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Biomedical subjects

Giampiero Spalluto

Publications and source records attributed to Giampiero Spalluto.

At least 19 recordsLinked to original sources
PubMed2007

Highlights on the development of A(2A) adenosine receptor agonists and antagonists.

Although significant progress has been made in the past few decades demonstrating that adenosine modulates a variety of physiological and pathophysiological processes through the interaction with four subtypes of a family of cell-surface G-protein-coupled receptors, clinical evaluation of some adenosine receptor ligands has been discontinued. Major problems include side effects due to the wide distribution of adenosine receptors, low brain penetration (which is important for the targeting of CNS diseases), short half-life of compounds, or a lack of effects, in some cases perhaps due to receptor desensitization or to low receptor density in the targeted tissue. Currently, three A(2A) adenosine receptor agonists have begun phase III studies. Two of them are therapeutically evaluated as pharmacologic stress agents and the third proved to be effective in the treatment of acute spinal cord injury (SCI), while avoiding the adverse effects of steroid agents. On the other hand, the great interest in the field of A(2A) adenosine receptor antagonists is related to their application in neurodegenerative disorders, in particular, Parkinson's disease, and some of them are currently in various stages of evaluation. This review presents an update of medicinal chemistry and molecular recognition of A(2A) adenosine receptor agonists and antagonists, and stresses the strong need for more selective ligands at the A(2A) human subtype.

Adenosine↗
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↗
PubMed2006

Progress in the pursuit of therapeutic adenosine receptor antagonists.

Ever since the discovery of the hypotensive and bradycardiac effects of adenosine, adenosine receptors continue to represent promising drug targets. First, this is due to the fact that the receptors are expressed in a large variety of tissues. In particular, the actions of adenosine (or methylxanthine antagonists) in the central nervous system, in the circulation, on immune cells, and on other tissues can be beneficial in certain disorders. Second, there exists a large number of ligands, which have been generated by introducing several modifications in the structure of the lead compounds (adenosine and methylxanthine), some of them highly specific. Four adenosine receptor subtypes (A1, A2A, A2B, and A3) have been cloned and pharmacologically characterized, all of which are G protein-coupled receptors. Adenosine receptors can be distinguished according to their preferred mechanism of signal transduction: A1 and A3 receptors interact with pertussis toxin-sensitive G proteins of the Gi and Go family; the canonical signaling mechanism of the A2A and of the A2B receptors is stimulation of adenylyl cyclase via Gs proteins. In addition to the coupling to adenylyl cyclase, all four subtypes may positively couple to phospholipase C via different G protein subunits. The development of new ligands, in particular, potent and selective antagonists, for all subtypes of adenosine receptors has so far been directed by traditional medicinal chemistry. The availability of genetic information promises to facilitate understanding of the drug-receptor interaction leading to the rational design of a potentially therapeutically important class of drugs. Moreover, molecular modeling may further rationalize observed interactions between the receptors and their ligands. In this review, we will summarize the most relevant progress in developing new therapeutic adenosine receptor antagonists.

Adenosine A1 Receptor Antagonists↗
PubMed2006

A3 adenosine receptor antagonists delay irreversible synaptic failure caused by oxygen and glucose deprivation in the rat CA1 hippocampus in vitro.

The role of adenosine A3 receptor activation during ischaemia-like conditions produced by oxygen and glucose deprivation (OGD) was evaluated with extracellular recordings from the CA1 region of rat hippocampal slices. In all, 7 min of OGD evoked tissue anoxic depolarisation (AD, peak at approximately 7 min from OGD start, n=20) and were invariably followed by irreversible loss of electrically evoked field epsps (fepsps, n=42).The selective adenosine A3 antagonists 3-propyl-6-ethyl-5[(ethylthio)carbonyl]-2-phenyl-4-propyl-3-pyridinecarboxylate (MRS 1523, 1-100 nM, n=31), N-[9-chloro-2-(2-furanyl)[1,2,4]-triazolo[1,5-c]quinazolin-5-yl]benzeneacetamide (MRS 1220, 100 nM, n=7), N-(2-methoxyphenyl)-N'-[2-(3-pyrindinyl)-4-quinazolinyl]-urea, (VUF 5574, 100 nM, n=3) and 5-[[(4-pyridyl)amino]carbonyl]amino-8-methyl-2-(2-furyl)-pyrazolo[4,3-e]1,2,4-triazolo[1,5-c]pyrimidine hydrochloride (1 nM, n=4), prevented the irreversible failure of neurotransmission induced by 7 min OGD (n=45) and the development of AD in 20 out of 22 monitored slices. When tested on OGD episodes of longer duration (8-10 min, n=18), 100 nM MRS 1523 prevented or delayed the appearance of AD and exerted a protective effect on neurotransmission for episodes of up to 9 min duration. In the absence of AD, the fepsp recovery was almost total, regardless of OGD episode duration. These findings support the notion that A3 receptor stimulation is deleterious during ischaemia and suggest that selective A3 receptor block may substantially increase the resistance of the CA1 hippocampal region to ischaemic damage.

Action Potentials↗
PubMed2006

Ligand-based homology modeling as attractive tool to inspect GPCR structural plasticity.

G protein-coupled receptors (GPCRs) represent the largest family known of signal-transducing molecules. They convey signals for light and many extracellular regulatory molecules. GPCRs have been found to be dysfunctional/dysregulated in a growing number of human diseases and they have been estimated to be the targets of more than 40% of the drugs used in clinical medicine today. The crystal structure of rhodopsin provides the first three-dimensional GPCR information, which now supports homology modeling studies and structure-based drug design approaches. Here, we review our recent work on adenosine receptors, a family of GPCRs and, in particular, on A(3) adenosine receptor subtype antagonists. We will focus on an alternative approach to computationally explore the multi-conformational space of the antagonist-like state of the human A(3) receptor. We define ligand-based homology modeling as new approach to simulate the reorganization of the receptor induced by the ligand binding. The success of this approach is due to the synergic interaction between theory and experiment.

Adenosine A3 Receptor Antagonists↗
PubMed2005

Autocorrelation of molecular electrostatic potential surface properties combined with partial least squares analysis as new strategy for the prediction of the activity of human A(3) adenosine receptor antagonists.

The combination of molecular electrostatic potential (MEP) surface properties (autocorrelation vectors) with the conventional partial least squares (PLS) analysis has been used for the prediction of the human A(3) receptor antagonist activities. Three-hundred-fifty-eight structurally diverse human A(3) receptor antagonists have been utilized to generate a novel ligand-based three-dimensional structure-activity relationship. Remarkably, our chemical library includes all 21 important chemical classes of human A(3) antagonists currently discovered, and it represents the largest molecular collection used to generate a general human A(3) antagonist structure-activity relationship. A robust quantitative model has been obtained as described by both cross-validated correlation coefficient (r(cv) = 0.81) and prediction capability (r(pred) = 0.82). The proposed MEP/PLS approach can be considered as an alternative hit identification tool in virtual screening applications.

Adenosine A3 Receptor Antagonists↗
PubMed2005

Anti-HIV properties of cationic fullerene derivatives.

A series of regioisomeric bis-fulleropyrrolidines bearing two ammonium groups have been synthesized and their activities against HIV-1 and HIV-2 have been evaluated. Two trans isomers have been endowed with interesting antiviral properties, confirming the importance of the relative positions of the substituent on the C(60) cage. In addition, reduced amphiphilicity of molecules to other compounds previously reported decreases their cytotoxicity in CEM cell cultures. None of the compounds showed any inhibitory activity against a variety of DNA and RNA viruses other than HIV.

Anti-HIV Agents↗
PubMed2005

Combined target-based and ligand-based drug design approach as a tool to define a novel 3D-pharmacophore model of human A3 adenosine receptor antagonists: pyrazolo[4,3-e]1,2,4-triazolo[1,5-c]pyrimidine derivatives as a key study.

A combined target-based and ligand-based drug design approach has been carried out to define a novel pharmacophore model of the human A(3) receptor antagonists. High throughput molecular docking and comparative molecular field analysis (CoMFA) have been used in tandem to assemble a new target based pharmacophore model. In parallel, to provide more accurate information about the putative binding site of these A(3) inhibitors, a rhodopsin-based model of the human A(3) receptor was built and a novel Y-shape binding motif has been proposed. Docking-based structure superimposition has been used to perform a quantitative study of the structure-activity relationships for binding of these pyrazolo-triazolo-pyrimidines to adenosine A(3) receptor using CoMFA. Both steric and the electrostatic contour plots obtained from the CoMFA analysis nicely fit on the hypothetical binding site obtained by molecular docking. On the basis of the combined hypothesis, we have designed, synthesized, and tested 17 new derivatives. Consistently, the predicted K(i) values were very close to the experimental values.

Adenosine A3 Receptor Antagonists↗
PubMed2005

Synthesis and biological evaluation of a new class of acyl derivatives of 3-amino-1-phenyl-4,5-dihydro-1H-pyrazol-5-one as potential dual cyclooxygenase (COX-1 and COX-2) and human lipoxygenase (5-LOX) inhibitors.

A series of acyl derivatives of 3-amino-1-phenyl-4,5-dihydro-1H-pyrazol-5-one as potential human 5-LOX and COX 1 and COX-2 inhibitors structurally related to the 1-phenyl-3-pyrazolidinone (phenidone, 1) have been synthesized and the activity against COX-1, COX-2 and human 5-LOX enzymes has been evaluated. All the derivatives showed poor activity against enzymes. These data, together with our previous studies, indicated that phenidone and related compounds are not suitable as human 5-LOX inhibitors and that pyrazoline nucleus should not be considered a good scaffold for inhibitors of human 5-LOX enzyme, suggesting the necessity to revisit the proposed mechanism of action of phenidone (1) in human models.

Animals↗
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

Techniques: Recent developments in computer-aided engineering of GPCR ligands using the human adenosine A3 receptor as an example.

G-protein-coupled receptors (GPCRs) represent the largest known family of signal-transducing molecules, and convey signals for light and many extracellular regulatory molecules. GPCRs are dysfunctional or dysregulated in several human diseases and are estimated to be the targets of >40% of the drugs used in clinical medicine today. The crystal structure of rhodopsin provides the first information on the three-dimensional structure of GPCRs, which now supports homology modeling studies and structure-based drug-design approaches. In this article, we review recent work on adenosine receptors, a family of GPCRs, and, in particular, on adenosine A(3) receptor antagonists. We focus on an iterative, bi-directional approach in which models are used to generate hypotheses that are tested by experimentation; the experimental findings are, in turn, used to refine the model. The success of this approach is due to the synergistic interaction between theory and experimentation.

Animals↗
PubMed2005

Carbon nanotube substrates boost neuronal electrical signaling.

We demonstrate the possibility of using carbon nanotubes (CNTs) as potential devices able to improve neural signal transfer while supporting dendrite elongation and cell adhesion. The results strongly suggest that the growth of neuronal circuits on a CNT grid is accompanied by a significant increase in network activity. The increase in the efficacy of neural signal transmission may be related to the specific properties of CNT materials, such as the high electrical conductivity.

Animals↗
PubMed2005

Non peptidic alphavbeta3 antagonists: recent developments.

The alphavbeta3 receptor, which are members of the group of the cellular adhesion molecules (CAM), are heterodimeric transmembrane glycoprotein receptors involved in processes such as cell-cell and cell-matrix adhesion, cell migration and signaling. Integrin alphavbeta3 receptor is expressed on almost all cells originating from the mesenchyme and seem to mediate several biological processes, including adhesion of osteoblasts to the bone matrix, migration of vascular smooth muscle cells, and angiogenesis. Many efforts were done in the last 10 years to individuate inhibitors for alphavbeta3 receptors, due to their involvement in important pathophysiological functions. In fact, selective alphavbeta3 antagonists offer new therapeutic opportunities for the treatment of several human pathologies like osteoporosis, restenosis and diseases involving neovascularization such as rheumatoid arthritis, tumor induced angiogenesis and metastasis. Purpose of this account is to summarize the recent developments in the field of non-peptidic alphavbetav antagonists.

Drug Design↗
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↗
PubMed2005

Autocorrelation of molecular electrostatic potential surface properties combined with partial least squares analysis as alternative attractive tool to generate ligand-based 3D-QSARs.

A database of 106 human A3 adenosine receptor antagonists was used to derive two alternative PLS models: one starting from CoMFA descriptors and the other starting from the autocorrelation descriptors. The peculiarity of this work is the introduction of autocorrelation vectors as molecular descriptors for the PLS analysis. The autocorrelation allows comparing molecules (and their properties) with different structures and with different spatial orientation without any previous alignment. In particular, Molecular Electrostatic Potential (MEP) was the property computed and its information encoded in autocorrelation vectors. The 3D spatial distribution and the values of the electrostatic potential is in fact largely responsible for the binding of a substrate to its receptor binding site. Validation was done with an external test set and the results of the two models were compared. Interestingly, our preliminary results seem to indicate that this new alternative approach could robustly compete with the already well consolidated CoMFA approach. In particular, we have suggested that it could be a very interesting tool to filter large structural database in several virtual screening applications.

Adenosine A3 Receptor Antagonists↗
PubMed2004

Hemolytic effects of water-soluble fullerene derivatives.

A series of water-soluble fullerene C(60) derivatives has been investigated for their cytotoxic and hemolytic properties, with the aim to correlate structure with toxicity. We observed that cationic chains induce significant toxicity while the presence of neutral or anionic moieties did not produce any response in our model. A validation of these experimental observations has been performed by theoretical studies in which hydrophilic and hydrophobic surface areas were correlated quantitatively with hemolytic properties.

Cell Survival↗