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Biomedical subjects

A Gasco

Publications and source records attributed to A Gasco.

At least 19 recordsLinked to original sources
PubMed2004

Identification of 2,3-diaminophenazine and of o-benzoquinone dioxime as the major in vitro metabolites of benzofuroxan.

1. The results of an in vitro study of the metabolism of benzofuroxan using either cytosolic or microsomal fractions obtained from rat liver are reported. 2. Benzofuroxan was incubated with an appropriate volume of cytosol or microsomal suspension; control incubations were performed without the beta-nicotinamide adenine dinucleotide phosphate-generating system or, alternatively, by using the subcellular fractions inactivated by heating. Incubation mixtures were analysed by high-performance liquid chromatography. Two principal metabolites (M1, M2) were identified in the cytosolic fraction only. The dependence of M2 formation on thiol cofactors, incubation time and protein concentration was examined. 3. The two metabolites were isolated and characterized by their 1H-, 13C-nuclear magnetic resonance, infrared and mass spectra. The structures of o-benzoquinonedioxime (2) and 2,3-diaminopleuozuc (3), were arranged to M1 and M2 respectively. The proposed structures were confirmed by the identity of the metabolites with authentic samples obtained by synthesis. X-ray analysis showed that the dioxime metabolite had an amphy configuration. 4. A metabolic scheme for the formation of the two products is proposed.

Animals↗
PubMed2003

Synthesis and vasodilating properties of N-alkylamide derivatives of 4-amino-3-furoxancarboxylic acid and related azo derivatives.

A series of N-alkylamide derivatives of 4-amino-3-furoxancarboxylic acids 5a-11a and their oxidation products, the azo derivatives 5b-11b, were synthesised and studied for their vasodilating properties. All the products were able to release rat aorta strips precontracted with (-)noradrenaline. Azo derivatives proved to be 20-200 times more potent than the parent amines. The large variation of lipophilicity within the two series does not seem to influence significantly the activity. Experiments carried out in the presence of oxyhaemoglobin (HbO(2)) suggest the involvement of nitric oxide (NO*) in the vasodilation.

Animals↗
PubMed2001

A new class of ibuprofen derivatives with reduced gastrotoxicity.

A new series of nonsteroidal antiinflammatory drugs (NSAIDs) obtained by linking ibuprofen to selected furoxan moieties and to related furazans were synthesized and tested for their antiinflammatory, antiaggregatory, and ulcerogenic properties. All the derivatives are endowed with antiinflammatory activity comparable to that of ibuprofen, but, unlike this drug, they display reduced acute gastrotoxicity. The masking of the ibuprofen-free carboxylic group seems to be principally at the basis of this reduced topical irritant action. The two furoxan derivatives 8 and 9 also trigger potent antiaggregatory effects, principally as a consequence of their NO-donor ability.

Animals↗
PubMed2001

Anti-Helicobacter pylori agents endowed with H2-antagonist properties.

New anti-Helicobacter pylori (H. pylori) agents endowed with H2-antagonists properties were obtained by combining the lamtidine derived pharmacophoric group with the antibiotic calvatic acid. All the compounds were tested for their irreversible H2-antagonist properties and for their ability to inhibit 20 H. pylori strains, two of them metronidazole resistant. The most active derivative (compound 4) displayed antimicrobial activity similar to metronidazole.

Animals↗
PubMed2001

Nitroanilines are the reduction products of benzofuroxan system by oxyhemoglobin (HbO2 2+).

Benzofuroxans are interesting compounds which display several biochemical and pharmacological properties. Recent studies from our laboratory demonstrate that they are reduced by ferrous salts at room temperature and that the principal reaction products are o-nitroanilines. This paper shows that simple benzofuroxan derivatives are also able to oxidise HbO2 2+ to methemoglobin (MetHb3+) (UV detection) and to form o-nitroanilines (HPLC detection). From a toxicological point of view this reaction is interesting, since it indicates that the blood is a site for metabolism of these compounds with consequent methemoglobinemia and formation of toxic compounds.

Aniline Compounds↗
PubMed2001

Searching for balanced hybrid NO-donor 1,4-dihydropyridines with basic properties.

PURPOSE: Model compounds containing NO-donor furoxan moieties at the 3-positioned basic lateral chain of 1, a 1,4-dihydropyridine related to nicardipine, were synthesized in order to study their vasodilating activity as well as their basic and lipophilic behaviour. METHODS: All the compounds were obtained by a modified Hantzsch approach. Potentiometry was used to determine pKa and lipophilicity descriptors. The furoxan 4-aryl-1,4-dihydropyridines were assessed for their ability to release nitrite, in the presence of a large excess of cysteine, by the Griess reaction. Vasodilating activity of the products in the absence and in the presence of ODQ, a well-known guanylate cyclase inhibitor, was evaluated on rat thoracic aorta. RESULTS: The compounds display low basicity values and for this reason their log Ds at physiological pH are identical to the log Ps of the neutral forms. Products 2, 3 display vasodilating action principally dependent on their Ca2+-antagonist properties, whereas 4 behaves as a well-balanced hybrid with mixed Ca2+-channel blocker and NO-dependent vasodilator activities. CONCLUSIONS. Nitrogen containing lateral chain at the 3-position of 1 is a suitable molecular region to be modified in order to obtain well-balanced furoxan NO-donor 1,4-DHPs. This manipulation produces a decrease in the basicity. General analysis of pKa and lipophilicity descriptors of these new DHPs suggest that molecular flexibility could influence both their basicity and log PI.

Animals↗
PubMed2001

Studies on agents with mixed NO-dependent and calcium channel antagonistic vasodilating activities.

PURPOSE: To obtain new cardiovascular agents with mixed Ca2+-channel antagonistic and NO-donor properties, a series of "hybrid" 1,4-dihydropyridines (1,4-DHPs), bearing NO-donating furoxan moieties on the 3-positioned lateral ester chain were synthesized and pharmacologically characterized. Furazan analogues were also prepared and investigated for control purposes, because they are unable to release NO. METHODS: Synthesis of the models was achieved by a modified Hantzsch approach. All of the final furoxan 1,4-DHPs were assessed for their ability to produce nitrite in the presence of a large excess of cysteine by the Griess reaction. Vasodilating activity was evaluated on rat aorta and expressed as EC50 and EC50MB values, obtained in the absence and in the presence of methylene blue (MB) respectively, a well-known guanylate cyclase inhibitor. Affinities to 1,4-DHP receptor on Ca2+-channels, expressed as IC50 values, were determined through displacement experiments of [3H]-nitrendipine on rat cortex homogenates. RESULTS: Some hybrid compounds (derivatives 15a, 15b, 16a, and 16b) displayed vasodilating activity depending predominantly on their Ca2+-channel blocker properties. By contrast, some others (derivatives 17a, 17b, and 21) behaved as well-balanced hybrids with mixed Ca2+-channel blocking and NO-dependent vasodilating activities. CONCLUSION: This work demonstrates the possibility of obtaining well-balanced hybrids endowed with mixed NO-donor and Ca2+-channel blocker properties using appropriate 1,4-DHP and furoxan moieties. A procedure for the individual evaluation of the NO-dependent vasodilator component and that due to Ca2+-channel blocking is proposed.

Animals↗
PubMed2000

In vitro and in vivo vasodilating activity of nitroso derivatives gem -substituted with electron-withdrawing groups.

A series of nitroso compounds gem -substituted with electron-withdrawing groups (R(2)C(X)NO, R=alkyl, X=NO(2), CN, Cl), were studied for their in vitro and in vivo vasodilating properties as well as for their ability to activate soluble guanylate cyclase (sGC) in RFL-6 cells. All the compounds, with the sole exception of chloro derivative, display good in vitro vasodilating action and are able to increase the basal level of cGMP. Their potencies as vasodilators decrease in the presence of oxyhaemoglobin, a scavenger of nitric oxide (NO). The haemodynamic profile of the most interesting compounds, assessed in anaesthetized pigs, is also in line with a release of NO from these compounds.

Action Potentials↗
PubMed2000

Nicorandil analogues containing NO-donor furoxans and related furazans.

The synthesis and in vitro vasodilating properties of hybrid compounds in which furoxan (1,2,5-oxadiazole 2-oxide) moieties, endowed with different NO-donor properties, were substituted for the nitroxy function of Nicorandil are reported. The corresponding cyanoguanidine analogues are also considered. This approach has led to a series of vasorelaxing compounds devoid of affinity for K(ATP) channels, whose activity is prevalently due to their ability to activate sGC, at the concentrations of the experiments. Related furazan (1,2,5-oxadiazole) derivatives, unable to release nitric oxide were also prepared and studied for control. The amide analogues of Nicorandil display feeble vasorelaxing action not involving the activation of K+ channels, while in the guanidine analogues, this mechanism seems to underlie this action.

Animals↗
PubMed1999

Synthesis and voltage-clamp studies of methyl 1,4-dihydro-2, 6-dimethyl-5-nitro-4-(benzofurazanyl)pyridine-3-carboxylate racemates and enantiomers and of their benzofuroxanyl analogues.

Racemic methyl 1,4-dihydro-2, 6-dimethyl-5-nitro-4-(benzofurazanyl)pyridine-3-carboxylates (+/-)-10 and (+/-)-11 and their benzofuroxanyl analogues (+/-)-12 and (+/-)-13 were prepared using a modified Hantzsch reaction that involved the condensation of nitroacetone with methyl 3-aminocrotonate and the appropriate aldehydes. The racemic mixtures were resolved into the corresponding enantiomers. Whole-cell voltage-clamp studies on L-type Ca2+ channels expressed in a rat insulinoma cell line (RINm5F) showed that all the dextrorotatory antipodes were effective agonists of L-type Ca2+ currents, while the levorotatory ones were weak Ca2+ entry blockers. The (+)-enantiomer of benzofurazan-5'-yl derivative 11 demonstrated unusual activity in that, in addition to producing a potentiation of L-type currents, it interfered with the voltage-dependent gating of L-type channels by producing a net delay of their activation at low voltages. This compound represents an interesting tool to probe L-type Ca2+ channel structure and function.

Animals↗
PubMed1999

Resolution of some 4-benzofurazanyl and 4-benzofuroxanyl 1, 4-dihydropyridine derivatives by chiral HPLC on whelk-o1 and some polysaccharide chiral stationary phases

The chromatographic chiral resolution of racemic methyl 1, 4-dihydro-2,6-dimethyl-5-nitro-4-benzofurazanyl-3-carboxylates 1 and 2 and their benzofuroxanyl analogues 3 and 4 were studied on Whelk-O1, Chiralcel OD-H, Chiralcel OJ, and Chiralpak AD and AS. These CSPs were selected on the basis of the results of structural searches in Chirbase. Examination of the data and cluster analysis pointed out the influence of benzofurazane-benzofuroxane change versus alpha-beta connection change on retention and enantioselectivity, respectively. The major contribution to the retention change arose from the type of heterocycle, whereas the major contribution to the enantioselectivity change came from the mode of connection (alpha or beta) almost irrespective of the nature of the heterocycle. It resulted in a similarity of behaviour between 1 and 2 on one hand and 3 and 4 on the other as far as capacity factors were concerned, and in a similarity of behaviour between 1 and 3 on the one hand and 2 and 4 on the other as far as enantioselectivities were concerned. Chiralpak AS was selected for semipreparative resolution of the enantiomers. The study of several CSPs allowed us to obtain correlations of structure with retention and enantioselectivity as well as the choice of a semipreparative support to provide the quantities for biological tests. Copyright 1999 Wiley-Liss, Inc.

Journal Article↗
PubMed1999

NO donor and biological properties of different benzofuroxans.

PURPOSE: To investigate the effect of benzofusion on NO donor properties and related biological activities of the furoxan system. The biological properties considered were the ability to increase the cytosolic levels of cGMP in C6 cells and vasodilation. METHODS: NO donor properties were investigated either in the presence or the absence of cysteine by using the Griess reaction, chemiluminescence, and gas chromatography. Increase of cytosolic cGMP levels were evaluated by radioimmunoassay. Vasodilating activity was assessed on rat aorta strips precontracted with noradrenaline, in the presence and the absence of oxyhemoglobin (HbO2) and methylene blue (MB), respectively. RESULTS: Benzofuroxan and its methyl and cyano derivatives were unable to release NO under the experimental conditions. Generally these compounds displayed feeble vasodilating properties and were able to weakly stimulate soluble guanylate cyclase (sGC). By contrast, benzodifuroxan and benzotrifuroxan were able to produce both NO* and its reduced form NO- , the nitroxyl anion. They displayed potent vasodilating properties and were able to increase cytosolic levels of cGMP in a concentration-dependent manner. CONCLUSIONS: The simple benzofuroxans considered here are devoid of the capability to release NO, they weakly stimulate sGC as well as manifest feeble vasodilating properties by a mechanism that does not involve a thiol-induced NO production. By contrast, benzodifuroxan and benzotrifuroxan behave as typical NO donor furoxans.

Animals↗
PubMed1999

N-Substituted analogues of S-nitroso-N-acetyl-D,L-penicillamine: chemical stability and prolonged nitric oxide mediated vasodilatation in isolated rat femoral arteries.

Previous studies show that linking acetylated glucosamine to S-nitroso-N-acetyl-D,L-penicillamine (SNAP) stabilizes the molecule and causes it to elicit unusually prolonged vasodilator effects in endothelium-denuded, isolated rat femoral arteries. Here we studied the propanoyl (SNPP; 3 carbon side-chain), valeryl (SNVP; 5C) and heptanoyl (SNHP; 7C) N-substituted analogues of SNAP (2C), to further investigate other molecular characteristics that might influence chemical stability and duration of vascular action of S-nitrosothiols. Spectrophotometric analysis revealed that SNVP was the most stable analogue in solution. Decomposition of all four compounds was accelerated by Cu(II) and cysteine, and neocuproine, a specific Cu(I) chelator, slowed decomposition of SNHP. Generation of NO from the compounds was confirmed by electrochemical detection at 37 degrees C. Bolus injections of SNAP (10 microl; 10(-8)-10(-3) M) into the perfusate of precontracted, isolated rat femoral arteries taken from adult male Wistar rats (400-500 g), caused concentration-dependent, transient vasodilatations irrespective of endothelial integrity. Equivalent vasodilatations induced by SNVP and SNHP were transient in endothelium-intact vessels but failed to recover to pre-injection pressures at moderate and high concentrations (10(-6)-10(-3) M) in those denuded of endothelium. This sustained effect (> 1 h) was most prevalent with SNHP and was largely reversed by the NO scavenger, haemoglobin. We suggest that increased lipophilicity of SNAP analogues with longer sidechains facilitates their retention by endothelium-denuded vessels; subsequent slow decomposition within the tissue generates sufficient NO to cause prolonged vasodilatation. This is a potentially useful characteristic for targeting NO delivery to areas of endothelial damage.

1-Octanol↗
PubMed1998

New 1,4-dihydropyridines conjugated to furoxanyl moieties, endowed with both nitric oxide-like and calcium channel antagonist vasodilator activities.

A series of 4-phenyl-1,4-dihydropyridines substituted at the ortho and meta positions of the phenyl ring with NO-donating furoxan moieties and their non-NO-releasing furazan analogues were synthesized and pharmacologically characterized. The vasodilator activities of these compounds were evaluated on rat aorta and expressed as EC50 values or as EC50iGC values when obtained in the presence of inhibitors of guanylate cyclase methylene blue (MB) and 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ). Affinities to 1, 4-DHP receptors on Ca2+ channels, expressed as IC50 values, were determined through displacement experiments of [3H]nitrendipine on rat cortex homogenates. A linear correlation between IC50 and EC50 values was found for compounds unable to release NO. EC50calcd values for derivatives containing NO-donor moieties, expression of the Ca2+-blocking component of their vasodilator activity, were interpolated on this linear regression. They showed a good correspondence with EC50iGC values determined in the presence of soluble guanylate cyclase inhibitors. Analysis of EC50iGC/EC50 ratios provided a useful tool to distinguish well-balanced hybrids from derivatives biased toward Ca2+-blocking or NO-dependent vasodilator activity. A detrimental effect on affinity to the 1, 4-DHP receptor, due to substitution at the ortho and meta positions of the 4-phenyl ring, was observed. SAR to explain this effect is proposed.

Animals↗
PubMed1998

Pyrazole analogues of prazosin.

A series of analogues of prazosin, in which 1-methyl or 1-phenylpyrazole moieties were substituted for the furan ring, were synthesized and studied for their alpha 1-adrenoceptor antagonist activity. The role of the five member heterocyclic substructures in determining the affinity for the alpha 1-receptor is briefly discussed.

Adrenergic alpha-Antagonists↗
PubMed1998

Mechanisms of liposomes/water partitioning of (p-methylbenzyl)alkylamines.

PURPOSE: The objective of this study was to compare and interpret the variations in lipophilicity of homologous (p-methylbenzyl)alkylamines (MBAAs) in isotropic (octanol/water) and anisotropic (zwitterionic liposomes/water) system. METHODS: Two experimental approaches were used, namely the pH-metric method to measure lipophilicity parameters in octanol/water and liposomes/water systems, and changes in NMR relaxation rates to validate the former method and to gain additional insights into the mechanisms of liposomes/water partitioning. RESULTS: For long-chain homologues (N-butyl to N-heptyl), the octanol/water and liposomes/water systems mostly expressed hydrophobicity. In contrast, the lipophilicity of the shorter homologues (N-methyl to N-propyl) in the two systems expressed various electrostatic and polar interactions. CONCLUSIONS: The study sheds light on the molecular interactions between zwitterionic liposomes and amphiphilic solutes in neutral and cationic form.

1-Octanol↗
PubMed1998

Characterisation of furoxancarbonitriles as a new class of vasodilators.

The synthesis, structural characterization, NO-donor properties, and in vitro vasodilating activities of a series of furoxancarbonitriles 2, 17-22a, b are reported. Some derivatives (2b, 2a, 18b, 21b, 22b) are more potent vasodilating agents than sodium nitroprusside (SNP), the reference compound, some others display similar potency (17b, 19b, 20b). Log EC50 values fit well on the linear correlation log EC50 versus log C0.1(1 min) (namely the logarithm of the concentration able to release 2.6 mumol l-1 min-1 of NO) found in a previous work. The haemodynamic profile in anaesthetised pigs for some selected derivatives (2a, b, 19a, b) is also presented. These profiles are consistent with that known for another furoxan NO-donor (4-hydroxymethyl-3-furoxancarboxamide, CAS 1609) and suggest similar characteristic of in vivo NO-release.

Animals↗