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279 results on '"Abate, Carmen"'

54. Perspectives of Cannabinoid Type 2 Receptor (CB2R) Ligands in Neurodegenerative Disorders: Structure–Affinity Relationship (SAfiR) and Structure–Activity Relationship (SAR) Studies

Author

Spinelli, Francesco, Capparelli, Elena, Abate, Carmen, Colabufo, Nicola A., and Contino, Marialessandra

Abstract

Up-regulation of CB2R on activated microglial cells, the first step in neurodegeneration, has been widely demonstrated, and this finding makes the receptor a promising target in the early diagnosis and treatment of several neurodegenerative disorders such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and multiple sclerosis (MS). The development of CB2R PET ligands could help demonstrate the neurodegenerative pathogenesis, thus providing useful tools for characterizing the role of neuroinflammation in the progression of these disorders. CB2R agonists and inverse agonists have emerged as neuroprotective agents, and CB2R agonists have entered several clinical trials. CB2R ligands have therefore received great attention, and different molecular scaffolds have been selected to target CB2R subtypes. This review is focused on structure–activity relationship (SAR) and structure–affinity relationship (SAfiR) studies performed on different scaffolds with the aim to identify the molecular features useful for the design of both therapeutic and diagnostic agents.

Published
2024
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62. Novel Derivatives of 1-Cyclohexyl-4-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)propyl]piperazine (PB28) with Improved Fluorescent and σ Receptors Binding Properties

Author

Abate, Carmen, primary, Niso, Mauro, additional, Marottoli, Roberta, additional, Riganti, Chiara, additional, Ghigo, Dario, additional, Ferorelli, Savina, additional, Ossato, Giulia, additional, Perrone, Roberto, additional, Lacivita, Enza, additional, Lamb, Don C., additional, and Berardi, Francesco, additional

Published
2014
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63. Quantum Dot Based Luminescent Nanoprobes for Sigma-2 Receptor Imaging

Author

Pati, Maria Laura, Fanizza, Elisabetta, Hager, Sonja, Groza, Diana, Heffeter, Petra, Laurenza, Amelita Grazia, Laquintana, Valentino, Curri, Maria Lucia, Depalo, Nicoletta, Abate, Carmen, and Denora, Nunzio

Abstract

The increasing importance of sigma-2 receptor as target for the diagnosis and therapy of tumors paves the way for the development of innovative optically traceable fluorescent probes as tumor cell contrast and therapeutic agents. Here, a novel hybrid organic–inorganic nanostructure is developed by combining the superior fluorescent properties of inorganic quantum dots (QDs), coated with a hydrophilic silica shell (QD@SiO2NPs), the versatility of the silica shell, and the high selectivity for sigma-2 receptor of the two synthetic ligands, namely, the 6-[(6-aminohexyl)oxy]-2-(3-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)propyl)-3,4-dihydroisoquinolin-1(2H)-one (MLP66) and 6-[1-[3-(4-cyclohexylpiperazin-1-yl)propyl]-1,2,3,4-tetrahydronaphthalen-5-yloxy]hexylamine (TA6). The proposed nanostructures represent a challenging alternative to all previously studied organic small fluorescent molecules, based on the same sigma-2 receptor affinity moieties. Flow cytometry and confocal fluorescence microscopy experiments, respectively, on fixed and living cancerous MCF7 cells, which overexpress the sigma-2 receptor, prove the ability of functionalized (QD@SiO2-TA6 and QD@SiO2-MLP66) NPs to be internalized and demonstrate their affinity to the sigma-2 receptor, ultimately validating the targeting properties conveyed to the NPs by sigma-2 ligand conjugation. The presented QD-based nanoprobes possess a great potential as in vitroselective sigma-2 receptor imaging agent and, consequently, could provide a significant impact to future theranostic applications.

Published
2018
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73. The σ1receptor agonist (+)-pentazocine increases store-operated Ca2+entry in MCF7σ1and SK-N-SH cell lines

Author

Gasparre, Giuseppe, Abate, Carmen, Carlucci, Roberto, Berardi, Francesco, and Cassano, Giuseppe

Abstract

The intracellular [Ca2+] is modulated by σ receptors. An important component of the cellular machinery governing the intracellular [Ca2+] is Store-Operated Calcium Entry (SOCE). Here we want to investigate whether ligands of σ receptors affect SOCE.

Published
2017
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74. The s1receptor agonist (+)-pentazocine increases store-operated Ca2+entry in MCF7s1and SK-N-SH cell lines

Author

Gasparre, Giuseppe, Abate, Carmen, Carlucci, Roberto, Berardi, Francesco, and Cassano, Giuseppe

Abstract

Background: The intracellular [Ca2+] is modulated by s receptors. An important component of the cellular machinery governing the intracellular [Ca2+] is Store-Operated Calcium Entry (SOCE). Here we want to investigate whether ligands of s receptors affect SOCE. Methods: The intracellular [Ca2+] was monitored, with the fluorescent Ca2+-sensitive probe Fura-2, in four cell lines with a different expression of s receptors, namely MCF7 (expressing s1receptors with a low density and overexpressing s2receptors), MCF7s1(overexpressing s1receptors), SK-N-SH, and HT-29. Results: When thapsigargin was used to deplete intracellular Ca2+stores, in a Ca2+-free incubation medium, the Ca2+influx (following Ca2+re-addition) was significantly increased by 1 µM (+)-pentazocine (s1receptor agonist) in MCF7s1(by 22.5%) and SK-N-SH (by 45.6%), but not in HT-29 and MCF7 cells. We have used, as a second approach, the “Mn2+quenching” protocol. In MCF7s1cells, after thapsigargin treatment, the fluorescence quenching induced by Mn2+influx (evidence of Ca2+influx) was significantly increased (by 25.8%) by 1 µM (+)-pentazocine, significantly decreased (by 18.0%) by BD1063 (s1receptor antagonist), and not affected by the presence of both ligands. These effects were not observed in MCF7 cells. Finally, in MCF7 cells, 1 µM PB28 (s2receptor agonist), did not affect both the Ca2+response after Ca2+re-addition and the fluorescence quenching induced by Mn2+influx. Conclusions: We propose that the s1receptor agonist (+)-pentazocine increases SOCE in MCF7s1and SK-N-SH cell lines. The s2receptor agonist PB28 does not affect SOCE in MCF7 cells.

Published
2017
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94. Novel Derivatives of 1-Cyclohexyl-4-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)propyl]piperazine(PB28) with Improved Fluorescent and σ Receptors Binding Properties.

Author

Abate, Carmen, Niso, Mauro, Marottoli, Roberta, Riganti, Chiara, Ghigo, Dario, Ferorelli, Savina, Ossato, Giulia, Perrone, Roberto, Lacivita, Enza, Lamb, Don C., and Berardi, Francesco

Subjects
*PIPERAZINE, *CANCER treatment, *CANCER diagnosis, *FLUORIMETRY, *LIGAND binding (Biochemistry), *FLOW cytometry
Abstract

Despite the promising potentialsof σ2receptorsin cancer therapy and diagnosis, there are still ambiguities relatedto the nature and physiological role of the σ2protein.With the aim of providing potent and reliable tools to be used inσ2receptor research, we developed a novel seriesof fluorescent σ2ligands on the basis of our previouswork, where high-affinity σ2ligand 1-cyclohexyl-4-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)-n-propyl]piperazine (1, PB28) was used as thepharmacophore. Compared to the previous compounds, these novel ligandsdisplayed improved fluorescence and σ2binding properties,were σ2-specifically taken up by breast tumor cells,and were successfully employed in confocal microscopy. Compound 14, which was the best compromise between pharmacologicaland fluorescent properties, was successfully employed in flow cytometry,demonstrating its potential to be used as a tool in nonradioactivebinding assays for studying the affinity of putative σ2receptor ligands. [ABSTRACT FROM AUTHOR]

Published
2014
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96. Development of 3,4-dihydroisoquinolin-1(2H)-one derivatives for the Positron Emission Tomography (PET) imaging of σ2 receptors.

Author

Abate, Carmen, Selivanova, Svetlana V., Müller, Adrienne, Krämer, Stefanie D., Schibli, Roger, Marottoli, Roberta, Perrone, Roberto, Berardi, Francesco, Niso, Mauro, and Ametamey, Simon M.

Subjects
*QUINOLINE derivatives, *ISOQUINOLINE, *POSITRON emission tomography, *BIOMARKERS, *CANCER diagnosis, *CANCER cell proliferation, *BLOOD-brain barrier, *PROGESTERONE receptors
Abstract

Abstract: σ2 Receptors are promising biomarkers for cancer diagnosis given the relationship between the proliferative status of tumors and their density. With the aim of contributing to the research of σ2 receptor Positron Emission Tomography (PET) probes, we developed 2-[3-[6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl]propyl]-3,4-dihydroisoquinolin-1(2H)-one (3), with optimal σ2 pharmacological properties and appropriate lipophilicity. Hence, 3 served as the lead compound for the development of a series of dihydroisoquinolinones amenable to radiolabeling. Radiosynthesis for compound 26, which displayed the most appropriate σ2 profile, was developed and σ2 specific binding for the corresponding [18F]-26 was confirmed by in vitro autoradiography on rat brain slices. Despite the excellent in vitro properties, [18F]-26 could not successfully image σ2 receptors in the rat brain in vivo, maybe because of its interaction with P-gp. Nevertheless, [18F]-26 may still be worthy of further investigation for the imaging of σ2 receptors in peripheral tumors devoid of P-gp overexpression. [Copyright &y& Elsevier]

Published
2013
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98. The sigma-1 receptor antagonist PB212 reduces the Ca2+-release through the inositol (1, 4, 5)-trisphosphate receptor in SK-N-SH cells

Author

Gasparre, Giuseppe, Abate, Carmen, Berardi, Francesco, and Cassano, Giuseppe

Subjects
*CALCIUM ions, *INOSITOL, *NEUROBLASTOMA, *INOSITOL trisphosphate receptors, *ENDOPLASMIC reticulum, *MITOCHONDRIA, *GENETIC regulation, *INTRACELLULAR calcium, *RADIOLIGAND assay
Abstract

Abstract: Sigma-1 receptors are specifically located at the endoplasmic reticulum–mitochondrion interface, but upon stimulation by ligands or under prolonged cellular stress, they translocate to other areas of the cell. Sigma-1 receptors are involved in the regulation of intracellular [Ca2+] by affecting the Ca2+-influx or the release from intracellular stores. In SK-N-SH cells, we measured the affinity of 4-methyl-1-[4-(6-methoxynaphthalen-1-yl)butyl]piperidine (PB212) at sigma-1 receptor by using a competition binding assay with specific radioligand; we obtained a K i value=316±19nM. PB212 also showed an antiproliferative effect in SK-N-SH cells (EC50 =32±4μM) but had no effect in MCF7 cells, which only express sigma-2 receptor; these findings suggest that PB212 behaves as a sigma-1 receptor antagonist. We have studied the effect of PB212 on Ca2+ homeostasis of the SK-N-SH cell line with the fluorescent probe Fura-2. 100μM PB212 induced a Ca2+-efflux from the endoplasmic reticulum through the inositol (1, 4, 5)-trisphosphate (IP3) receptor. Moreover, [PB212] ranging from 1 to 100μM reduced the Ca2+-response, triggered by carbachol or bradykinin that engage the phospholipase C/IP3 pathway; such a response is generally increased by sigma-1 receptor agonists. On the other hand, PB212 did not reduce the Ca2+-response mediated by IP3 in LoVo cells, which do not express neither sigma-1 nor sigma-2 receptors, and in MCF7 cells. The fact that the activity of the sigma-1 receptor can be experimentally modulated by agonists and antagonists supports the intriguing hypothesis that some endogenous molecules, unknown at the moment, modulate the sigma-1 receptor and its cellular targets. [Copyright &y& Elsevier]

Published
2012
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99. Synthesis and binding assays of novel 3,3-dimethylpiperidine derivatives with various lipophilicities as σ1 receptor ligands

Author

Ferorelli, Savina, Abate, Carmen, Pedone, Maria P., Colabufo, Nicola A., Contino, Marialessandra, Perrone, Roberto, and Berardi, Francesco

Subjects
*ORGANIC synthesis, *PIPERIDINE, *RADIOLIGAND assay, *ISOMERASES, *DRUG lipophilicity, *CARBOCYCLIC acids, *LIGANDS (Biochemistry)
Abstract

Abstract: Starting from two carbocyclic analogs, a series of 3,3-dimethylpiperidine derivatives was prepared and tested in radioligand binding assays at σ1 and σ2 receptors, and at Δ8–Δ7 sterol isomerase (SI) site. The novel compounds mostly bear heterocyclic rings or bicyclic nucleus of differing lipophilicities. Compounds 18a and 19a,b demonstrated the highest σ1 affinity (Ki =0.14–0.38nM) with a good selectivity versus σ2 binding. Among them, 18a had the lowest C log D value (3.01) and only 19b was selective versus SI too. Generally, it was observed that more planar and hydrophilic heteronuclei conferred a decrease in affinity for both σ receptor subtypes. [Copyright &y& Elsevier]

Published
2011
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100. Arylamides hybrids of two high-affinity σ2 receptor ligands as tools for the development of PET radiotracers

Author

Abate, Carmen, Ferorelli, Savina, Contino, Marialessandra, Marottoli, Roberta, Colabufo, Nicola Antonio, Perrone, Roberto, and Berardi, Francesco

Subjects
*CANCER diagnosis, *AMIDES, *LIGANDS (Biochemistry), *RADIOACTIVE tracers, *POSITRON emission tomography, *PIPERAZINE, *ISOQUINOLINE, *ENDOPLASMIC reticulum, *P-glycoprotein
Abstract

Abstract: 1-Cyclohexyl-4-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)propyl]piperazine 1 (PB28) and 2-Methoxy-5-methyl-N-[4-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)butyl]benzamide 2 (RHM-1) represent leads for tumor diagnosis, given their high affinity at σ2 receptors. With the purpose of obtaining good candidates for σ2 PET tracers development, hybrid structures between 1 and 2 were designed. Excellent σ1/σ2 selectivities were reached when 6,7-dimethoxytetrahydroisoquinoline was linked to an o-methoxy substituted arylamide (11a, 12a, 15a), and for these benzamides an intramolecular H-bond in the active conformation at the σ sites, was hypothesized. However these excellent σ2 ligands were accompanied by interaction with P-gp, which may limit their use as σ2 receptor PET agents when tumors overexpress P-gp. Compound 15a whose P-gp interaction was just moderate represents an interesting tool for the development of σ2 PET tracers useful in tumors overexpressing P-gp. [Copyright &y& Elsevier]

Published
2011
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