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The need for increasingly personalized medicine solutions (precision medicine) and quality medical treatments, has led to a growing demand and research for image-guided therapeutic solutions. Positron emission tomography (PET) is a powerful imaging technique that can be established using complementary imaging systems and selective imaging agents—chemical probes or radiotracers—which are drugs labeled with a radionuclide, also called radiopharmaceuticals. PET has two complementary purposes: selective imaging for diagnosis and monitoring of disease progression and response to treatment. The development of selective imaging agents is a growing research area, with a high number of diverse drugs, labeled with different radionuclides, being reported nowadays. This review article is focused on the use of pyrazoles as suitable scaffolds for the development of 18F-labeled radiotracers for PET imaging. A brief introduction to PET and pyrazoles, as key scaffolds in medicinal chemistry, is presented, followed by a description of the most important [18F]pyrazole-derived radiotracers (PET tracers) that have been developed in the last 20 years for selective PET imaging, grouped according to their specific targets.

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“…Additionally, the Ki values were required to differ at least by a factor of two. D 2 like-selective compounds showed binding affinities ≤500 nM at D 2 R and D 3 R. The final datasets consisting of 29 (SC1-SC29 [46-60]), 25 (SC30-SC54 [53,[61][62][63][64][65][66][67][68][69][70][71][72]), 152 (SC55-SC206 [56,69,) and 78 (SC207-SC284 [53,56,62,63,65,66,79,87,89,96,[99][100][101][103][104][105][106][107][108][109][110][111][112][113][114][115][116][117][118]) molecules, respectively, are shown in Tables S1-S4.…”

Section: Dataset Assembly For Molecular Docking (Chembl Validation)mentioning

confidence: 99%

Dopamine Receptor Ligand Selectivity—An In Silico/In Vitro Insight

et al. 2023

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Different dopamine receptor (DR) subtypes are involved in pathophysiological conditions such as Parkinson’s Disease (PD), schizophrenia and depression. While many DR-targeting drugs have been approved by the U.S. Food and Drug Administration (FDA), only a very small number are truly selective for one of the DR subtypes. Additionally, most of them show promiscuous activity at related G-protein coupled receptors, thus suffering from diverse side-effect profiles. Multiple studies have shown that combined in silico/in vitro approaches are a valuable contribution to drug discovery processes. They can also be applied to divulge the mechanisms behind ligand selectivity. In this study, novel DR ligands were investigated in vitro to assess binding affinities at different DR subtypes. Thus, nine D2R/D3R-selective ligands (micro- to nanomolar binding affinities, D3R-selective profile) were successfully identified. The most promising ligand exerted nanomolar D3R activity (Ki = 2.3 nM) with 263.7-fold D2R/D3R selectivity. Subsequently, ligand selectivity was rationalized in silico based on ligand interaction with a secondary binding pocket, supporting the selectivity data determined in vitro. The developed workflow and identified ligands could aid in the further understanding of the structural motifs responsible for DR subtype selectivity, thus benefitting drug development in D2R/D3R-associated pathologies such as PD.

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Development of molecular tools based on the dopamine D3 receptor ligand FAUC 329 showing inhibiting effects on drug and food maintained behavior

Cited by 9 publications

References 50 publications

Fluorescent ligands for dopamine D2/D3 receptors

Fluorescent ligands for dopamine D2/D3 receptors

Pyrazoles as Key Scaffolds for the Development of Fluorine-18-Labeled Radiotracers for Positron Emission Tomography (PET)

Dopamine Receptor Ligand Selectivity—An In Silico/In Vitro Insight

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