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M Zappalà

Publications and source records attributed to M Zappalà.

At least 37 records · Page 2Linked to original sources
PubMed1998

3,5-Dihydro-4H-2,3-benzodiazepine-4-thiones: a new class of AMPA receptor antagonists.

Synthesis and evaluation of anticonvulsant activity of a series of 2,3-benzodiazepin-4-ones (2) chemically related to 1-(4'-aminophenyl)-4-methyl-7,8-(methylenedioxy)-5H-2,3-benzodiazepine (1, GYKI 52466) have been reported in our recent publications. Compounds 2 manifested marked anticonvulsant properties acting as 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA) receptor antagonists. In an attempt to better define the structure-activity relationships (SAR) and to obtain more potent and selective anticonvulsant agents, 1-aryl-3,5-dihydro-4H-2, 3-benzodiazepine-4-thiones 3 were synthesized from the corresponding isosteres 2. The evaluation is reported of their anticonvulsant effects, both in the audiogenic seizures test with DBA/2 mice and against the maximal electroshock- and pentylenetetrazole-induced seizures in Swiss mice. New derivatives 3 showed higher potency, less toxicity and longer-lasting anticonvulsant action than those of the parent compounds 2 in all tests employed. Analogous to derivatives 2, new compounds 3 do not affect the benzodiazepine receptor (BZR) while they do antagonize AMPA-induced seizures; their anticonvulsant activity is reversed by pretreatment with aniracetam but not with flumazenil, thus suggesting a clear involvement of AMPA receptors. Electrophysiological data indicate a noncompetitive blocking mechanism at the AMPA receptor sites for 3i, the most active of the series and over 5-fold more potent than 1.

Acoustic Stimulation↗
PubMed1998

7,8-Methylenedioxy-4H-2,3-benzodiazepin-4-ones as novel AMPA receptor antagonists.

The synthesis and anticonvulsant activity of novel 7,8-methylenedioxy-4H-2,3-benzodiazepin-4-ones 3a-e, structurally-related to GYKI 52466 1, a well-known noncompetitive AMPA-receptor antagonist, are reported. The new compounds possess marked anticonvulsant properties and, in analogy to 1, antagonize seizures induced by AMPA. In addition, when compared to the model compound 1, compounds 3 show a longer-lasting anticonvulsant activity and a lower toxicity.

Acoustic Stimulation↗
PubMed1998

High-performance liquid chromatographic determination of new 2,3-benzodiazepines.

A simple high-performance liquid chromatographic assay with ultraviolet detection at 254 nm for simultaneous determination of 2,3-benzodiazepine derivatives (2,3-BZ2 and 2,3-BZ2Me) and their metabolites in rat plasma is described. The procedure involves a fast extraction of the drugs from the buffered sample using methanol. The extract is evaporated to dryness at 45 degrees C and the residue is redissolved in methanol (twice). A 20-microl aliquot is injected into the liquid chromatograph and eluted with methanol-water (65:35, v/v) on a C18 reversed-phase column. At a flow-rate of 1.5 ml/min the detection time was 3.1 min for 2,3-BZ2, 5.06 min for 2,3-BZ2Me and 10.9 min for prazepam, used as internal standard for the quantification of the studied compounds. The method has been used to investigate the steady-state concentrations of two 2,3-benzodiazepine derivatives in Sprague-Dawley rat plasma.

Animals↗
PubMed1998

Synthesis, structure and in vitro anti-human immunodeficiency virus activity of novel 3-methyl-1H,3H-thiazolo[3,4-a]benzimidazoles.

A series of novel 1-aryl-3-methyl-1H,3H-thiazolo[3,4-a]benzimidazoles, TBZ analogues, were synthesized and investigated as anti-human immunodeficiency virus (HIV) agents in order to study the effects of structural modifications on antiviral activity and cytotoxicity. They were proved to inhibit significantly HIV-1 replication in vitro without showing inhibitory activity on HIV-2 or simian immunodeficiency virus. Their potency was influenced by the presence of suitable substituents in the phenyl ring at C-1 as well as by their stereochemical characteristics. In fact, the most active compound of the series was the trans-1-(2,6-difluorophenyl)-3-methyl-1H,3H-thiazolo[3,4- a]benzimidazole, in which the butterfly-like conformation is stabilized by two intramolecular hydrogen bonds between the fluorine atoms and H-1 and H-3. This was made possible by the trans arrangement of C-1 and C-3 substituents, as shown by X-ray and NMR analysis.

Anti-HIV Agents↗
PubMed1997

1-Aryl-3,5-dihydro-4H-2,3-benzodiazepin-4-ones: novel AMPA receptor antagonists.

Our previous publication (Eur. J. Pharmacol. 1995, 294, 411-422) reported preliminary chemical and biological studies of some 2,3-benzodiazepines, analogues of 1-(4-aminophenyl)-4-methyl-7,8-(methylenedioxy)-5H-2,3-benzodiazepine (1, GYKI 52466), which have been shown to possess significant anticonvulsant activity. This paper describes the synthesis of new 1-aryl-3,5-dihydro-4H-2,3-benzodiazepin-4-ones and the evaluation of their anticonvulsant effects. The observed findings extend the structure-activity relationships previously suggested for this class of anticonvulsants. The seizures were evoked both by means of auditory stimulation in DBA/2 mice and by pentylenetetrazole or maximal electroshock in Swiss mice. 1-(4'-Aminophenyl)- (38) and 1-(3'-aminophenyl)-3,5-dihydro-7,8-dimethoxy-4H-2,3-benzodiazepin- 4-one (39), the most active compounds of the series, proved to be more potent than 1 in all tests employed. In particular, the ED50 values against tonus evoked by auditory stimulation were 12.6 micromol/kg for derivative 38, 18.3 micromol/kg for 39, and 25.3 micromol/kg for 1. Higher doses were necessary to block tonic extension induced both by maximal electroshock and by pentylenetetrazole. In addition these compounds exhibited anticonvulsant properties that were longer lasting than those of compound 1 and were less toxic. The novel 2,3-benzodiazepines were also investigated for a possible correlation between their anticonvulsant activities against convulsions induced by 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA) and their affinities for benzodiazepine receptors (BZR). The 2,3-benzodiazepines did not affect the binding of [3H]flumazenil to BZR, and conversely, their anticonvulsant effects were not reversed by flumazenil. On the other hand the 2,3-benzodiazepines antagonized seizures induced by AMPA and aniracetam in agreement with an involvement of the AMPA receptor. In addition, both the derivative 38 and the compound 1 markedly reduced the AMPA receptor-mediated membrane currents in guinea-pig olfactory cortical neurons in vitro in a noncompetitive manner. The derivatives 25 and 38-40 failed to displace specific ligands from N-methyl-D-aspartate (NMDA), AMPA/kainate, or metabotropic glutamate receptors.

Acoustic Stimulation↗
PubMed1997

Synthesis and characterization in solid and solution of trans-dichloro-1-(2', 6'-difluorophenyl)-1H,3H-thiazolo [3,4-a]-benzimidazole(tri-n-propyl-phosphine)-palladium(II)": a palladium(II) complex of a ligand with anti-HIV properties.

The 1-(2',6'-difluorophenyl)-1H,3H-thiazolo[3,4-a]benzimidazole (L), a highly potent nonnucleoside HIV-1 reverse transcriptase inhibitor, has been reacted with [Pd2Cl4(PPr3n)2] in order to study its coordinating properties towards metal ions. The structure of the synthesized product has been examined in solution by 1H and 13C NMR, and in solid by X-ray analysis. [Pd(PPr3n)(L)Cl2] has a trans structure and L coordinates through imine nitrogen. The loss of anti-HIV properties of L, by complexation, suggests that, unless biological inactivation is simple due to steric reasons, the imine nitrogen atom is an active site of the molecule.

Anti-HIV Agents↗
PubMed1997

Anti-HIV agents. V. Synthesis, structure and in vitro anti-HIV activity of novel 1H,3H-naphtho[2',3':4,5]imidazo[1,2-c]thiazoles.

A series of 1H,3H-naphtho[2',3':4,5]imidazo[1,2-c]thiazoles, TBZ analogues, was prepared in order to explore the influence on anti-HIV activity of the spatial requirements of the hydrophobic moiety fused to imidazothiazole system. In spite of a butterfly-like conformation evidenced by X-ray analysis of compound 4g, the results of in vitro screening suggest that the replacement of the benzene fused ring by the naphthyl moiety negatively influences the activity of analogous thiazolobenzimidazole derivatives, some of which are potent non-nucleoside HIV-1 RT inhibitors.

Anti-HIV Agents↗
PubMed1995

Novel pyrrolo- and thiazolo-imidazoles.

In this study, the synthesis and the stereochemical features of novel tricyclic derivatives containing an imidazole nucleus are described. The biological properties of the synthesized compounds as well as some aspects of the structure activity relationship are also discussed.

Animals↗
PubMed1994

Anticonvulsant activity of pyrrolo[1',2':1,2]imidazo[4,5-b]pyridines, pyrrolo[2',1':2,3]imidazo[4,5-c] pyridines and pyrrolo[2,1-f]purines in DBA/2 mice.

1. The behavioural and anticonvulsant effects of eight pyrroloimidazopyridines (PI1a-d and PI2a-d) and four pyrrolopurines (PP) were studied after intraperitoneal administration in DBA/2 mice, a strain genetically susceptible to sound-induced seizures. 2. The anticonvulsant effects were evaluated in DBA/2 mice on seizures evoked by means of auditory stimulation (109 dB, 12-16 kHz) in animals placed singly under a perspex dome. 3. Hypothermic activity was observed after the highest doses of the pyrroloderivatives studied. 4. Our study demonstrated that the anticonvulsant effect of pyrroloimidazopyridines (PI1-7,8,8a,9-tetrahydro-6H-pyrrolo-[1',2':1,2]imidazo[4,5-b]pyrid in-6- ones) and pyrrolopurines (PP) was generally better than corresponding pyrrolobenzimidazoles (PB) and pyrroloimidazopyridines (PI2-5,5a,6,7-tetrahydro-8H-pyrrolo[2',1':2,3]imidazo[4,5-c]pyridin-8- ones) and, in some cases, comparable to that of phenytoin and desmethylclobazam. 5. The anticonvulsant potency of the derivatives studied cannot be directly related to their lipophilicity.

Animals↗
PubMed1994

Synthesis and antitumor activity evaluation of 1-[(arylidene)amino]adamantanes.

Several 1-[(arylidene)amino]adamantanes were synthesized and evaluated in vitro as antitumor agents against 60 human tumor cell lines. Some of these derivatives showed specificity for human leukemia cell lines and 1-[(2-bromobenzylidene)amino]adamantane (2) (NSC 631076-L), the most active compound, was selected by the Biological Evaluation Committee (BEC), for in vivo testing.

Adamantane↗
PubMed1994

Structure-activity relationships in thienodiazepine and benzodiazepine derivatives.

The structural and electronic characteristics as well as the anticonvulsant properties and benzodiazepine receptor binding of thieno[3,4-b][1,4]diazepine and 1,5-benzodiazepine derivatives are compared and discussed. The data obtained suggest that the electronic rather than the structural properties appear mainly responsible for the variant degree of anticonvulsant activity exhibited by the tested compounds.

Acoustic Stimulation↗
PubMed1994

Aminopyrazinyl derivatives: synthesis and evaluation of antiinflammatory and related activities.

Some amides, 1-substituted methylenediamines and 2-substituted thiazolidin-4-ones, all containing the aminopyrazinyl moiety, were synthesized and tested in the experimental models of acute and chronic inflammations and as potential analgesic agents. The first series of compounds are inactive, whereas the N,N'-di-(2-pyrazinyl)-methylene-diamines and the 3-(2'-pyrazinyl)-thiazolidinones 6, 7, 11, 12 and even more 16 and 17 were found to be endowed with antiinflammatory and analgesic properties and low acute toxicity, the two latter being the most interesting.

Animals↗
PubMed1993

Molecular requirement for anticonvulsant activity in a series of thiazolo-1,4-benzodiazepine derivatives and comparison with classical benzodiazepines.

1. The behavioural and anticonvulsant effects of several thiazolo[3,2-d][1,4]benzodiazepines (TBZ) were studied after intraperitoneal administration in DBA/2 mice, a strain genetically susceptible to sound-induced seizures. 2. Anticonvulsant effects on seizures evoked by means of auditory stimulation (109 dB, 12-16 kHz) were evaluated in DBA/2 mice placed singly under a perspex dome. 3. Hypothermic activity was observed after the highest doses of the benzodiazepines studied. 4. In addition, some TBZ were examined for anticonvulsant properties with respect to clonus induced by pentylenetetrazol. 5. Our study demonstrated that some thiazolobenzodiazepine derivatives were more potent than clobazam, desmethylclobazam and chlordiazepoxide, and less potent than diazepam, desmethyldiazepam and alprazolam. 6. In the series of tricyclic benzodiazepines, thiazole nucleus fusion to the "d" edge of the 7-membered ring results in an effective increase of the energy barrier for the heptatomic system reversal, and is probably responsible for, jointly with the lack of C=N double bonds, lower activity with respect to the 1,4-benzodiazepine precursors. 7. The potency of various thiazolobenzodiazepine derivatives as inhibitors of specific [3H]flunitrazepam binding to membranes from cerebellum or hippocampus was evaluated. 8. All tested compounds produced concentration-dependent inhibition of [3H]flunitrazepam binding. 9. The pharmacological activity of TBZ2, the most active compound of this series, was significantly reduced by treatment with flumazenil (2.5 mg/kg i.p.), suggesting clear involvement of a benzodiazepine mechanism in the anticonvulsant activity of these compounds.

Acoustic Stimulation↗