Design, synthesis and evaluation of bitopic arylpiperazinephenyl-1,2,4-oxadiazoles as preferential dopamine D3 receptor ligands

Cao, Yunxia; Min, Chengchun; Acharya, Srijan; Kim, Kyeong-Man; Cheon, Seung Hoon

doi:10.1016/j.bmc.2015.12.002

Cited by 17 publications

(11 citation statements)

References 17 publications

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“…To a solution of endo -NRB (1.0 g, 2.0 mmol) in DMF (6 ml) was added NaH (160 mg, 4.0 mmol, 60% w/w in oil), and the resulting mixture stirred at room temperature for 15 min, then at 80°C for a further 15 min A solution of 4-[( tert -butoxycarbonyl)amino]butyl methanesulfonate (Cao et al, 2016 ) (0.59 g, 2.2 mmol) in DMF (2 ml) was added, and the resulting mixture stirred at 100°C for 4 h. The reaction mixture was then allowed to cool, diluted with water and extracted with EtOAc. The separated organic phase was washed with brine, dried over anhydrous Na 2 SO 4 , filtered and the solvent removed in vacuo .…”

Section: Methodsmentioning

confidence: 99%

An NBD Derivative of the Selective Rat Toxicant Norbormide as a New Probe for Living Cell Imaging

et al. 2016

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Norbormide (NRB) is a unique compound that acts directly on rat vascular myocytes to trigger a contractile process, through an as yet unknown mechanism, which results in the selective contraction of rat peripheral arteries. To gain insight into the mechanisms involved in NRB rat-selective activity, we investigated the subcellular distribution of NRB-AF12, a nitrobenzoxadiazole (NBD)-derivative of NRB, in living NRB-sensitive and NRB-insensitive cells. In both cell types, NRB-AF12 localized to the endoplasmic reticulum (ER), Golgi apparatus, mitochondria, lysosomes, and endosomes; however, in NRB-sensitive cells, the fluorescence also extended to the plasma membrane. NRB-AF12 was rapidly internalized into the cells, could easily be washed out and then reloaded back into the same cells, all with a high degree of reproducibility. Cells exposed for 24 h to NRB-AF12 did not show apparent signs of toxicity, even at concentrations of the dye (10 μM) much higher than those required for fluorescence labeling (500 ηM). The distribution pattern of NRB-AF12 fluorescence was near identical to that of ER-Tracker® (Er-Tr), a fluorescent derivative of glibenclamide, a known KATP channel blocker. Displacement tests did not demonstrate, but at the same time did not rule out the possibility of a common target for ER-Tr, NRB-AF12, NRB, and glibenclamide. On the basis of these results we hypothesize a common target site for NRB-AF12 and ER-Tr, and a similar target profile for NRB and glibenclamide, and propose NRB-AF12 as an alternative fluorescence probe to ER-Tracker. Furthermore, NRB-based fluorescence derivatives could be designed to selectively label single cellular structures.

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Section: Methodsmentioning

confidence: 99%

An NBD Derivative of the Selective Rat Toxicant Norbormide as a New Probe for Living Cell Imaging

et al. 2016

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“…Starting with the phenylpiperazine derivative BP 897 (Pilla et al ., ), a number of original compounds with D3 receptor selectivity higher than 50‐fold were designed (Micheli & Heidbreder, ; Boeckler & Gmeiner, ). A patent survey indicates that, since 2005, 110 patents or patent applications have been published, which shows that this is still a very active research area today, in both academic and industrial laboratories (Cao et al ., ; Capet et al ., ; Micheli et al ., ,b; Sun et al ., ). The most representative compounds of this class are SB‐277011A (Reavill et al ., ; Stemp et al ., ), S33084 (Millan et al ., ,b), ABT‐925 (Gross et al ., ; Geneste et al ., ), GSK598809 (Searle et al ., ), and F17141 (Sokoloff et al ., ).…”

Section: D3 Receptors and Schizophreniamentioning

confidence: 97%

The dopamine D3 receptor, a quarter century later

Sokoloff¹,

Foll

2016

Eur J of Neuroscience

196

164

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This review updates the existing knowledge suggesting a role for the D3 receptor in schizophrenia and drug addiction. The D3 receptor is expressed in brain regions controlling reward, emotions, and motivation. Antipsychotics bind in vitro to the D3 receptor with similar affinity as to the D2 receptor, and occupancy of D3 receptors in vivo by these compounds given acutely at clinical dosage have been demonstrated in Positron Emission Tomography (PET) studies. The D3 receptor modulates glutamatergic pathways from the prefrontal cortex to subcortical areas, either directly by interacting with N-methyl-D-aspartate (NMDA) receptors in the nucleus accumbens, or indirectly by controlling dopamine release from ventral tegmental area neurons. In animals, D3 receptor antagonists reverse behavioral manifestations of NMDA receptor blockade and improve cognitive performances in various paradigms. Two D3 receptor-selective compounds have reached clinical trials in schizophrenia, with negative results seemingly due to insufficient target engagement; the results with a third compound, F17464, have not been disclosed yet. There is converging evidence that D3 receptors do not control the reinforcing effects of drugs of abuse (with the exception of alcohol under low requirement), but rather affects the motivation to take the drugs under high requirement, reactivity to drug-associated cues, and drug-seeking behaviors triggered by stimuli associated with relapse in humans. D3 receptor expression measured by PET is upregulated in humans with various drug addictions. A single administration of the D3 receptor-selective antagonist, GSK598809, in humans transiently alleviated craving in smokers after overnight abstinence. The clinical development of D3-selective compounds will benefit from initial assessment of target engagement through the use of PET.

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“…Unlike in D 3 R, the ECL1 in D 2 R is relatively short and thus cannot accommodate the allosteric pharmacophore of 11. 71 Moreover, the short ECL1 for D 2 R influences the orientation of transmembrane helix 2 unfavorably. 72 Vass et al reported a fragment based docking approach on D 3 R, which resulted in the synthesis of a new type of bitopic ligands (e.g., 12).…”

Section: ■ Bitopic Ligandsmentioning

confidence: 99%

“…In a molecular modeling study, 11 was docked into the D 3 R crystal structure and was found to bind in a bitopic mode . Several studies were performed to determine what induced the marked selectivity for D 3 R, ranging from computational methods to mutagenesis studies and functional assays with 11 fragments. − The size and shape of extracellular loop (ECL) 1 was found to be an important determinant for subtype selectivity. Unlike in D 3 R, the ECL1 in D 2 R is relatively short and thus cannot accommodate the allosteric pharmacophore of 11 .…”

Section: Bitopic Ligandsmentioning

confidence: 99%

Bitopic Ligands and Metastable Binding Sites: Opportunities for G Protein-Coupled Receptor (GPCR) Medicinal Chemistry

2017

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G protein-coupled receptors (GPCRs) belong to a large superfamily of membrane receptors mediating a variety of physiological functions. As such they are attractive targets for drug therapy. However, it remains a challenge to develop subtype selective GPCR ligands due to the high conservation of orthosteric binding sites. Bitopic ligands have been employed to address the selectivity problem by combining (linking) an orthosteric ligand with an allosteric modulator, theoretically leading to high-affinity subtype selective ligands. However, it remains a challenge to identify suitable allosteric binding sites. Computational studies on ligand binding to GPCRs have revealed transient, low-affinity binding sites, termed metastable binding sites. Metastable binding sites may provide a new source of allosteric binding sites that could be exploited in the design of bitopic ligands. Unlike the bitopic ligands that have been reported to date, this type of bitopic ligands would be composed of two identical pharmacophores. Herein, we outline the concept of bitopic ligands, review metastable binding sites, and discuss their potential as a new source of allosteric binding sites.

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Design, synthesis and evaluation of bitopic arylpiperazinephenyl-1,2,4-oxadiazoles as preferential dopamine D3 receptor ligands

Cited by 17 publications

References 17 publications

An NBD Derivative of the Selective Rat Toxicant Norbormide as a New Probe for Living Cell Imaging

An NBD Derivative of the Selective Rat Toxicant Norbormide as a New Probe for Living Cell Imaging

The dopamine D3 receptor, a quarter century later

Bitopic Ligands and Metastable Binding Sites: Opportunities for G Protein-Coupled Receptor (GPCR) Medicinal Chemistry

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