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Biomedical subjects

G Tarzia

Publications and source records attributed to G Tarzia.

At least 55 records · Page 3Linked to original sources
PubMed1988

Benzodiazepine receptor ligands. Synthesis and pharmacological evaluation of 6-aryl-3,8-disubstituted-1,2,4-triazolo[3,4-a]phthalazines.

A series of 6-aryl-3,8-disubstituted-1,2,4-triazolo[3,4-a]phthalazines was synthesised starting from suitable o-benzoylbenzoic acids. The compounds were tested in vitro for inhibition of the specific binding of 3H-Diazepam to benzodiazepine receptors in preparations of membranes from rat brain synaptosomes. None of the compounds was notably active in this test.

Animals↗
PubMed1987

Metabolic oxidation of the pyrrole ring: structure and origin of some urinary metabolites of the anti-hypertensive pyrrolylpyridazinamine, mopidralazine. III: Studies with the 13C-labelled drug.

The metabolism of the anti-hypertensive drug, mopidralazine, N-(2',5'-dimethyl-1H-pyrrol-1-yl)-6-(4"-morpholinyl)-3-pyridazinamine, was reinvestigated in rats using the [2'(5')-13CH3]-labelled drug to determine the significance of the pharmacologically active intermediate 3-hydrazino-6-(4-morpholinyl)pyridazine. The previously proposed mesonic structure of the major metabolite I, i.e., 5'-hydroxy-3',6'-dimethyl-1'-[6-(4"-morpholinyl)-3-pyridazinyl]pyrida zinium hydroxide inner salt, was confirmed by chemical synthesis, X-ray diffraction analysis and 1H n.m.r. of the [3',6'-13CH3]-labelled metabolite I. Metabolite II, 3-methyl-6-(4-morpholinyl)-triazolo [4,3-6 b]pyridazine and metabolite VII, 3-methyl-7-(4-morpholinyl)-3H-pyridazino[1,6-c]pyridazine, were shown to retain the 13CH3 labelling of mopidralazine, whereas metabolite X, 3-acetyl-hydrazino-6-(4-morpholinyl)-pyridazine, loses the labelling, indicating that their formation involves two different pathways. It is hypothesized that the oxidation of the pyrrole leads to ring opening followed by a chemical rearrangement giving rise directly to metabolites II and VII or, with the intermediacy of the pharmacologically active 3-hydrazino-6-(4-morpholinyl) derivative and an enzymic acetylation or conjugation with pyruvic acid, to metabolites X, II and VII.

Animals↗
PubMed1987

Heterocyclic GABA analogues. Displacement of radiolabelled 3H-GABA from rat brain membrane preparations.

2,5-Dimethyl-1H-pyrrol-1-yl-butanoic acid (I) and 2,5-diethyl-1H-pyrrol-1-yl-butanoic acid (V) were synthesised as non basic analogues of 4-aminobutanoic acid (GABA) to investigate the influence of the pKa of the 4-nitrogen on the in vitro binding to GABA receptors. (I) displaced 3H-GABA from specific binding sites of synaptosomal membrane preparations from rat cerebellum with an IC50 of 0.5 microM and (V) with an IC50 of 0.4 microM. (I) was inactive in vivo in the bicuculline anticonvulsant test (mice i.p.). The authors conclude that a basic nitrogen is not necessary for the binding to the GABAergic receptors although the ensuing complex is likely to be pharmacologically ineffective.

Animals↗
PubMed1987

3-(1-Iminoethyl)-4,5-cycloalkylpyridine-2,6-diol derivatives. A novel class of benzodiazepine receptor antagonists and partial agonists.

A series of 3-(1-iminoethyl)-4,5-cycloalkylpyridine-2,6-diol derivatives have been prepared from isoxazolo [5,4-b] pyridones. Some of these compounds had affinity for the benzodiazepine receptors in vitro and in vivo radioligand displacement assays. These compounds did not have any anticonvulsant properties and were not active in pharmacological tests predictive of antianxiety activity, but antagonised the anticonvulsant and muscle-relaxant effects of diazepam and had proconvulsant properties.

Animals↗
PubMed1986

Zetidoline metabolism by rat liver microsomes. Formation of metabolites with potential neuroleptic activity.

1-(3'-Chlorophenyl)-3-[2-(3,3-dimethyl-1-azetidinyl)ethyl] imidazolidin-2-one, zetidoline, a new neuroleptic agent, when incubated with rat liver microsomes was rapidly metabolized to six free (mets B, D, I, L, M and N) and two conjugated metabolites (mets E and F). Sites of the metabolic attack (oxidation) were primarily the aromatic moiety, then the imidazolidinone and the azetidine rings. The metabolites were purified and structures assigned by means of EI-MS, 1H-NMR and chemical synthesis (mets B, D, L and M). The main metabolites, zetidoline, some chemical analogues and a few known dopamine antagonists were tested as in vitro inhibitors of 3H-zetidoline and 3H-spiperone binding to rat striatal membranes, and as in vivo inducers of prolactin release in female rats (inhibition of the estrus cycle). Two zetidoline metabolites, namely 4'-hydroxy zetidoline (met. B) and 5-hydroxy zetidoline (met. L), were found to have both in vitro and in vivo activities comparable to those of the parent drug. Identification of these active hydroxylated metabolites appears important both in the search of new leads of neuroleptics and for designing pro-drugs derivatives with improved pharmacokinetic profiles.

Animals↗
PubMed1986

Angiotensin converting enzyme inhibitors as antihypertensive agents: 1-[(2-mercaptocycloalkyl)carbonyl]-L-prolines.

The synthesis of 1-[(2-mercaptocyclopentyl)carbonyl]-L-prolines, 1-[(2-mercaptocyclobutyl)carbonyl]-L-prolines and related benzoyl derivatives as pure isomers is described. The abilities of all the compounds to inhibit angiotensin converting enzyme (ACE) in vitro and in vivo and to lower the systolic blood pressure in renal hypertensive dogs were determined. Three of them, namely 1-[[2-(benzoylthio)cyclopentyl]carbonyl]-L-proline (10f(R,S], 1-[(2-mercaptocyclopentyl)carbonyl]-L-proline (10g(R,S], and 1-[[2-(benzoylthio)cyclobutyl]carbonyl]-L-proline (16f(R,S], were found to be as potent as captopril in reducing blood pressure. The influence of chirality and ring size on the ACE inhibition is described.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1986

2-(1,1'-Biphenyl-4-yl)- 1,2,4-triazole[5,1-a] isoquinoline (L 14105), a potential orally active contragestational agent for the bitch: studies in the rat, hamster and dog.

In the search for second generation post-coital pregnancy terminating agents belonging to the class of 2-phenyl-triazole[5,1-a]isoquinolines, the contragestational profile of (1,1'-biphenyl)-4-yl-1,2,4-triazole[5,1-a]isoquinoline, referred to as L 14105, was investigated in hamsters, rats, and bitches. Following subcutaneous or intramuscular administration in oily vehicles, L 14105 shows a very high anti-fertility activity in the three animal species, being from 1.8 to 2.5 times more effective than the parent drug, DL 717-IT. Unlike DL 717-IT, L 14105 possesses a high activity when administered by the oral route. The results obtained in the bitch make it confirm its potential use as a new orally active agent for the interruption of unwanted pregnancies.

Abortifacient Agents↗
PubMed1985

Metabolic fate of zetidoline, a new neuroleptic agent, in man.

Healthy volunteers administered orally a single dose (20 mg) of [2-14C]zetidoline, a new dopamine antagonist, exhibited rapid absorption of radioactivity with peak plasma levels of 250-300 ng/ml achieved in 1 h. The compound underwent intensive metabolic first-pass so that plasma radioactivity was represented mostly by two products, metabolite B endowed with neuroleptic activity, and metabolite D inactive, while unchanged zetidoline was not detected. Disappearance of radioactivity from plasma was rapid with a half-life of 1.78 +/- 0.20 h. The simultaneous assay of plasma prolactin showed increased levels of the hormone (+ 464% at the peak time) up to the 6th h after dosing, with plasma concentration profile which mimic those of metabolite B. The radioactive test-dose was eliminated mainly via the kidneys with an average urinary recovery of 84.7 +/- 1.7% in 4 days (73.4 +/- 1.1% within 8 h). The main urinary metabolite (metabolite G) and two minor ones (metabolites B and D) were purified and their structures assigned by IR, MS and NMR spectroscopy, they are: 1-(3-chloro-4-hydroxyphenyl)-3 [2-(3,3-dimethyl-1-azetidinyl)ethyl]imidazolidin-2-one, metabolite B; 1-[2-(3,3-dimethyl-1-azetidinyl)ethyl]-imidazolidin-2-one, metabolite D and the 4'-O-sulphate ester of metabolite B, metabolite G. The metabolic fate of zetidoline in man follows the same phase I reactions demonstrated in rats and dogs, while the phase II reaction is sulphoconjugation instead of the glucuronidation observed in animals.

Adult↗
PubMed1985

Benzodiazepine receptor binding and anticonflict activity in a series of 3,6-disubstituted pyridazino[4,3-c]isoquinolines devoid of anticonvulsant properties.

A series of 3,6-disubstituted pyridazino[4,3-c]isoquinolines were synthesized and tested for their ability to inhibit the binding of [3H]diazepam to rat brain receptors in vitro. Compounds bearing a phenyl, 4-methoxyphenyl, or methyl group at position 3 and a dialkylamino group at position 6 showed the highest affinity in the binding assay and were subsequently evaluated for their anticonflict and anticonvulsant effects. All of these compounds (5a-1 and 5q) were active in the Vogel rat conflict procedure, but none prevented convulsions in mice induced either by metrazol or bicuculline. 3-Phenyl-6-pyrrolidinylpyridazino[4,3-c]isoquinoline (5d) with a Ki = 11.4 nM in the binding assay exhibited the best potency in the anticonflict assay (MED 5 mg/kg ip) and did not produce neuromuscular impairment at the highest dose tested (50 mg/kg ip).

Animals↗
PubMed1985

Characterization of [3H]zetidoline binding to rat striatal membranes.

The binding of [3H]zetidoline, a novel neuroleptic agent, to rat brain striatal membranes was investigated in-vitro. The optimal binding conditions for [3H]zetidoline differed from those for [3H]spiperone in pH, temperature and time. [3H]Zetidoline has high affinity for striatal dopamine receptors. Its binding is saturable, stereo-specific, has a low non-specific component and is reversible and tissue specific. The Scatchard analysis gave a biphasic curve, indicating that [3H]zetidoline interacts with more than one population of receptor sites (B'max = 67 fmol mg-1 protein, K'd = 0.11 nM; B"max = 500 fmol mg-1 protein, K'd = 2.49 nM). Kinetic analysis of rates of association and dissociation yielded a Kd value in agreement with that measured at equilibrium. Inhibition studies indicated that only dopamine and dopaminergic agents are able to displace [3H]zetidoline from its binding sites, and in a different rank order from that for displacement of [3H]spiperone. (-)-Sulpiride was especially effective in inhibiting [3H]zetidoline specific binding. Furthermore, like that of [3H]benzamides, [3H]zetidoline binding appears to be highly Na+-dependent and Li+ only partially substitutes Na+.

Animals↗
PubMed1985

Metabolic pathways of the anti-hypertensive agent, N-(2,5-dimethyl-1H-pyrrol-1-yl)-6-(4-morpholinyl)-3-pyridazinamine+ ++ hydrochloride. I. Studies in the rat.

The metabolic fate of a new anti-hypertensive, 1-pyrrolyl pyridazinamine, was studied in male Wistar rats after both p.o. and i.v. administration (1 mg/kg). The compound undergoes rapid metabolism, disappearing from the central compartment with a half-life of about 0.5 h. Plasma concn. of the parent drug and its major metabolite I following i.v. and p.o. administration suggest a route-dependent first-pass metabolism. Ten metabolites were isolated from the urine and identified by u.v., i.r., mass and 1H-n.m.r. spectroscopy. The structure of some was confirmed by 13C-n.m.r. and chemical synthesis. All biotransformations are restricted to the pyrrole ring which undergoes oxidative cleavage followed by a series of chemical rearrangements. A minor pathway leads to the formation of methyl sulphinyl and methyl sulphonyl pyrroles. It is suggested that, as with natural indoles, the pyrrole might be oxidized by a 2,3-dioxygenase. The three major metabolites, I, II and IX, along with two minor ones, VI and VII, were inactive when tested i.v. for antihypertensive activity.

Administration, Oral↗
PubMed1985

Metabolic pathways of the anti-hypertensive agent, N-(2,5-dimethyl-1H-pyrrol-1-yl)-6-(4-morpholinyl)-3-pyridazinamine hydrochloride. II: Studies in the dog.

The metabolic fate of a new anti-hypertensive, 1-pyrrolyl-pyridazinamine, was studied in male Beagle dogs given both p.o. and i.v. doses of the 14C-labelled drug (1 mg/kg). The compound given as a single i.v. injection disappeared from the central compartment with a half-life of about 0.9 h. Plasma levels of total 14C were represented mostly by metabolites. Eight urinary metabolites designated as metabolites I, II and XI-XVI were purified and their structures assigned by means of u.v., i.r., n.m.r. and mass spectrometry. Quantitatively the primary metabolic attack involved the morpholine moiety of the molecule which undergoes oxidative opening. A minor pathway afforded the cleavage of the pyrrole followed by chemical rearrangements to form six-membered sidnone-like products or a triazole derivative. The major (XIII) and three minor metabolites were studied for their antihypertensive activity in rats and were shown to be inactive.

Administration, Oral↗
PubMed1984

Antiinflammatory properties of a series of 4-amino-5-arylpyrazoles.

A series of ethyl 4-amino-5-arylpyrazol-3-yl carboxylates were prepared from arylacetonitriles and ethyl diazoacetate. The compounds were evaluated for their analgesic and antiinflammatory properties, that were not, however, sufficiently interesting to justify the further development of the compounds. The synthesis of the compounds could be a useful extension of the original report by A. Bertho on the reaction between ethyl cyanoacetate and ethyl diazoacetate to yield diethyl 4-aminopyrazole-3,5-dicarboxylate.

Animals↗
PubMed1979

Synthesis and anti-inflammatory properties of some pyrrolo(1H,3H)[3,4-d]pyrimidin-2-ones and pyrrolo(1H,6H)[3,4-d]pyrimidin-2-ones.

The unequivocal synthesis of some terms belonging to the two isomeric classes of the pyrrolo(1H,3H)[3,4-d]pyrimidin-2-ones and of the pyrrolo(1H,6H)[3,4-d]pyrimidin-2-ones is reported. Some of these compounds are active in inhibiting the development of the carrageenin edema, of the granuloma cotton pellet and of the adjuvant arthritis in the rat when administered orally.

Animals↗
PubMedDate not supplied

Disposition of premazepam, an anti-anxiety pyrrolodiazepine, in the cynomolgus monkey.

The plasma levels, tissue distribution and the urinary elimination of total radioactivity and of unchanged premazepam were determined in cynomolgus monkeys given intravenously the 14C labelled pyrrolo diazepine. Following the i.v. injection, both total 14C and the unchanged drug disappeared from the central compartment in a biphasic manner with terminal half-lives of 11.9 and 3.7 h respectively. Elimination occurred mainly via the kidneys with 58% of the administered 14C and 16% of premazepam recovered in 48 h. Tissue distribution of radioactivity (whole-body autoradiography) showed as target tissues the emunctory organs and the melanin rich choroid of the eyes and the traiv follicles. Interestingly, five min after the i.v. dose the distribution of premazepam in the brain indicated an homogeneous diffusion in the different areas with a preferential affinity for the grey matter.

Animals↗