Rosaria Volpini

University of Camerino, Camerino, The Marches, Italy

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Publications (140)366.22 Total impact

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    ABSTRACT: A new series of 5-methyl-thiazolo[5,4-d]pyrimidine-7-ones bearing different substituents at position 2 (aryl, heteroaryl and arylamino groups) was synthesized and evaluated in radioligand binding assays to determine their affinities at the human (h) A1, A2A, and A3 adenosine receptors (ARs). Efficacy at the hA2B and antagonism of selected ligands at the hA3 were also assessed through cAMP experiments. Some of the new derivatives exhibited good to high hA3AR affinity and selectivity versus all the other AR subtypes. Compound 2-(4-chlorophenyl)-5-methyl-thiazolo[5,4-d]pyrimidine-7-one 4 was found to be the most potent and selective ligand of the series (Ki hA3 = 18 nM). Molecular docking studies of the reported derivatives were carried out to depict their hypothetical binding mode in our hA3 receptor model. Copyright © 2015 Elsevier Masson SAS. All rights reserved.
    European Journal of Medicinal Chemistry 05/2015; 96. DOI:10.1016/j.ejmech.2015.04.010 · 3.43 Impact Factor
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    ABSTRACT: The glutamate metabotropic receptor 5 (mGluR5) and the adenosine A2A receptor (A2 A R) represent major non-dopaminergic therapeutic targets in Parkinson's disease (PD) to improve motor symptoms and slow down/revert disease progression. The 6-hydroxydopamine rat model of PD was used to determine/compare the neuroprotective and behavioral impacts of single and combined administration of one mGluR5 antagonist, 2-methyl-6-(phenylethynyl)pyridine (MPEP) and two A2 A R antagonists, (E)-phosphoric acid mono-[3-[8-[2-(3-methoxyphenyl)vinyl]-7-methyl-2,6-dioxo-1-prop-2-ynyl-1,2,6,7-tetrahydropurin-3-yl]propyl] (MSX-3) and 8-ethoxy-9-ethyladenine (ANR 94). Chronic treatment with MPEP or MSX3 alone, but not with ANR94, reduced the toxin-induced loss of dopaminergic neurons in the substantia nigra pars compacta. Combining MSX-3 and MPEP further improved the neuroprotective effect of either antagonist. At the behavioral level, ANR 94 and MSX-3 given alone significantly potentiated L-DOPA-induced turning behavior. Combination of either A2 A R antagonist with MPEP synergistically increased L-DOPA-induced turning. This effect was dose-dependent and required subthreshold drug concentration, which per se had no motor stimulating effect. Our findings suggest that co-treatment with A2 A R and mGluR5 antagonists provides better therapeutic benefits than those produced by either drug alone. Our study sheds some light on the efficacy and advantages of combined non-dopaminergic PD treatment using low drug concentration and establishes the basis for in-depth studies to identify optimal doses at which these drugs reach highest efficacy. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Journal of Neurochemistry 05/2015; DOI:10.1111/jnc.13162 · 4.24 Impact Factor
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    ABSTRACT: A new series of 9-propyladenines bearing a phenylalkylamino group in 2- or a phenylalkyl chain in N6–position, and further substituted with a bromine atom or a 2-furyl ring in 8-position, were synthesized and tested at human adenosine receptors. The novel compounds proved to be A2A adenosine receptors antagonists and some of them showed high A2A affinity, but moderate selectivity (18: KiA2A = 6.6 nM). Molecular modeling studies gave some explanation of the different activities of the compounds, giving suggestions for the synthesis of new A2A adenosine receptor antagonists.
    Medicinal Chemistry Communication 04/2015; 6(5). DOI:10.1039/C5MD00034C · 2.63 Impact Factor
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    ABSTRACT: The purinergic P2X receptors are ligand-gated cation channels activated by the endogenous ligand ATP. They assemble as homo- or heterotrimers from seven cloned subtypes (P2X1-7) and all trimer subunits present a common topology consisting in intracellular N- and C- termini, two transmembrane domains and a large extracellular domain. These membrane proteins are present in virtually all mammalian tissues and regulate a large variety of responses in physio- and pathological conditions. The development of ligands that selectively activate or block specific P2X receptor subtypes hence represents a promising strategy to obtain novel pharmacological tools for the treatment of pain, cancer, inflammation, and neurological, cardiovascular, and endocrine diseases. The publication of the crystal structures of zebrafish P2X4 receptor in inactive and ATP-bound active forms provided structural data for the analysis of the receptor structure, the interpretation of mutagenesis data, and the depiction of ligand binding and receptor activation mechanism. In addition, the availability of ATP-competitive ligands presenting selectivity for P2X receptor subtypes supports the design of new potent and selective ligands with possibly improved pharmacokinetic profiles, with the final aim to obtain new drugs. This study describes molecular modelling studies performed to develop structural models of the human and rat P2X receptors in inactive and active states. These models allowed to analyse the role of some non-conserved residues at ATP binding site and to study the receptor interaction with some non-specific or subtype selective agonists and antagonists.
    European Journal of Medicinal Chemistry 01/2015; 89. DOI:10.1016/j.ejmech.2014.10.071 · 3.43 Impact Factor
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    ABSTRACT: Export Date: 27 July 2015
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    ABSTRACT: In this work, we have highlighted data reported in literature trying to draw a complete picture of the structures and biological activity of agonists andorthosteric antagonists of P2X receptors. Actually, only few P2X receptor agonists have been found and most of them are derived from modification of the natural ligand ATP and, are P2X receptor subtype unselective. In particular, BzATP (9) is one of the most potent P2X receptor agonist with EC50value in the nanomolarrange at some subtypes.Differently fromagonists, P2X receptor antagonists belong to different chemical classes such as high molecular weight aryl polysulfonate molecules like suramin and its simplified derivatives and anthraquinone compounds. All these molecules resulted non selective at P2X receptors, and they are endowed with micromolar activity and not favourable pharmacokinetic properties due to the presence of highlyseveral charged groups. Also modification of the natural ligand ATP led to the discovery of P2X receptor antagonists like TNP-ATP (29), which, although not selective, showed high potency at P2X1, P2X3 (IC50 of 0.006 µM and 0.001 µM, respectively), and heteromeric P2X2/3 receptors. Also the dinucleotide inosine polyphosphate Ip5I (33) was found to be a potent and selective antagonist at P2X1 vs P2X3receptors with IC50 = 0.003 µM. A big improvement has been gained from the interest of pharmaceutical companies that in the last years discovered, through the use of high-throughput screening, potent and selective antagonists endowed with novel structures, some of which currently in clinical trials for several therapeutic applications.
    Current Medicinal Chemistry 12/2014; 22(7). DOI:10.2174/0929867321666141215093513 · 3.85 Impact Factor
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    ABSTRACT: Objectives We investigated the effects of novel selective and non-selective adenosine receptor agonists (ARs) on cardioprotection.Methods Male rabbits divided into six groups were subjected to 30-min heart ischaemia and 3-h reperfusion: (1) control group, (2) postconditioning (PostC) group, (3) group A: treated with the non-selective agonist (S)-PHPNECA, (4) group B: treated with the A1 agonist CCPA, (5) group C: treated with the A2A agonist VT 7 and (6) group D: treated with the A3 agonist AR 170. The infarcted (I) and the areas at risk (R) were estimated as %I/R. In additional rabbits of all groups, heart samples were taken for determination of Akt, eNOS and STAT 3 at the 10th reperfusion minute.Key findings(S)-PHPNECA and CCPA reduced the infarct size (17.2 ± 2.9% and 17.9 ± 2.0% vs 46.8 ± 1.9% in control, P < 0.05), conferring a benefit similar to PostC (26.4 ± 0.3%). Selective A2A and A3 receptor agonists did not reduce the infarct size (39.5 ± 0.8% and 38.7 ± 3.5%, P = NS vs control). Akt, eNOS and STAT 3 were significantly activated after non-selective A1 ARs and PostC.Conclusions Non-selective and A1 but not A2A and A3 ARs agonists are essential for triggering cardioprotection. The molecular mechanism involves both RISK and the JAK/STAT pathways.
    05/2014; DOI:10.1111/jphp.12238
  • European Neuropsychopharmacology 03/2014; 24:S23. DOI:10.1016/S0924-977X(14)70026-4 · 5.40 Impact Factor
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    ABSTRACT: A2B receptor agonists are studied as possible therapeutic tools for a variety of pathological conditions. Unfortunately, medicinal chemistry efforts have led to the development of a limited number of potent agonists of this receptor, in most cases with a low or no selectivity versus the other adenosine receptor subtypes. Among the developed molecules, two structural families of compounds have been identified based on nucleoside and non-nucleoside (pyridine) scaffolds. The aim of this work is to analyse the binding mode of these molecules at 3D models of the human A2B receptor to identify possible common interaction features and the key receptor residues involved in ligand interaction. The A2B receptor models are built by using two recently published crystal structures of the human A2A receptor in complex with two different agonists. The developed models are used as targets for molecular docking studies of nucleoside and non-nucleoside agonists. The generated docking conformations are subjected to energy minimization and rescoring by using three different scoring functions. Further analysis of top-score conformations are performed with a tool evaluating the interaction energy between the ligand and the binding site residues. Results suggest a set of common interaction points between the two structural families of agonists and the receptor binding site, as evidenced by the superimposition of docking conformations and by analysis of interaction energy with the receptor residues. The obtained results show that there is a conserved pattern of interaction between the A2B receptor and its agonists. These information and can provide useful data to support the design and the development of A2B receptor agonists belonging to nucleoside or non-nucleoside structural families.
    12/2013; 1(1):24. DOI:10.1186/2193-9616-1-24
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    ABSTRACT: A3 Adenosine receptors are promising drug targets for a number of diseases and intense efforts are dedicated to develop selective agonists and antagonists of these receptors. A series of adenosine derivatives with 2-(ar)-alkynyl chains, with high affinity and different degrees of selectivity for human A3 Adenosine receptors was tested for the ability to inhibit forskolin-stimulated adenylyl cyclase. All these derivatives are partial agonists at A3 Adenosine receptors; their efficacy is not significantly modified by the introduction of small alkyl substituents in the N(6)-position. In contrast, the adenosine-5'-N-ethyluronamide (NECA) analogues of 2-(ar)-alkynyladenosine derivatives are full A3 agonists. Molecular modeling analyses were performed considering both the conformational behavior of the ligands and the impact of 2- and 5'-substituents on ligand-target interaction. The results suggest an explanation for the different agonistic behavior of adenosine and NECA derivatives, respectively. A sub-pocket of the binding site was analyzed as a crucial interaction domain for receptor activation.
    Biochemical pharmacology 10/2013; 87(2). DOI:10.1016/j.bcp.2013.10.011 · 4.65 Impact Factor
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    ABSTRACT: Selective adenosine receptor modulators are potential tools for numerous therapeutic applications, including cardiovascular, inflammatory, and neurodegenerative diseases. In this work, the synthesis and biological evaluation at the four human adenosine receptor subtypes of a series of 9-substituted 8-(2-furyl)adenine derivatives are reported. Results show that 8-(2-furyl)-9-methyladenine is endowed with high affinity at the A2A subtype. Further modification of this compound with introduction of arylacetyl or arylcarbamoyl groups in N(6)-position takes to different effects on the A2A affinity and in particular on the selectivity versus the other three adenosine receptor subtypes. A molecular modelling analysis at three different A2A receptor crystal structures provides an interpretation of the obtained biological results.
    European Journal of Medicinal Chemistry 10/2013; 70C:525-535. DOI:10.1016/j.ejmech.2013.10.006 · 3.43 Impact Factor
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    ABSTRACT: Ligands that selectively block P2X3 receptors localized on nociceptive sensory fibres may be useful for the treatment of chronic pain conditions including neuropathic pain, migraine, and inflammatory pain. With the aim at exploring the suitability of adenine moiety as a scaffold for the development of antagonists of this receptor, a series of 9-benzyl-2-aminoadenine derivatives were designed and synthesized. These new compounds were functionally evaluated at rat or human P2X3 receptors expressed in human embryonic kidney (HEK) cells and on native P2X3 receptors from mouse trigeminal ganglion sensory neurons using patch clamp recording under voltage clamp configuration. The new molecules behaved as P2X3 antagonists, as they rapidly and reversibly inhibited (IC50 in the low micromolar range) the membrane currents induced via P2X3 receptor activation by the full agonist α,β-methyleneATP. Introduction of a small lipophilic methyl substituent at the 6-amino group enhanced the activity, in comparison to the corresponding unsubstituted derivative, resulting in the 9-(5-iodo-2-isopropyl-4-methoxybenzyl)-N(6)-methyl-9H-purine-2,6-diamine (24), which appears to be a good antagonist on recombinant and native P2X3 receptors with IC50 = 1.74 ± 0.21 μM.
    European Journal of Medicinal Chemistry 04/2013; 65C:41-50. DOI:10.1016/j.ejmech.2013.04.037 · 3.43 Impact Factor
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    ABSTRACT: A liquid chromatographic stationary phase containing immobilized membranes from cells expressing A(2A) adenosine receptor (A(2A)AR) is firstly described. Cellular membranes from CHO cells stably transfected with human A(2A)AR vector (A(2A)(+)) and from the same cell line transfected with the corresponding empty vector (A(2A)(-)) were entrapped on immobilized artificial membrane (IAM) support and packed into 6.6 mm I.D. glass columns to create A(2A)(+)-IAM and A(2A)(-)-IAM stationary phases. Frontal chromatography experiments on both A(2A)(+)-IAM and A(2A)(-)-IAM columns demonstrated the presence of a low specific interaction with the receptor. However, immobilized A(2A) retained its ability to specifically bind known ligands as demonstrated by the agreement of the calculated K (d) values with two different chromatographic protocols in comparison to previously reported data. In order to maximize the specific interaction, the same cellular membranes were immobilized on the inner surface of a silica capillary (40 cm × 100 μm I.D.) by non-covalent interactions using the avidin-biotin coupling system to create two open tubular columns A(2A)(+)-OT and A(2A)(-)-OT. The open tubular system was characterized by ranking experiments for affinity studies in mixture useful for the selection of new potential candidates.
    Analytical and Bioanalytical Chemistry 09/2012; 405(2-3). DOI:10.1007/s00216-012-6353-4 · 3.58 Impact Factor
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    ABSTRACT: The present study examined the effect of two A(2A) adenosine receptor (AR) agonists, CGS 21680 and VT 7, on high-palatability food (HPF) intake in a model of binge eating in sated rats and on low-palatability food (LPF) intake in food-deprived rats. Binge eating was induced in female rats by three 8-day cycles of food restriction/refeeding, followed by acute stress. Two groups of rats were used: NR+NS rats normally fed and not stressed and R+S rats exposed to cycles of food restriction/refeeding and then stressed. R+S rats had higher intake of HPF than the NR+NS controls. The two A(2A)AR agonists were tested at doses of 0.1 and 0.05 mg/kg intraperitoneally; VT 7 did not modify locomotor activity at either dose, whereas CGS 21680 only slightly reduced it at the higher dose tested. The injection of 0.1 mg/kg of both agonists markedly reduced HPF intake both in R+S and in NR+NS rats. The dose of 0.05 mg/kg was inactive. CGS 21680 and VT 7, 0.1 mg/kg, also reduced the standard LPF intake in 24 h food-deprived rats; however, they did not reduce water intake, indicating that their effect on food intake is selective. The dose of 0.05 mg/kg was inactive. Thus, A(2A)AR agonists exert a rather general effect on food intake, inhibiting both HPF intake in sated rats and LPF intake in food-deprived rats. They may potentially be useful pharmacological agents to control binge-related eating disorders and to reduce food overconsumption associated with obesity.
    Behavioural pharmacology 06/2012; 23(5-6):567-74. DOI:10.1097/FBP.0b013e3283566a60 · 2.19 Impact Factor
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    ABSTRACT: RationaleA2A adenosine receptors (A2AARs) have been proposed to be involved in drug addiction; however, preclinical studies about the effects of A2AAR ligands on alcohol consumption have provided inconsistent results. ObjectivesThe present study evaluated the effect of intraperitoneal injections of the A2AAR antagonist ANR 94, and the A2AAR agonists CGS 21680 and VT 7 on voluntary drinking and operant self-administration of 10% ethanol in Marchigian Sardinian alcohol-preferring (msP) rats. ResultsVoluntary ethanol drinking was increased by ANR 94 in acute and subchronic experiments, while it was reduced by A2AAR agonists. The effect of CGS 21680 was abolished by a low dose of ANR 94, confirming its mediation by A2AARs. Ethanol self-administration was reduced by CGS 21680 and VT 7, while ANR 94 slightly but significantly increased it. Blood alcohol levels were not modified by A2AAR agonists, indicating that their effect is not related to ethanol pharmacokinetics. The effect of VT 7 on ethanol drinking was behaviourally selective; ethanol and food intake were reduced, but water intake was increased, and total fluid intake was not different from that of controls. Moreover, VT 7 did not affect locomotor activity. CGS 21680 (0.1mg/kg) did not modify total fluid intake, but 0.2 and 0.3mg/kg reduced total fluid intake and locomotor activity. ConclusionThese results provide evidence that A2AAR agonists reduce ethanol consumption in msP rats, which represent an animal model of alcohol abuse related to stress, anxiety and depression. A2AARs may represent a potential target for treatment of alcohol abuse. KeywordsA2A Adenosine receptor–A2A Adenosine receptor agonist–A2A Adenosine receptor antagonist–Alcohol intake–Alcohol self-administration–Alcohol-preferring rats
    Psychopharmacology 02/2012; 219(4):945-957. DOI:10.1007/s00213-011-2430-1 · 3.99 Impact Factor
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    ABSTRACT: Nucleoside analogues may represent good candidates for the discovery of new antibacterial agents, therefore, a library of adenosine analogues was assessed for their antibacterial activity, and the relationship between the structure and activity of these molecules was outlined. Antibacterial activity was evaluated against that of reference strains of Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pneumoniae, Escherichia coli and Pseudomonas aeruginosa. We tested 54 adenosine analogues, modified both at ribose and base moieties, including adenine and 1/3-deazaadenine derivatives substituted in the 2- and/or N(6)-positions and bearing N-9 sugar moieties, such as ribose, 2'-deoxyribose, 3'-deoxyribose, 2',3'-dideoxyribose or cycloalkyl groups like cyclopentane. The data obtained, MIC and minimal bactericidal concentrations demonstrated that the presence of bulky substituents such as cycloheptyl and cyclooctyl rings on the N(6)-amino, together with a chlorine atom in the 2-position, conferred antibacterial activity against the Gram-positive group with MIC values ranging from 16 to 128 mg l(-1). The intact sugar moiety seemed to be not essential for antimicrobial activity and nucleosides bearing deoxyribose or cyclopentyl groups associated with bulky substituents in N(6)-position showed good antimicrobial properties. Furthermore, N-1 proved to be non-crucial and the 2-chloro-N(6)-cyclooctyl-1-deaza-3'-deoxyadenosine and 2',3'-dideoxyadenosine compounds were among the more active in the series with an MIC of 32 mg l(-1) against Staph. aureus and Strep. pneumoniae. None of the analogues was active against the two gram-negative species tested. Hence, adenosine derivatives bearing bulky substituents in the N(6)-position may represent good lead compounds for the future discovery of a novel series of antibacterial agents.
    Journal of Medical Microbiology 12/2011; 61(Pt 4):525-8. DOI:10.1099/jmm.0.038174-0 · 2.27 Impact Factor
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    ABSTRACT: A new series of 9-methyladenines, bearing different bulky groups at the 8-position, were prepared and their affinity for the four human adenosine receptor subtypes were evaluated. All the synthesized compounds showed affinities at the A1, A2A, and A3AR subtypes ranging from nanomolar to micromolar levels with different degrees of A1 selectivity, while they resulted nearly inactive at A2BAR. In particular, 9-methyl-8-[4-(4-methylbenzyloxy)phenyl]-adenine showed A1AR affinity in the nanomolar range and good levels of selectivity versus the other receptor subtypes. Furthermore, a functional assay at mouse ileum allowed to assess the potency of selected compounds at A1AR subtype. Results showed that all the tested derivatives are neutral antagonists and their Kb values are in good agreement with the Ki values from radioligand binding assay at human A1AR, confirming that the effect is due to inhibition of this subtype.
    Collection of Czechoslovak Chemical Communications 11/2011; 76(11):1379. DOI:10.1135/cccc2011091 · 1.14 Impact Factor
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    ABSTRACT: Neuropeptide S (NPS) is a 20-amino acid peptide of great interest due to its possible involvement in several biological processes, including food intake, locomotion, wakefulness, arousal, and anxiety. Structure-activity relationship studies of NPS have identified key points for structural modifications with the goal of modulating NPS receptor (NPSR) agonist activity or achieving antagonism at the same receptor. Only limited information is available for nonpeptide NPSR antagonists. In the last year, several studies have been reported in literature which present various series of small molecules as antagonists of this receptor. The results allow a comparison of the structures and activities of these molecules, leading to the design of new ligands with increased potency and improved pharmacological and pharmacokinetic profiles. This work presents a brief overview of the available information regarding structural features and pharmacological characterization of published nonpeptide NPSR antagonists.
    ChemMedChem 09/2011; 6(7):1163-71. DOI:10.1002/cmdc.201100038 · 3.05 Impact Factor
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    ABSTRACT: In this work, an innovative and non-radioactive functional cAMP assay was validated at the GPR17 receptor. This assay provides a simple and powerful new system to monitor G protein-coupled receptor activity through change in the intracellular cAMP concentration by using a mutant form of Photinus pyralis luciferase into which a cAMP-binding protein moiety has been inserted. Results, expressed as EC(50) or IC(50) values for agonists and antagonists, respectively, showed a strong correlation with those obtained with [(35)S]GTPγS binding assay, thus confirming the validity of this approach in the study of new ligands for GPR17. Moreover, this method allowed confirming that GPR17 is coupled with a G(αi).
    Purinergic Signalling 07/2011; 7(4):463-8. DOI:10.1007/s11302-011-9245-8 · 3.51 Impact Factor

Publication Stats

2k Citations
366.22 Total Impact Points

Institutions

  • 1991–2015
    • University of Camerino
      • Dipartimento di Scienze Chimiche
      Camerino, The Marches, Italy
  • 2004
    • University of Wuerzburg
      • Institute for Pharmacology and Toxicology
      Würzburg, Bavaria, Germany