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G Spadoni

Publications and source records attributed to G Spadoni.

At least 19 recordsLinked to original sources
PubMed2000

Hazardous materials transportation: a risk-analysis-based routing methodology.

This paper introduces a new methodology based on risk analysis for the selection of the best route for the transport of a hazardous substance. In order to perform this optimisation, the network is considered as a graph composed by nodes and arcs; each arc is assigned a cost per unit vehicle travelling on it and a vehicle capacity. After short discussion about risk measures suitable for linear risk sources, the arc capacities are introduced by comparison between the societal and individual risk measures of each arc with hazardous materials transportation risk criteria; then arc costs are defined in order to take into account both transportation out-of-pocket expenses and risk-related costs. The optimisation problem can thus be formulated as a 'minimum cost flow problem', which consists of determining for a specific hazardous substance the cheapest flow distribution, honouring the arc capacities, from the origin nodes to the destination nodes. The main features of the optimisation procedure, implemented on the computer code OPTIPATH, are presented. Test results about shipments of ammonia are discussed and finally further research developments are proposed.

Cost-Benefit Analysis↗
PubMed2000

Through ARIPAR-GIS the quantified area risk analysis supports land-use planning activities.

The paper first summarises the main aspects of the ARIPAR methodology whose steps can be applied to quantify the impact on a territory of major accident risks due to processing, storing and transporting dangerous substances. Then the capabilities of the new decision support tool ARIPAR-GIS, implementing the mentioned procedure, are described, together with its main features and types of results. These are clearly shown through a short description of the updated ARIPAR study (reference year 1994), in which the impact of changes due to industrial and transportation dynamics on the Ravenna territory in Italy were evaluated. The brief explanation of how results have been used by local administrations offers the opportunity to discuss about advantages of the quantitative area risk analysis tool in supporting activities of risk management, risk control and land-use planning.

Accidents↗
PubMed2000

Design and synthesis of melatonin receptors agonists and antagonists.

We review our work towards the design and synthesis of high-affinity melatonin (N-acetyl-5-methoxytryptamine) agonist and antagonist compounds. High affinity melatonergic agonists were obtained by shifting the melatonin side chain from C3 to N1 of the indole ring system. Conversely, by moving the side chain from C3 to C2 it was possible to obtain melatonin antagonist compounds, albeit of moderate affinity.

Animals↗
PubMed2000

A new melatonin receptor ligand with mt1-agonist and MT2-antagonist properties.

It has been difficult, so far, to obtain melatonin analogs possessing high selectivity for the respective melatonin receptors, mt1 and MT2. In the present work, we report the synthesis and pharmacological characterization of a new compound N-¿2-[5-(2-hydroxyethoxy)-1H-indol-3-yl)] ethyl¿ acetamide or 5-hydroxyethoxy-N-acetyltryptamine (5-HEAT). To assess the activity of the compound, the following tests were performed: affinity determination for the high- and low-affinity receptor states (2-[125I]iodomelatonin binding), potency and intrinsic activity in inducing G protein activation ([35S]GTPgammaS binding assay). 5-HEAT showed little selectivity for the mt1 receptor, with pKi values of 7.77 for mt1 and 7.12 for the MT2 receptors, respectively. 5-HEAT was able to differentiate between the high- and the low-affinity receptor states in the mt1 but not in the MT2 receptor. 5-HEAT induced a high level of G protein activation when acting through the mt1 receptor, with a relative intrinsic activity of 0.92. On the contrary, it elicited only minimal MT2 receptor-mediated G protein activation, with a relative intrinsic activity of 0.16, and was also able to inhibit the melatonin-induced MT2 receptor-mediated G protein activation, with a pKB value of 7.4. In conclusion, it appears that 5-HEAT possesses very different efficacies at the two melatonin receptors, behaving as a full melatonin receptor agonist at the mt1 and as an antagonist/weak partial agonist at the MT2 receptor. Therefore, it is a promising ligand for use in functional studies aimed at distinguishing between the effects mediated by the different melatonin receptors in the human.

3T3 Cells↗
PubMed1999

Melatonin.

Melatonin is the principal hormone secreted by the pineal gland, produced in humans with a circadian rhythm characterized by elevated blood levels during the night. It is involved in the regulation of several rhythmic functions in various vertebrates, and participates in the processing of photoperiodic information. Although its role in human physiologic and pathologic processes is not yet completely understood, MLT exerts a number of actions, in physiological or pharmacological concentrations, which could be of interest for future therapeutic uses. The mechanisms involved in MLT actions include interaction with membrane receptors, recently classified as mt1/MT2/MT3, and with nuclear sites corresponding to orphan members of the nuclear receptor superfamily, RZR/ROR; MLT also acts as a radical scavenger, exerting a protective action against various oxidative injuries. The present review is mainly addressed to the medicinal chemistry of ligands at the MLT membrane receptors, focusing on the models of binding interaction published in the literature. Several different pharmacophore and 3D-QSAR models have been reported so far, and a re-consideration of known active compounds, in the light of the recently developed biological tests on cloned receptors, could help to resolve the incongruities among these models; to this end, additional information is becoming available from new, conformationally constrained ligands, and from antagonist compounds with a selective affinity for receptor subtypes.

Animals↗
PubMed1998

Melatonin receptor ligands: synthesis of new melatonin derivatives and comprehensive comparative molecular field analysis (CoMFA) study.

The CoMFA methodology was applied to melatonin receptor ligands in order to establish quantitative structure-affinity relationships. One hundred thirty-three compounds were considered: they were either collected from literature or newly synthesized in order to gain information about the less explored positions. To this end, various melatonin derivatives were prepared and their affinity for quail optic tecta melatonin receptor was tested. Compounds were aligned on the putative active conformation of melatonin proposed by our previously reported pharmacophore search, and their relative affinities were calculated from the displacement of 2-[125I]-iodomelatonin on different tissues expressing aMT receptors. Compounds were grouped into three sets according to their topology. Subset A: melatonin-like compounds; subset B: N-acyl-2-amino-8-methoxytetralins and related compounds; subset C:N-acyl-phenylalkylamines and related compounds. CoMFA models were derived for each set, using the steric, electrostatic, and lipophilic fields as structural descriptors; the PLS analyses were characterized by good statistical parameters, taking into account the heterogeneity of the binding data, obtained with different experimental protocols. From the CoMFA model for the melatonin-like compounds, besides the well-known positive effect of 2-substitution, a low steric tolerance for substituents in 1, 6, and 7, and a negative effect of electron-rich 4-substituents were observed; the information provided by the newly synthesized compounds was essential for these results. Moreover, a comprehensive model for the 133 compounds, accounting for a common alignment and a common mode of interaction at the melatonin receptor, was derived (Q2 = 0.769, R2 = 0.905). This model validates our previously reported pharmacophore search and offers a clear depiction of the structure-affinity relationships for the melatonin receptor ligands.

Animals↗
PubMed1998

2-[N-Acylamino(C1-C3)alkyl]indoles as MT1 melatonin receptor partial agonists, antagonists, and putative inverse agonists.

The synthesis of several novel indole melatonin analogues substituted at the 2-position with acylaminomethyl (8-11), acylaminoethyl (5a-k), or acylaminopropyl (13) side chains is reported. On the basis of a novel in vitro functional assay (specific binding of [35S]GTPgammaS), which can discriminate agonist from partial agonist, antagonist, and inverse agonist ligands, 5a,g, h,j and 13 were shown to be partial agonists, 5d,e and 8-11 competitive antagonists, and 5b,c,k putative inverse agonists. Binding and functional assays were performed on cloned human MT1 receptor. Structure-activity relationship considerations indicate that N-[1-aryl-2-(4-methoxy-1H-indol-2-yl)(C1-C2)alkyl]alkanamides represent a lead structure for this type of ligands.

3T3 Cells↗
PubMed1998

(E)-3-(2-(N-phenylcarbamoyl)vinyl)pyrrole-2-carboxylic acid derivatives. A novel class of glycine site antagonists.

The synthesis and preliminary biological evaluation of novel (E)-3-(2-(N-phenylcarbamoyl)-vinyl)pyrrole-2-carboxylic acids bearing alkyl, acyl, alkoxy, phenyl, and halo substituents at the 4- and 5-positions of the pyrrole ring are reported. These compounds were studied for their in vitro affinity at the strychnine-insensitive glycine-binding site of the N-methyl-D-aspartate (NMDA) receptor complex. In the [3H]glycine binding assay (E)-4,5-dibromo-3-(2-(N-phenylcarbamoyl)vinyl)pyrrole-2-carboxylic acid 6w (pKi = 7.95 +/- 0.01) and the 4-bromo-5-methyl 6j (pKi = 7.24 +/- 0.01) and 4,5-dimethyl 6g (pKi = 6.70 +/- 0.03) analogues were the most active compounds of the series. Qualitative structure-activity analysis points to a negative correlation between bulk of the C-4 and C-5 substituents and affinity which is enhanced by halo-substituents. QSAR analysis by the Hansch descriptors F, R, pi, and MR, on a subset of compounds with pKi > or = 4, indicates that electron-withdrawing groups at C-4 and C-5 enhance the affinity. Bulk and lipophilicity are also relevant for the substituents at these positions. 6g was found to be a full antagonist (alpha = 0; enhancement of the [3H]TCP binding). The in vivo potency of 6g, 6j, and 6w was evaluated by the inhibition of NMDA-induced convulsions in mice by both the i.v. and po routes; 6w was the most active compound (ED50 = 3 x 10(-3) (0.8-10) g/kg, i.v. and 30 x 10(-3) (4.5-61) g/kg, p.o.). The results of this study indicate that the 3,4-disubstitutedpyrrole-2-carboxylate represents a novel template for the design of new glycine antagonists.

Acrylamides↗
PubMed1998

1-Aminocylopropane-1-carboxylic acid derivatives as ligands at the glycine-binding site of the N-methyl-D-aspartate receptor.

Several 1-aminocyclopropane-1-carboxylic acid derivatives were prepared and tested for activity at the glycine-binding site of the N-methyl-D-aspartate (NMDA) receptor complex. Structural modifications involved the amino group, the carboxylic function or position 2 of the ring. When tested in a [3H]-MK-801 binding assay in the presence of glutamic acid, some of the compounds were able to activate the receptor. Two of them (3e and 6) are selective ligands for the glycine site of the NMDA receptor.

Amino Acids↗
PubMed1997

Conformationally restrained melatonin analogues: synthesis, binding affinity for the melatonin receptor, evaluation of the biological activity, and molecular modeling study.

The design, synthesis, and biological profile of several indole melatonin analogues with a conformationally restricted C3 amidoethane side chain are presented. Examination of the accessible conformations of the melatonin side chain led us to explore some of its fully or partially restricted analogues, 2-12, the binding affinity values of which were utilized to gain further insight on the melatonin binding site. Two pharmacophoric models have been devised for melatonin and the active compounds by conformational analysis and superimposition performed using the DISCO program. In these models, the melatonin side chain can adopt a gauche/anti conformation out of the indole plane. Another contribution of this study regards the observation of a possible binding point interaction around the C2 position of the indole, as suggested by the remarkably increased binding affinity observed in the C2-substituted analogues 6 and 9 and especially in the more rigid analogue 5. The biological activity and the efficacy of the new compounds were tested by measuring the inhibition of the forskolin-stimulated cAMP accumulation and the GTP gamma S index. Both analyses demonstrated that all of the compounds were full agonists with the exception of 4 and 9, which showed a slight reduction in efficacy and would seem to be partial agonists.

Animals↗
PubMed1997

1-(2-Alkanamidoethyl)-6-methoxyindole derivatives: a new class of potent indole melatonin analogues.

A new series of indole melatonin analogues, bearing the amido ethyl side chain attached at the N-1 position of the indole nucleus, were synthesized and tested for their affinity for the melatonin receptor isolated from quail optic tecta in a series of in vitro ligand-binding experiments using 2-[125I]iodomelatonin as the labeled ligand. The biological activity was evaluated using two models: effects on the forskolin-stimulated cAMP accumulation in explants from quail optic tecta and evaluation of the GTP gamma S index derived from competition experiments performed in the absence or presence of GTP gamma S. Compounds 2a and 2k-n, obtained by shifting the methoxy group and the ethylamido side chain from the C-5 and C-3 positions of melatonin to the C-6 and N-1 positions of the indole nucleus, exhibited an affinity similar to that of melatonin itself, as well as full agonist activity. Optimization of the C-2 substituent by introducing Br, phenyl, or COOCH3 (2b-d) resulted in a significantly enhanced affinity (in the picomolar range) and improved agonist biological activity. Compounds lacking the methoxy group and bearing an N-alicyclic group (2h-j) behaved as partial agonists or antagonists.

Animals↗
PubMed1993

2-Substituted 5-methoxy-N-acyltryptamines: synthesis, binding affinity for the melatonin receptor, and evaluation of the biological activity.

A series of 2-substituted 5-methoxy-N-acyltryptamines was synthesized and their affinity for the melatonin receptor, isolated from whole quail brains, was tested in a succession of in vitro ligand-receptor binding experiments, using 2-[125I]iodomelatonin as a labeled ligand. Optimization of the C2 substituent and the N-acyl group resulted in compounds having picomolar affinity for the receptor (vs nanomolar affinity for melatonin). In two tests for evaluation of the biological activity (effects on the spontaneous firing activity of single neurons in the rabbit parietal cortex in situ, and the Syrian hamster gonadal regression model in vivo) most of the analogs behaved as agonists. Isopropyl substitution at C2 alone, or concomitantly with cyclopropyl substitution at the N-acyl position, resulted in much lower affinity and weaker biological effect, or lack of activity in the latter case. Of interest are the compounds 4d (R = phenyl, R1 = CH3) and 4g (R = phenyl, R1 = cyclopropyl), which expressed high affinity for the receptor and apparent antagonistic activity under the conditions of the experimental models employed, though the analog 4g (R = phenyl, (R1 = cyclopropyl) seemingly was a weak antagonist and in situ expressed mixed activity in the higher concentration range. Cyclopropyl substitution at the N-acyl position inevitably resulted in lower affinity for the receptor and weaker biological activity. These data demonstrate that the N-acetyl group is important for both affinity and agonist biological activity. The substituents at C2 are crucial for the affinity of the compound for the receptor and can be utilized to create putative high-affinity agonists or antagonists.

Animals↗
PubMed1993

1-Aminocyclopropane-1-carboxylic acid derivatives: a new, general synthesis and NMDA receptor complex binding affinity study.

A new synthesis of 1-aminocyclopropane-1-carboxylic acid and of its (E)- and (Z)-2-substituted analogues (R = CH3;i-Pr;C6H5) has been performed by means of the "diazo-addition" method, starting from N-(diphenylmethylene)-2,3-dehydro-1-amino-1-carboxylate precursors. The (E)- and (Z)-2-phenyl and the (Z)-2-methylcyclopropaneamino acids have been obtained with high diastereospecificity. All the cyclopropaneamino acids prepared were tested for their affinity for some glutamate receptors and resulted inactive, with the exception of compounds (E)-1b and (Z)-1c which showed a shallow displacement of [3H]-glycine binding.

Amino Acids↗
PubMed1992

2-Bromomelatonin: synthesis and characterization of a potent melatonin agonist.

A practical synthesis of N-[2-(2-bromo-5-methoxy-1H-indol-3-yl)ethyl]- acetamide (2-bromomelatonin) was achieved by direct bromination of melatonin with N-bromosuccinimide (NBS) in anhydrous acetic acid at room temperature under nitrogen, followed by flash-chromatography. 1H-NMR and mass spectra showed the bromine to be incorporated at the C-2 position of the indole moiety. Tests performed in vitro with isolated melatonin receptors from rabbit parietal cortex demonstrated that the relative binding affinity of 2-bromomelatonin was about ten times higher than that of melatonin and close to that of 2-iodomelatonin. 2-Bromomelatonin behaved as a potent agonist in the physiological studies. It showed enhanced activity in inhibiting the spontaneous firing activity of cortical neurons and similarly to melatonin and 2-iodomelatonin potentiated significantly the inhibitory effect of GABA. 2-Bromomelatonin was also an extremely effective agonist in the tests performed in vivo in the Syrian hamster gonadal regression model.

Animals↗
PubMed1990

Structural requirements for inhibitors of poly(ADP-ribose) polymerase.

The purpose of this study was to examine the structure/activity relationships of a series of substituted benzamides as poly(ADP-ribose) polymerase inhibitors. The experimental approach has involved the use of in vitro and in vivo assays in order to gather information either on the intrinsic activity of the benzamides or on the effect of various pharmacodynamic parameters on the activity in vivo. Although some discrepancies between the data obtained in vivo and in vitro were found in this study, results seem to indicate that most powerful inhibitors were characterized by acylation of the -NH2 function in the 3 position or by substitution in this same position with hydroxy or methoxy groups. The best inhibitors were not cytotoxic under these experimental conditions. Computed calculations of molecular electrostatic potential of these molecules were also performed and a good correlation was found between the similarity index and the experimental inhibitory activity.

Benzamides↗
PubMed1990

7-Substituted theophyllines. Part VI--N-[2-(4-chlorophenoxy)-1-phenyl-alkyl]-alkylamido derivatives.

The new amides are inhibitors of cholesterol biosynthesis in vitro as well as in vivo. These compounds are also inhibitors in vivo of triglyceride biosynthesis and of platelet aggregation. All tests showed activity (values expressed as percentage variation) much greater than clofibrate. Besides, all compounds have no effect on coagulation or diuresis and showed low acute toxicity.

Animals↗