Biomedical subjects

Chiara Bolcato

Publications and source records attributed to Chiara Bolcato.

4 recordsLinked to original sources

PubMed2006

The application of a 3D-QSAR (autoMEP/PLS) approach as an efficient pharmacodynamic-driven filtering method for small-sized virtual library: application to a lead optimization of a human A3 adenosine receptor antagonist.

We have recently reported that the combination of molecular electrostatic potential (MEP) surface properties (autocorrelation vectors) with the conventional partial least squares (PLS) analysis can be used to produce a robust ligand-based 3D structure-activity relationship (autoMEP/PLS) for the prediction of the human A3 receptor antagonist activities. Here, we present the application of the 3D-QSAR (autoMEP/PLS) approach as an efficient and alternative pharmacodynamic filtering method for small-sized virtual library. For this purpose, a small-sized combinatorial library (841 compounds) was derived from the scaffold of the known human A3 antagonist pyrazolo-triazolo-pyrimidines. The most interesting analogues were further prioritized for synthesis and pharmacological characterization. Remarkably, we have found that all the newly synthetized compounds are correctly predicted as potent human A3 antagonists. In particular, two of them are correctly predicted as sub-nanomolar inhibitors of the human A3 receptor.

Adenosine A3 Receptor Antagonists↗

PubMed2006

Synthesis and biological studies of a new series of 5-heteroarylcarbamoylaminopyrazolo[4,3-e]1,2,4-triazolo[1,5-c]pyrimidines as human A3 adenosine receptor antagonists. Influence of the heteroaryl substituent on binding affinity and molecular modeling investigations.

Some pyrazolotriazolopyrimidines bearing different heteroarylcarbamoylamino moieties at the N5-position are described. We previously reported the synthesis of a water soluble compound with high potency and selectivity versus the human A3 adenosine receptor as antagonist, and herein we present an enlarged series of compounds related to the previously mentioned one. These compounds showed A3 adenosine receptor affinity in the nanomolar range and different levels of selectivity evaluated in radioligand binding assays at human A1, A2A, A2B, and A3 adenosine receptors. In particular, the effect of the heteroaryl substituents at the N5 position has been analyzed. This study allows us to recognize that the presence of a pyridinium moiety in this position not only increases water solubility but also improves or retains potency and selectivity at the human A3 adenosine receptors. In contrast, replacement of pyridine with different heterocycles produces loss of affinity and selectivity at the human A3 adenosine receptors. A molecular modeling study has been carried out with the aim to explain these various binding profiles.

Adenosine A3 Receptor Antagonists↗

PubMed2005

Synthesis, biological studies and molecular modeling investigation of 1,3-dimethyl-2,4-dioxo-6-methyl-8-(substituted) 1,2,3,4-tetrahydro [1,2,4]-triazolo [3,4-f]-purines as potential adenosine receptor antagonists.

A new series of potential adenosine receptor antagonists with a [1,2,4]-triazolo-[3,4-f]-purine structure have been synthesized, and their affinities at the four adenosine receptor subtypes (A1, A2A, A2B and A3) have been evaluated. The design was based on the demonstrated approach to novel A3 adenosine receptor antagonists of adding a third ring to the xanthine structure. Unfortunately, all the synthesized compounds were completely inactive at all four adenosine receptor subtypes independently of their substitutions. Preliminary molecular modeling investigation has demonstrated that only a low degree of steric and electrostatic complementarity has been observed for all the new synthesized triazolo-purines with respect to other structurally related A3 receptor antagonists. This analysis yielded valuable information about structure-activity relationships and further design of potential adenosine receptor antagonists.

Adenylyl Cyclases↗

PubMed2005

A2B adenosine receptor antagonists: recent developments.

There are pharmacological evidences that A(2B) receptors are involved in inflammatory processes, such as asthma. For this reason, many efforts has been made for identifying selective A(2B) antagonists as anti-asthmatic agents. The updated material related to this field has been rationalised and arranged in order to offer an overview of the topic.

Adenosine A2 Receptor Antagonists↗