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R Pellicciari

Publications and source records attributed to R Pellicciari.

At least 19 recordsLinked to original sources
PubMed2006

Dynamic ligand-exchange chiral stationary phase from S-benzyl-(R)-cysteine.

S-benzyl-(R)-cysteine (R-SBC) is a new chiral ligand-exchange stationary phase which has proved to be effective in the analytical separation of some natural and unnatural underivatized amino acids with fair to good separation and resolution factors. The dynamic coating of the RP-18 solid support with S-Benzyl-(R)-cysteine (R-SBC) gives rise to a stable and efficient chiral stationary phase (CSP) that has been successfully employed. The mechanism of chiral recognition is discussed and a molecular modeling study aimed at identifying molecular descriptors responsible for observed different behaviours of analytes upon different albeit closely related selectors is discussed.

Amino Acids↗
PubMed2001

Design, synthesis and preliminary evaluation of novel 3'-substituted carboxycyclopropylglycines as antagonists at group 2 metabotropic glutamate receptors.

Two novel 3'-substituted carboxycylopropylglycines, (2S,1'S,2'S,3'R)-2-(3'-xanthenylmethyl-2'-carboxycyclopropyl)glycine (8a) and (2S,1'S,2'S,3'R)-2-(3'-xanthenylethyl-2'-carboxycyclopropyl)glycine (8b), were synthesized and evaluated as mGluR ligands. Compound 8b showed to be a potent group II antagonist with submicromolar activity.

Animals↗
PubMed2001

Modeling of poly(ADP-ribose)polymerase (PARP) inhibitors. Docking of ligands and quantitative structure-activity relationship analysis.

Poly(ADP-ribose)polymerase-1 (PARP-1) is a nuclear enzyme that has recently emerged as an important player in the mechanisms leading to postischemic neuronal death, and PARP inhibitors have been proposed as potential neuroprotective agents. With the aim of clarifying the structural basis responsible for PARP inhibition, we carried out a computational study on 46 inhibitors available through the literature. Our computational approach is composed of three parts. In the first one, representative PARP inhibitors have been docked into the crystallographic structure of the catalytic domain of PARP by using the Autodock 2.4 program. The docking studies thus carried out have provided an alignment scheme that has been instrumental for superimposing all the remaining inhibitors. Upon the basis of this alignment scheme, a quantitative structure-activity relationship (QSAR) analysis has been carried out after electrostatic and steric interaction energies have been computed with the RECEPTOR program. The QSAR analysis yielded a predictive model able to explain much of the variance of the 46-compound data set. The inspection of the QSAR coefficients revealed that the major driving force for potent inhibition is given by the extension of the contact surface between enzyme and inhibitors while electrostatic energy and hydrogen bonding capability play a minor role. Finally, the projection of the QSAR coefficients back onto the X-ray structure of the catalytic domain of PARP provides insights into the role played by specific amino acid residues. This information will be useful to address the design of new selective and potent PARP inhibitors.

Catalytic Domain↗
PubMed2001

QSAR and molecular modeling studies of baclofen analogues as GABA(B) agonists. Insights into the role of the aromatic moiety in GABA(B) binding and activation.

An integrated QSAR/molecular modeling study is carried out on a series of baclofen analogues with the aim of addressing the role of their aromatic moiety in GABA(B) receptor binding and activation. The strong correlation found between electronic descriptors (HOMO and LUMO orbital energies) and the biological activity expressed as receptor binding is discussed also on the basis of available experimental mutagenesis data and of the results obtained from homology modeling of GABA(B) receptor. In particular, it can be inferred from the QSAR analysis that the ability of being involved in aromatic-aromatic pi interaction is the distinctive feature of the p-chlorophenyl moiety of baclofen. This conclusion is confirmed by homology modeling and docking studies which indicate that the p-chlorophenyl moiety of baclofen is disposed into a pocket formed by Tyr366 and Tyr395. These results are discussed in terms of mechanism of GABA(B) activation promoted by baclofen or GABA.

Baclofen↗
PubMed2001

Synthesis and preliminary biological evaluation at the glycineB site of (+)- and (-)-3-oxetanylglycine, novel non-proteinogenic amino acids.

Two novel non-proteinogenic amino acids, (+)- and (-)-3-oxetanylglycine were synthesized and evaluated for their ability to diplace [3H]-glycine from the glycine site of the NMDA receptor complex. The lack of activity of these compounds at concentrations up to 100 microM may help in understanding the topological requirements of the glycine site of the NMDA receptor complex.

Amino Acids↗
PubMed2001

Synthesis and biological evaluation of 2-(3'-(1H-tetrazol-5-yl) bicyclo[1.1.1]pent-1-yl)glycine (S-TBPG), a novel mGlu1 receptor antagonist.

The design and synthesis of 2-(3'-(1H-tetrazol-5-yl)bicyclo[1.1.1]pent-1-yl)glycine (S-TBPG), a novel mGluR1 antagonist is reported. S-TBPG is characterized by the bioisosteric replacement of the distal carboxy group of 2-(3'-carboxybicyclo [1.1.1]pent-1-yl)glycine (S-CBPG) by a tetrazolyl moiety. Despite a moderate reduction in potency, S-TBPG is a selective mGluR1 antagonist (69 microM), with no activity at other mGluR subtypes. The interesting biological profile of S-TBPG, coupled with its peculiar chemical structure, is discussed in terms of the structure activity relationship (SAR) of mGluR1 antagonists.

Cell Line↗
PubMed2001

Homology model of the closed, functionally active, form of the amino terminal domain of mGlur1.

The amino terminal domain (ATD) of metabotropic glutamate receptors (mGluRs) contains the neurotransmitter binding site and is related in sequence to leucine/isoleucine/valine binding proteins (LIVBP). It has been proposed that the ATD of mGluRs shares with periplasmic binding proteins a common mechanism of ligand binding and processing which involves the equilibrium between closed and open forms. The availability of the X-ray structure of LIVBP in its open, unliganded form, has allowed the construction of homology models of the ATD of mGluR1 which have been instrumental in clarifying the mode of binding of agonists and antagonists. We propose in this paper the use of the X-ray structure of AmiC. the controller of transcription antitermination in the amidiase operon of Pseudomonas aerugimosa as suitable template for the construction of the closed form of the ATD of mGluR1. The resulting model of the closed form of the ATD of mGluR1 indicates that several interdomain hydrogen bonds and salt bridges may be formed upon domain contraction and that the ligand directly participates to this interdomain network.

Amino Acid Sequence↗
PubMed2001

Poly(ADP-ribose) polymerase inhibitors attenuate necrotic but not apoptotic neuronal death in experimental models of cerebral ischemia.

An excessive activation of poly(ADP-ribose) polymerase (PARP) has been proposed to play a key role in post-ischemic neuronal death. We examined the neuroprotective effects of the PARP inhibitors benzamide, 6(5H)-phenanthridinone, and 3,4-dihydro-5-[4-1(1-piperidinyl)buthoxy]-1(2H)-isoquinolinone in three rodent models of cerebral ischemia. Increasing concentrations of the three PARP inhibitors attenuated neuronal injury induced by 60 min oxygen-glucose deprivation (OGD) in mixed cortical cell cultures, but were unable to reduce CA1 pyramidal cell loss in organotypic hippocampal slices exposed to 30 min OGD or in gerbils following 5 min bilateral carotid occlusion. We then examined the necrotic and apoptotic features of OGD-induced neurodegeneration in cortical cells and hippocampal slices using biochemical and morphological approaches. Cortical cells exposed to OGD released lactate dehydrogenase into the medium and displayed ultrastructural features of necrotic cell death, whereas no caspase-3 activation nor morphological characteristics of apoptosis were observed at any time point after OGD. In contrast, a marked increase in caspase-3 activity was observed in organotypic hippocampal slices after OGD, together with fluorescence and electron microscope evidence of apoptotic neuronal death in the CA1 subregion. Moreover, the caspase inhibitor Z-VAD-FMK reduced OGD-induced CA1 pyramidal cell loss. These findings suggest that PARP overactivation may be an important mechanism leading to post-ischemic neurodegeneration of the necrotic but not of the apoptotic type.

Animals↗
PubMed2000

C60 carboxyfullerene exerts a protective activity against oxidative stress-induced apoptosis in human peripheral blood mononuclear cells.

C60 carboxyfullerene is a novel buckminsterfullerene-derived compound that behaves as a free-radical scavenger. In the present report, we investigated whether this drug exerts a protective activity against oxidative stress-induced apoptosis. Human peripheral blood mononuclear cells (PBMCs) were challenged by 2-deoxy-d-ribose (dRib) or TNF-alpha plus cycloheximide as agents that trigger apoptosis by interfering with the redox status of cell and mitochondrial membrane potential. We found that carboxyfullerene was able to protect quiescent PBMCs from apoptosis caused either by 2-deoxy-d-ribose or TNF-alpha plus cycloheximide by a mechanism partially involving the mitochondrial membrane potential integrity, known to be associated with early stages of apoptosis. These results represent the first indication for a target activity of buckminsterfullerenes on cells of the immune system and their mitochondria.

Adult↗
PubMed2000

Synthesis, molecular modeling and preliminary biological evaluation of 1-amino-3-phosphono-3-cyclopentene-1-carboxylic acid and 1-amino-3-phosphono-2-cyclopentene-1-carboxylic acid, two novel agonists of metabotropic glutamate receptors of group III.

On the basis of a pharmacophore definition of mGlu4 agonists, the two novel semi-rigid derivatives 12 and 13 were designed and synthesized. The preliminary biological evaluation demonstrated that both compounds interact with hmGlu4a, while ineffective at group II receptor subtypes. In particular, derivative 13 is a full hmGlu4a agonist with an EC50 = 17 microM.

Animals↗
PubMed2000

Conservation of the ligand recognition site of metabotropic glutamate receptors during evolution.

Mammalian metabotropic glutamate receptors (mGluRs) are classified into 3 groups based on their sequence similarity and ligand recognition selectivity. Recently, we identified a Drosophila mGluR (DmGlu(A)R) which is about equidistant, phylogenetically, from the 3 mGluR groups. However, both the G-protein coupling selectivity and the pharmacological profile of DmGlu(A)R, as analysed with mutated G-proteins and a few compounds, look similar to those of mammalian group-II mGluRs. In the present study we carefully examined the pharmacological profile of DmGlu(A)R, and compared it to those of the rat mGlu(1a), mGlu(2) and mGlu(4a) receptors, representative of group-I, II and III respectively. The pharmacological profile of DmGlu(A)R was found to be similar to that of mGlu(2)R, and only very small differences could be identified at the level of their pharmacophore models. These data strongly suggest that the binding sites of these two receptors are similar. To further document this idea, a 3D model of the mGlu(2) binding domain was constructed based on the low sequence similarity with periplasmic amino acid binding proteins, and was used to identify the residues that possibly constitute the ligand recognition pocket. Interestingly, this putative binding pocket was found to be very well conserved between DmGlu(A)R and the mammalian group-II receptors. These data indicate that there has been a strong selective pressure during evolution to maintain the ligand recognition selectivity of mGluRs.

Amino Acid Sequence↗
PubMed2000

Evaluation of hydrophobic/hydrophilic balance of bile acids by comparative molecular field analysis (CoMFA).

A comparative molecular field analysis (CoMFA) model, employing standard steric and electrostatic fields, is able to predict the hydrophobic/hydrophilic balance, expressed as reverse-phase HPLC capacity factor, for a series of both naturally occurring and semi-synthetic bile acids. The very high values of cross-validated R(2) (Q(2)) demonstrate that the CoMFA method can give useful information on the hydrophobic balance of newly synthesized bile acids.

Bile Acids and Salts↗
PubMed2000

C3-fullero-tris-methanodicarboxylic acid protects cerebellar granule cells from apoptosis.

Buckminsterfullerenols were recently investigated for their protective properties in different models of acute and chronic neurodegeneration. We tested C3-fullero-tris-methanodicarboxylic acid in our in vitro model of apoptotic neuronal death, which consists of shifting the culture K+ concentration from 25 to 5 mM for rat cerebellar granule cells. The impairment of mitochondrial respiratory function as well as chromatin derangement and fragmentation of DNA in apoptotic oligonucleosomes that occur in these conditions were protected by this compound in a concentration-dependent way. To assess whether antioxidant activity could account for the rescue of cerebellar granule cells from apoptosis, we tested the fullerene derivative under FeSO4-induced oxidative stress and found significant protection. Thus, we visualized membrane and cytoplasmic peroxides and reactive oxygen species and found a significant reduction of the species after 24 h in 5 mM K+ with the fullerene derivative. Such evidence suggests that this compound exerts a protective role in cerebellar granule cell apoptosis, likely reducing the oxidative stress.

Animals↗
PubMed2000

Carboxyfullerenes protect human keratinocytes from ultraviolet-B-induced apoptosis.

Carboxyfullerene, a water-soluble carboxylic acid derivative of a fullerene, which acts as a free-radical scavenger, was investigated as a protective agent against ultraviolet-light-induced damage in human keratinocytes. First, we demonstrate that carboxyfullerene is not cytotoxic for these cells. In addition, this compound significantly reduces the ultraviolet-B-induced inhibition of keratinocyte proliferation and protects keratinocytes from apoptosis caused by ultraviolet B irradiation in a time- and dose-dependent fashion. Furthermore, the percentage of cells with depolarized mitochondria is significantly lower in ultraviolet-B-irradiated keratinocytes pretreated with carboxyfullerene than in cells provided with diluent alone. Carboxyfullerene also protects human keratinocytes from apoptosis induced by exposure to deoxy-D-ribose, a sugar that causes cell death through a pathway involving oxidative stress. On the other hand, ultraviolet B downregulates bcl-2 levels in human keratinocytes, and carboxyfullerene fails to prevent this effect. These results suggest that carboxy- fullerene protects human keratinocytes from ultraviolet B damage possibly via a mechanism interfering with the generation of reactive oxygen species from depolarized mitochondria without the involvement of bcl-2.

Apoptosis↗
PubMed1999

Modeling of amino-terminal domains of group I metabotropic glutamate receptors: structural motifs affecting ligand selectivity.

On the basis of a new sequence alignment between the amino terminal domains of mGlu1 and mGlu5 receptor subtypes and leucine/isoleucine/valine binding protein (LIVBP), three-dimensional models of the binding sites of the two group I metabotropic glutamate receptor subtypes were constructed. The 3D-models thus obtained showed a high degree of similarity. In the region of the putative binding site, identified by Ser165 and Thr188 (mGlu1) or Ser152 and Thr175 (mGlu5), the only nonconserved residue is Pro369 (mGlu1), which is substituted by Gln356 in mGlu5. Although not directly involved in ligand binding, these residues may provide a subtle difference in the steric environment of the two active sites that may account for the observed subgroup selectivity of recently reported ligands.

Amino Acid Sequence↗
PubMed1999

Pharmacophore models of group I and group II metabotropic glutamate receptor agonists. Analysis of conformational, steric, and topological parameters affecting potency and selectivity.

A wide variety of conformationally constrained glutamate analogues, active as group I or group II metabotropic glutamate receptor agonists, were employed in a molecular modeling study aimed at the definition of group I and group II agonist pharmacophoric models. The results of this study can be summarized as follows: (i) Recognition sites of both group I and group II mGluRs can adequately be described by five-point pharmacophores. (ii) An extended conformation of glutamate is required for interaction with both group I and group II mGluRs. Group I receptors, however, can also be activated by a more folded conformation if only four pharmacophore points are considered. (iii) Conformational preferences are, however, not sufficient to explain the potency and selectivity of the whole set of ligands. Volume comparison analysis allowed us to define steric environments for group I and group II mGluRs. Group I mGluRs are characterized by a region of allowed volume in proximity of the distal acidic function, whereas group II mGluRs are characterized by a small polar pocket whose occupancy confers high potency and selectivity. Finally, our study points out the necessity of a careful analysis of the energetic requirements needed to attain the putative bioactive conformations and of explicitly considering the conformational mobility of carboxylate groups.

Excitatory Amino Acid Agonists↗