Novel 1,5-benzodiazepines as CCK-B ligands. Effect of aryl-carbamic substituents at the C-3 position together with halogen substitution on the benzo-fused ring.
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Animals↗
Biomedical subjects
G Tarzia
Publications and source records attributed to G Tarzia.
2,3-Dihydro-6,7-dichloro-pyrido[2,3-b]pyrazine-8-oxide as selective glycine antagonist with in vivo activity.
2,3-Dihydro-6,7-dichloro-pyrido[2,3-b]pyrazine-8-oxide was synthesized and evaluated for in vitro/in vivo antagonistic activity at the strychnine insensitive glycine binding site on the NMDA receptor revealing it to be a useful tool to evaluate the effectiveness of glycine antagonists in vivo.
Animals↗
Synthesis and receptor binding affinity of cholecystokinin receptor ligands: 2-and 1-indolyl derivatives of PD134308.
The synthesis of two "dipeptoids" structurally related to the CCK-B antagonist CI-988 (PD134308) is described. The 2- and 1-indolyl derivatives 4a, b were prepared in order to define the role of the tryptophan moiety in this series of "dipeptoids". They were evaluated as competitors in the binding of [3H]-CCK8S on guinea pig brain CCK-B receptors.
Animals↗
Synthesis and antimicrobial evaluation of 2 beta-chloromethyl-6 beta-carbamoylmethyl-penam-1,1-dioxide-3-carboxylic acid.
A new 2 beta-Chloromethyl-6 beta-carbamoylmethyl-penam-1,1-dioxide-3-carboxylic acid was synthesised and evaluated for its antimicrobial and beta-lactamase inhibitory activity. The compound was found to be inactive.
Amoxicillin↗
Synthesis of novel 6-alpha and 6-beta-alkylcarbonylmethyl substituted penems.
6-alpha and 6-beta Alkylcarbonylmethyl penems were synthesized from 6-alpha-bromo and 6-oxo penicillanates respectively and their in vitro antibacterial activity was studied. The compounds were generally active against Gram-positive but not against Gram-negative strains, the compounds of the 6-beta series being more active. Relatively to imipenem, taken as reference compound, the penems resulted more stable towards chemical hydrolysis in Tris-HCl buffered medium (pH 7.4) but more sensitive towards dehydropeptidase-I (DHP-I).
Anti-Bacterial Agents↗
Synthesis and antimicrobial activity of DNA-gyrase inhibiting derivatives of 4-oxo-1,4-dihydro-3-pyridinecarboxylic acid.
A series of 6-substituted-1-aryl-4-oxo-1,4-dihydronicotinic acids were synthesised as monocyclic analogues of the quinolones. The 6-(2-aryl-1-methylethenyl)- and of the 6-(2-arylethenyl)-substituted compounds were shown to possess antibacterial properties that correlate with DNA gyrase inhibitory activity. Differently from the quinolones the antimicrobial activity of the compounds of this study is predominantly against Gram positive strains. The structure-activity relationships ascertained for these monocyclic compounds differ from those established for the quinolones.
Anti-Bacterial Agents↗
Mass spectrometric approaches in structural characterization of cephalosporins.
The mass spectrometric behaviour of five structurally different cephalosporins has been studied in detail by means of different ionization/desorption methods (electron impact, fast atom bombardment, desorption chemical ionization, laser-induced vaporization) and metastable ion studies (linked scans and mass-analysed ion kinetic energy spectrometry). The best results were obtained by fast atom bombardment mass spectrometry, leading to both molecular ions and fragment ions diagnostic for structural identification.
Cephalosporins↗
Benzodiazepine receptor ligands. Synthesis and in vitro binding activity of some 6-substituted-3-aryl-1,2,4-triazolo[3,4-a]phthalazines.
Some 3-aryl-6-hydroxymethyl-1,2,4-triazolo[3,4-a]phthalazines (VI a,b) and 3-aryl-6-(2-hydroxyethyl)-1,2,4-triazolo[3,4-a]phthalazines (XVIII) have been synthesized. From (VI b) some 3-aryl-6-(alkylamino)methyl- and 3-aryl-6-(alkoxy)methyl-1,2,4-triazolo[3,4-a]phthalazines have been prepared and evaluated in vitro for their ability to inhibit selective 3H-diazepam (3H-DZ) binding to benzodiazepine-receptors (BZRs) from homogenates of synaptosomes from rat brains. Several compounds have been shown to displace 3H-DZ from BZRs with Ki (nM) values ranging from 2.2 to 88, comparable to those of the reference drugs including Diazepam.
Animals↗
Deaminoteicoplanin and its derivatives. Synthesis, antibacterial activity, and binding strength to Ac-D-Ala-D-Ala.
Teicoplanin and its acid hydrolysis products were deaminated with hydroxylamine-O-sulfonic acid (HOS). A few amides of these deaminoteicoplanins were also prepared. The loss of the terminal amino group reduces in vitro activity against staphylococcal and streptococcal bacteria to one-half to one-third, while binding strength to Ac-D-Ala-D-Ala, measured by differential UV spectroscopy, is reduced to one-tenth that of teicoplanin. The in vitro activity is further reduced by the presence of serum, and this is attributable to the increased lipophilicity and total negative charge of the deamino compounds. Comparison of UV spectra of deaminoteicoplanins with those of parent compounds made it possible to single out the most acid phenol group of teicoplanin aglycon (OH-4; pK = 8.2).
Anti-Bacterial Agents↗
Synthesis and biological evaluation of de(acetylglucosaminyl)didehydrodeoxy derivatives of teicoplanin antibodies.
A series of 34-de(acetylglucosaminyl)-34-deoxy derivatives of 34,35- and 35,52-didehydro teicoplanin antibiotics have been synthesized from teicoplanin and its N-acetylglucosamine containing pseudoaglycons under basic conditions. The structures of these compounds have been determined by 1H NMR, UV, and FAB-MS. 35,52-Unsaturated derivatives maintained in vitro and in vivo antimicrobial activity to a different extent as well as the ability for binding to Ac2-L-Lys-D-Ala-D-Ala, a bacterial cell-wall model for the site of action of glycopeptide antibiotics. In contrast, 34,35-unsaturated compounds were markedly less active and possessed a negligible affinity for the synthetic tripeptide.
Acetylglucosamine↗
Synthesis and biological properties of N63-carboxamides of teicoplanin antibiotics. Structure-activity relationships.
The condensation of the carboxyl function of teicoplanin A2 (CTA) and its acidic hydrolysis pseudoaglycons (TB, TC) and aglycon (TD) with amines carrying various functional groups and chains produced amide derivatives with different isoelectric points and lipophilicities. Amide formation did not affect the ability of these compounds to bind to Ac2-L-Lys-D-Ala-D-Ala, a model for the natural peptide binding site in bacterial cell walls. The antimicrobial activities of teicoplanin amides were found to depend mostly on their ionic and lipophilic character and on the type and number of sugars present. Positively charged amides were generally more in vitro active than the respective unmodified antibiotics against Gram-positive organisms. In particular, most basic amides of CTA were markedly more active than teicoplanin against coagulase-negative staphylococci. A few amides of TC and most of those of TD also showed a certain activity against Gram-negative bacteria. In experimental Streptococcus pyogenes septicemia in the mouse, some basic amides were more active than the parent teicoplanins when administered subcutaneously. Some of those of CTA were also slightly more effective than teicoplanin by oral route.
Amides↗
Dechloro teicoplanin antibiotics.
Mono- and didechlorinated derivatives of the antibiotic teicoplanin, its pseudoaglycones and aglycone, and of one amide and ester of deglucoteicoplanin were prepared under selective reductive conditions. The selectivity and rate of dehalogenation were studied and compared to those of vancomycin and deglucovancomycin. The influence of the chlorine substituents on the mechanism of action and antibacterial activity of teicoplanin antibiotics was also investigated.
Animals↗
Benzodiazepine receptor ligands. Synthesis and preliminary pharmacological evaluation of 2-aminoalkyl-8-chloro- and 2-aryl-1,2,4-triazolo[3,4-a]phthalazine-3(2H)-ones.
Some 2-aminoalkyl-8-chloro- and 2-aryl-1,2,4-triazolo[3,4-a]-phthalazine-3-(2H)-ones were synthesized and preliminarily tested in vitro and in vivo as potential benzodiazepine-receptor (BZRs) ligands. 2-Aryl-1,2,4-triazolo[3,4-a]-phthalazine-3(2H)-ones displaced in vitro 3H-diazepam (3H-DZ) from rat brain specific binding sites with Ki (nM) comparable to DZ and chlordiazepoxide used as reference compounds. The specific binding of the triazolones of this study was not enhanced in vitro by 4-aminobutyric acid (GABA) and in vivo they did not show any activity in counteracting the pentylenetetrazole (PTZ) induced convulsions (mice). One of these compounds (IV a) antagonized the effects of DZ in the bicuculline (BIC) induced convulsions test (mice) and the DZ induced muscle relaxant effects in the horizontal wire test.
Animals↗
Benzodiazepine receptor ligands. Synthesis and preliminary pharmacological evaluation of some 3,7-disubstituted-4H-[1,2,4]triazino[3,4-a]phthalazines and 3,7-disubstituted-4H-[1,2,4]triazino[3,4-a]phthalazine-4-ones.
Some disubstituted triazinophthalazines and traizinophthalazinones were synthesized and tested in vitro for inhibition of the 3H-diazepam (3H-DZ) specific binding to benzodiazepine receptors (BZRs) in membranes from synaptosomes of rat brain and in vivo for their effects on the conditioned behaviour (rat). These compounds showed Ki values (nM) in the in vitro test ranging from 220 to more than 3000 and some of them had approximate ED50S of 30 mg/kg, i.p. (rat) in the conditioned avoidance behaviour test (CR2).
Animals↗
X-ray structure determination of mexiprostil, a new gastroprotective 16-methoxy-16-methyl-PGE1 analogue.
Mexiprostil is a new gastroprotective 16-methoxy-16-methyl-PGE1 methyl ester. To assign the absolute configuration at C-15, a crystalline high-melting C-1 ester analog 5 11,15-dihydroxy-16-methoxy-16-methyl-9-oxoprost-13-en-1-oic acid 4-(4-bromobenzamide)phenyl ester (15R, 16R) was prepared and submitted to single crystal X-ray analysis. Since C-8, C-11, C-12 and C-16 are shown to have R configurations, the X-ray diffraction results established that the configuration at C-15 is also R.
Alprostadil↗
6-(Alkylamino)-3-aryl-1,2,4-triazolo[3,4-a]phthalazines. A new class of benzodiazepine receptor ligands.
Some 6-(alkylamino)-3-aryl-1,2,4-triazolo[3,4-a]phthalazines have been shown to displace diazepam from rat brain specific binding sites, in vitro, with Ki (nM) values comparable to those of reference benzodiazepines and to have anticonvulsant (pentylenetetrazole test, mice) and anticonflict activity (Vogel test, rat) in vivo. Separation between the doses causing anticonflict effects (Vogel test, rat) and those impairing motor coordination (rotarod test, rat) has been shown for N,N-bis(2-methoxyethyl)-3-(4-methoxyphenyl)-1,2,4-triazolo[3,4-a] phthalazin-6-amine (80). This compound, unlike diazepam, was inactive in counteracting the strychnine (mouse) and maximal electroshock (mouse) induced convulsions and in the "aggressive monkey" model. These differences from the classical benzodiazepines in the animal tests indicate that 80 may have some selective anxiolytic activity.
Aggression↗
Benzodiazepine receptor ligands. Synthesis and preliminary pharmacological evaluation of some 3-aryl-6-thioalkyl-, 3-aryl-6-alkylsulphinyl-, 3-aryl-6-alkylsulphonyl-, and 3-aryl-6-alkoxy-1,2,4-triazolo[3,4-a]phthalazines.
A series of 3-aryl-6-alkoxy- and some 3-aryl-6-thioalkyl-, 3-aryl-6-alkylsulphinyl-, and 3-aryl-6-alkylsulphonyl-1,2,4-triazolo[3,4-a]phthalazines were synthesised and tested for inhibition of the in vitro binding of 3H-Diazepam to benzodiazepine receptors in membranes isolated from rat brain synaptosomes. 6-Alkoxy-3-(4'-methoxy)phenyl-1,2,4-triazolo[3,4-a]phthalazines were more active than or as active as diazepam in the binding assay (Ki nM) but unlike diazepam their binding to the benzodiazepine receptors was not enhanced by 4-aminobutyric acid. These compounds did not antagonize pentylenetetrazole induced convulsions and were inactive in modifying the conditioned behaviour of rats. Compound (II a) counteracted the muscle relaxant effects of diazepam (traction test). These results suggest that (II a) may be a benzodiazepine receptor antagonist.
Animals↗
Prolyl derivatives of enalapril as potential angiotensin converting enzyme inhibitors.
The synthesis of a new class of potential angiotensin converting enzyme (ACE) inhibitors, analogs of enalapril, is reported. In these molecules the C-terminal amino acidic sequence Ala-Pro of enalapril was replaced by the sequence Pro-Pro. The compounds were tested both in vitro and in vivo. They showed no in vivo activity but only a week in vitro inhibitory activity.
Angiotensin-Converting Enzyme Inhibitors↗