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Biomedical subjects

F Sparatore

Publications and source records attributed to F Sparatore.

At least 37 records · Page 2Linked to original sources
PubMed1997

New benzamide-derived 5-HT3 receptor antagonists which prevent the effects of ethanol on extracellular dopamine, and fail to reduce voluntary alcohol intake in rats.

A set of substituted benzamides, characterized by the presence of a bulky quinolizidine moiety, were subjected to binding assays for 5-HT3 and D2 receptors on membranes obtained from the bovine area postrema ([3H]-GR65630) and the rat striatum ([3H]-spiperone) respectively. These benzamides resulted unsuitable for the recognition of D2 receptors, while a few of them, devoid of 5-HT4 receptor activity, had consistent affinity for central 5-HT3 receptors, inhibiting also potently the ethanol-induced dopamine efflux from the mesolimbic dopamine terminal region. However they failed in attenuating voluntary alcohol consumption in rats, as observed with several other chemically unrelated 5-HT3 antagonists. Thus the 5-HT3-mediated inhibition of alcohol-induced striatal release of dopamine by substituted benzamides is not a requisite for affecting ethanol intake.

Alcohol Drinking↗
PubMed1996

Synthesis and preliminary pharmacological investigation of N-lupinyl-2-methoxybenzamides.

A set of eleven N-lupinyl-2-methoxybenzamides, variously substituted on the benzene ring, together with two related compounds, were prepared and subjected to a large pharmacological screening, though not all compounds were tested in each assay. Compounds 1-10 displaced [125I]-iodosulpride from D2 receptors only at very high concentration (IC50 > 5 microM). At micromolar concentrations, compounds 1, 12, and 13 inhibited the binding of [3H]-pirenzepine and of [3H]-di-o-tolylguanidine respectively on M1 and sigma receptors; in the last case comp. 13 was more active (IC50 = 0.3 microM) than the epimeric 1. Compounds 1-10 at 10-25 mg/kg p.o. protected mice against electroshock induced seizures; 1-sulpiride was inactive in this test. Compound 1 exhibited in three tests antiarrhythmic activity superior to that of quinidine and lidocaine. The same antagonized, in vitro, guinea pig ileum contractile response induced by several agents, and enhanced the intestinal transit rate in mice (charcoal bolus test). The last activity (shown in lower degree also by comp. 5) could be related to agonism with 5HT4 receptors, as could be expected for orthopramides with conformationally restricted side chains. This possibility is presently under investigation.

Animals↗
PubMed1996

7-(N-substituted)amino-2,3-polymethylene benzofurane derivatives with tracheal relaxant activity.

A set of twelve 7-(N-substituted)amino-2,3-polymethylenebenzofuranes (1-12) together with three related compounds (13-15) was prepared. Ten selected compounds were tested for tracheal relaxant activity in vitro and two of them (6,7) were also subjected to a broad pharmacological screening. Five compounds (2,7,9,12,14) at the concentration of 30 micrograms/ml exhibited high tracheal relaxant activity (73-94% tone reduction) that was superior than that of theophylline at the same concentration. The 7-(N-trifluoromethylsulfonyl)amino-2,3-tetramethylenebenzofuran e (9) was highly active till the concentration of 1 microgram/ml giving a stronger tracheal relaxation than amrinone at 3 micrograms/ml. On the other hand the general screening did not show any other major activity. The benzofurane derivatives 1-13 were obtained through obvious steps from the corresponding 7-nitrobenzofuranes, which were prepared by a Fischer indole-like cyclization of O-[(2-nitro)phenyl] ketone oximes. In one case two peculiar side products were isolated.

Animals↗
PubMed1995

Preparation and pharmacological activities of homolupinanoyl anilides.

On the pattern of well known dialkylaminoacyl anilides, a set of N-homolupinanoyl anilides was prepared and subjected to a broad pharmacological screening with in vivo and in vitro assays. As expected most compounds exhibited a strong antiarrhythmic activity, often comparable or superior to that of lidocaine and quinidine. Compound 1 exhibited an unusual profile as antiarrhythmic, being devoid of local anesthetic activity, calcium channel and beta adrenoceptor antagonism. Calcium channel blocking activity was seen in all aminobenzophenone derivatives, but not in the simpler anilides. Noteworthy are also the capacity of compound 7 to protect mice from a lethal dose of KCN, the moderate antihypertensive activity of 10 and, above all, the antagonism to guinea pig ileum contractile responses induced by several agents exhibited by compound 11, which deserves further investigation for a potential use in irritable bowel syndrome. Compound 11 showed also good relaxant activity on tracheal strips and inhibitory activity against arachidonate induced platelet aggregation. Finally, compound 11 displaced several radioligands from their respective binding sites. Most potent was displacement of [3H]pirenzepine (IC50 < or = 0.01 microM) from M1 binding sites of rat brain, while displacement of [3H] methylscopolamine from rat heart (M2) and submaxillary salivary glands (M3) preparations was much weaker (IC50 approximately equal to 2.4 and 1.3 microM, respectively).

Adrenergic alpha-1 Receptor Antagonists↗
PubMed1994

Choleretic activity of 3-[ring substituted benzotriazol-1(2)-yl]alkanoic and alkenoic acids.

In order to investigate the influence of structural modifications on the high choleretic activity of 3-(benzotriazol-1-yl)butanoic acid, a set of new benzotriazolyl alkanoic and alkenoic acids was prepared and, together with some other acids previously described, tested in rats by i.v. administration at the dose of 0.5 mmol/kg. Most of the tested compounds exhibited a good choleretic activity comparable with or higher than that of the model acid and of dehydrocholic acid (+56% mean increase of bile volume during 4 hours). Influence of nature and position of substituents was shown in some cases: a moderate decrease of activity was observed for methoxy derivatives and for the introduction of a methyl group in position 6, while a trifluoromethyl group in the same position enhanced the activity (10). Activity was maintained after the introduction of unsaturation in the chain (17,18), but was completely suppressed when unsaturation was associated with a shortening of the alkenoic chain (16). Moving the butanoic chain from position 1 to position 2 in the case of the nitroderivative (15) produced a striking increase of activity (from +42 to +118 mean variation of bile volume during 4 hours), while the same change in the unsubstituted acid 1 abolished the activity.

Animals↗
PubMed1994

Preparation and pharmacological activities of 10-homolupinanoyl-2-R-phenothiazines.

Pursuing our researches on quinolizidinyl derivatives of phenothiazine and on the ground of antidepressive, diuretic, antianginal and antiarrhythmic activities of several 10-(3-dialkylamino) propionylphenothiazines (as chloracizine, moricizine, etc.), six 10-homolupinanoyl-2-R-phenothiazines were prepared and subjected to a broad pharmacological screening with in vivo and in vitro assays. Most of these compounds exerted strong antiarrhythmic activity (compounds 1, 3 and 5 were comparable or superior to lidocaine and quinidine in three tests), calcium antagonism on guinea pig ileum and left atria, antagonism to smooth muscle contractile responses induced by several agents and inhibition of rabbit platelet aggregation induced by PAF and ADP. A few other activities were characteristic of single compounds, as antagonism to central and peripheral effects of oxotremorine 1, moderate antihypertensive activity 5, local anesthetic activity and antagonism to substance P 2, antiinflammatory activity with low or absent gastric irritation 2, 3, powerful saluretic action 6, inhibition of arachidonate induced platelet aggregation 1 and antagonism to PAF induced mortality 1, 4. The last activity is very unusual and deserves further investigation. The capacity of compound 1 to displace specific ligands from several receptors was also investigated. Significant binding for M1 (IC50 = 0.03 microM), M3 (IC50 = 10 microM), sigma receptors and Na+ channels (IC50 = 1 microM) were evidentiated.

Animals↗
PubMed1994

Quinolizidine derivatives with antitubercular activity.

By reacting lupinylmagnesium chloride with suitable aromatic ketones, several lupinyldiarylcarbinols were obtained, whose dehydration gave the corresponding lupinylidenediarylmethanes. By reduction of three of these unsaturated compounds, the corresponding lupinyldiarylmethanes were also obtained. Direct condensation of lupinine with fluorene gave the 9-epi-lupinylfluorene. The quinolizidine derivatives obtained were tested against Mycobacterium tuberculosis H37RV. Nine compounds resulted endowed with good antitubercular activity with MIC < 8 micrograms/ml, while the remaining were only moderately active. Most interesting was the lupinylidene derivative 13 with MIC > 0.1 < 0.5 micrograms/ml.

Antitubercular Agents↗
PubMed1994

Rosmaricine derivatives as potential antitumoral agents.

A group of N-(alkylaminoacyl)-O,O-dimethylrosmaricines was prepared and, together with a set of rosmaricine derivatives previously described by us, evaluated for activity against lymphocytic leukemia P 388. Only one compound exhibited a borderline activity, while all the others were inactive.

Animals↗
PubMed1994

N-[(N-halogenoacyl)imino]acenaphthene-quinoxalines as potential antitumoral agents.

Applying a reaction formerly studied by the Authors between acenaphthenequinone and N1-(2-amino)phenyl-N2-acylhydrazines, a group of N-[(N-alpha- and beta- halogenoacyl)imino]acenaphthenequinoxalines were obtained. On account of the reactivity of the halogen atom, they are potentially interesting as antitumoral agents. In contrast with the beta-chloropropionyl derivative, the alpha-halogenoacyl derivatives were formed in low yields and with the simultaneous loss of the whole halogenoacylimino group. Thus, an alternative synthetic route was set up, consisting in the N-imination of acenaphthenequinoxalines by means of O-mesitylenesulfonylhydroxylamine, followed by acylation of the intermediate N-iminoacenaphthenequinoxalines. The National Cancer Institute of Bethesda evaluated the activity against lymphocytic leukemia P 388 on some of the numerous compounds now described. Only the N-chloroacetyliminoacenaphthenequinoxaline exhibited, at the dose of 50 mg/Kg i.p., 35% increase of the average survival time of treated mice. All the remaining compounds were inactive.

Animals↗
PubMed1993

Thiolupinine and some derivatives of pharmacological interest.

The (quinolizidin-1 alpha-yl)methanthiol (thiolupinine) was prepared and, utilizing the thiol group reactivity, several S-substituted derivatives were obtained among which was a group of 3-[(lupinylthio)methyl]indoles. Eight of the prepared compounds were subjected to a broad pharmacological screening that evidentiated for many of them good level of the following activities in vivo and in vitro: antiarrhythmic, local anesthetic, negative chronotropic on isolated atria, calcium antagonism on ileum and atria, inhibition of spontaneous contraction of isolated trachea, inhibition of guinea pig ileum contractions induced by angiotensin I and II, bradykinin and cholecystokinin, inhibition of platelet aggregation induced by PAF and ADP. Single compounds were remarkable for additional antagonistic activities: 4 against P1-purine receptor, 8 against substance P, 12 against methacholine and 13 strongly inhibited arachidonate induced platelet aggregation. Very peculiar was the ability of compound 6 to protect mice from PAF induced mortality.

Anesthetics, Local↗
PubMed1993

Synthesis and evaluation of gastroprotective activity of omeprazole related benzimidazole, imidazo[4,5-b]pyridine and quinoxaline 2-substituted derivatives.

Twenty compounds possessing benzimidazole, imidazo[4,5-b]pyridine and quinoxaline structure bearing either a substituted arylmethylmercapto- or an arylmethylsulfinyl group in position 2 were prepared in order to evaluate an antiulcer and gastroprotective activity in rat pylorus ligature, in comparison with omeprazole at the dose of 50 mg/kg after i.m. administration. One third of these compounds showed a moderate activity, being about half potent as omeprazole.

Animals↗
PubMed1993

Amides and formamidines with antinociceptive activity (note I).

Pursuing our investigations on N-aryl or N-cycloalkyl substituted amides and formamidines with antiinflammatory and/or analgesic activity, two set of cycloalkyl substituted amides and formamidines were prepared and tested for analgesic activity against a chemical stimulus. Some compounds, particularly the amides 7, 11, 17 and the formamidine 35 proved to be endowed with this activity.

Amides↗
PubMed1993

Amides and formamidines with antinociceptive activity (note II).

Forty amides, formamidines and trifluoromethylsulfonylamides bearing on the nitrogen a cyclohexyl residue, eventually 2-substituted, were prepared and tested for analgesic activity against a chemical stimulus. Good activity was exhibited by amides 9, 11 and 28, by formamidine 34, as well as by triflyamide 40. Eleven additional compounds exhibited a moderate activity.

Amides↗
PubMed1993

N-[4-(R',R"-phenylazo)aryl]aminolupinanes with antitubercular activity.

A set of twelve N-[4-(R-phenylazo)aryl]aminolupinanes (10a-c; 11a-i) was prepared by coupling the suitably substituted phenyldiazonium salts with N-(2,3-xylyl)-aminolupinane and with N-(5,6,7,8-tetrahydronaphth-1-yl)- aminolupinane. These compounds, as well as the N-(4-amino-2,3-xylyl)aminolupinane and the N-(4-amino-5,6,7,8-tetrahydronaphth-1-yl)-aminolupinane, that could be obtained from the former through an in vivo reductive cleavage of the azo group, exhibited a high activity against Mycobacterium tuberculosis H37RV with M.I.C. in the range 0.1-1 microgram/ml.

Antitubercular Agents↗
PubMed1993

Synthesis and antimicrobial activity of arylazoenamines.

The possibility to obtain new arylazoenamines endowed with antifungal activity was examined by reacting with acids the arylhydrazones of several keto- and aldo-tert, amines as dimethyl-3-aminoacetone, 3-quinuclidinone, 1-methyl-3-piperidone and 2-formyl-1-methylpyrrolidine. The reaction was successful only in the last two cases. From each 1-methyl-3-piperidone arylhydrazone two isomeric arylazoenamines were formed, which were identical with those obtained from the analogous arylhydrazone of 2-formyl-1-methylpyrrolidine. The structure of these compounds was settled on the ground of UV, IR, NMR and mass spectra and confirmed by means of X-ray analysis. A mechanism is proposed for the formation of arylazoenamines through the contraction of piperidine ring and enlargement of the pyrrolidinic one. The prepared compounds [3-arylazo-1-methyl-delta 2-piperideines 17 and 1-methyl-2(arylazo)methylene pyrrolidines 18 exhibited only a very weak antibacterial activity, but were moderately active against several Candida species and other yeast-like fungi.

Anti-Bacterial Agents↗
PubMed1992

Cyclopentenyl ethylamines active on CNS.

Two new cyclopentenylethylamines were prepared and were submitted to a pharmacological screening together with some others previously described and now reprepared. All compounds exhibited different degrees of depressive activity on CNS and good analgesic activity. Compound 5, bearing a phenyl group on the carbon atom to which the amino group is connected, appears rather interesting being the most active as analgesic and the least toxic. Compounds 2 and 3 are able to antagonize in a certain degree lethal doses of physostigmine and also, respectively, of pentylenetetrazole and strychnine.

Analgesics↗
PubMed1992

Synthesis of substituted DL-3(5-benzazolyl)alanines as dopa and alpha-methyldopa analogs and their effects on dopamine beta-hydroxylase, tyrosinase and diphenoloxidase.

The influence of bioisosteric replacement of catechol moiety of L-Dopa and alpha-Methyldopa with benzimidazole and benzotriazole ring has been examined on dopamine beta-hydroxylase and tyrosinase, in order to evidentiate an inhibitory activity on the synthesis of catecholamines and a possible antihypertensive action. The preliminary results obtained so far showed that inhibition of dopamine hydroxylase occurs at 5 x 10(-4) M concentration for the most active compounds bearing a trifluoromethyl group in the azole ring (2a,c). An analogous result was observed in the case of tyrosinase inhibition with compound 2c, while other compounds (2a,e) were equiactive (92% inhibition) at higher concentration (1 x 10(-3) M). Compound 2c was also the most active in inhibition of diphenoloxidase (83% at 6 x 10(-5) M concentration).

Adrenal Glands↗