Diego Dal Ben

Publications (35) View all

• Article: The importance of alkynyl chain presence for the activity of adenine nucleosides/nucleotides on purinergic receptors.

  D Dal Ben, M Buccioni, C Lambertucci, G Marucci, R Volpini, G Cristalli
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  ABSTRACT: The first demonstrations in the early seventies that adenosine had marked effects in the cerebral cortex, which were independent of its role in intermediary metabolism and could be antagonised by methylxanthines, were followed by the observations that other purine derivatives, notably ATP, may also play a critical role in cell function. In 1978 Burnstock first introduced the terms Pl for the nucleoside receptors and P2 for the nucleotide receptors, based on the most fundamental divisions of purine receptors between those for nucleosides such as adenosine and those for nucleotides such as ATP. At present, the P1 (adenosine) receptor family presents 4 subtypes, while the P2 (ATP, ADP and UTP) receptor family has been divided into P2X ionotropic receptors and P2Y metabotropic G protein-coupled receptors (GPCRs). While knowledge on the purinergic receptor pharmacology was increasing, the development of potent and selective ligands for these receptors has been a target of medicinal chemistry research for several decades. In particular, synthesis of 2-substituted adenosines was carried out in many laboratories starting from seventies aimed at finding adenosine derivatives more resistant than the parent nucleoside to rapid uptake into cells, to deamination by adenosine deaminase, and to phosphorylation by adenosine kinase. In the present review the synthesis of alkynyl derivatives of adenine, adenosine, N-alkylcarboxamidoadenosine, and adenine nucleotides, which have been tested on purinergic receptors, will be summarized. Furthermore, the contribution of chemistry, molecular modelling, and pharmacology to the development of structure-activity relationships in this class of purinergic receptor ligands will be outlined.
  Current Medicinal Chemistry 03/2011; 18(10):1444-63. · 4.86 Impact Factor
• Article: Innovative functional cAMP assay for studying G protein-coupled receptors: application to the pharmacological characterization of GPR17.

  Michela Buccioni, Gabriella Marucci, Diego Dal Ben, Dania Giacobbe, Catia Lambertucci, Laura Soverchia, Ajiroghene Thomas, Rosaria Volpini, Gloria Cristalli
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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. · 3.16 Impact Factor
• Article: Synthesis, structure-affinity relationships, and molecular modeling studies of novel pyrazolo[3,4-c]quinoline derivatives as adenosine receptor antagonists.

  Ombretta Lenzi, Vittoria Colotta, Daniela Catarzi, Flavia Varano, Lucia Squarcialupi, Guido Filacchioni, Katia Varani, Fabrizio Vincenzi, Pier Andrea Borea, Diego Dal Ben, Catia Lambertucci, Gloria Cristalli
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  ABSTRACT: This paper reports the study of new 2-phenyl- and 2-methylpyrazolo[3,4-c]quinolin-4-ones (series A) and 4-amines (series B), designed as adenosine receptor (AR) antagonists. The synthesized compounds bear at the 6-position various groups, with different lipophilicity and steric hindrance, that were thought to increase human A(1) and A(2A) AR affinities and selectivities, with respect to those of the parent 6-unsubstituted compounds. In series A, this modification was not tolerated since it reduced AR affinity, while in series B it shifted the binding towards the hA(1) subtype. To rationalize the observed structure-affinity relationships, molecular docking studies at A(2A)AR-based homology models of the A(1) and A(3) ARs and at the A(2A)AR crystal structure were carried out.
  Bioorganic & medicinal chemistry 06/2011; 19(12):3757-68. · 2.82 Impact Factor
• Article: Evidence for the existence of a specific g protein-coupled receptor activated by guanosine.

  Rosaria Volpini, Gabriella Marucci, Michela Buccioni, Diego Dal Ben, Catia Lambertucci, Carmen Lammi, Ram C Mishra, Ajiroghene Thomas, Gloria Cristalli
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  ABSTRACT: Guanosine, released extracellularly from neurons and glial cells, plays important roles in the central nervous system, including neuroprotection. The innovative DELFIA Eu-GTP binding assay was optimized for characterization of the putative guanosine receptor binding site at rat brain membranes by using a series of novel and known guanosine derivatives. These nucleosides were prepared by modifying the purine and sugar moieties of guanosine at the 6- and 5'-positions, respectively. Results of these experiments prove that guanosine, 6-thioguanosine, and their derivatives activate a G protein-coupled receptor that is different from the well-characterized adenosine receptors.
  ChemMedChem 06/2011; 6(6):1074-80. · 3.15 Impact Factor
• Article: Neuropeptide S receptor: recent updates on nonpeptide antagonist discovery.

  Diego Dal Ben, Ippolito Antonini, Michela Buccioni, Catia Lambertucci, Gabriella Marucci, Ajiroghene Thomas, Rosaria Volpini, Gloria Cristalli
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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 03/2011; 6(7):1163-71. · 3.15 Impact Factor