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B Testa

Publications and source records attributed to B Testa.

At least 163 records · Page 9Linked to original sources
PubMed1987

L-dopa esters as potential prodrugs: effect on brain concentration of dopamine metabolites in reserpinized mice.

The intraperitoneal administration of L-dopa and a series of ester prodrugs of L-dopa to reserpinized mice produced elevations of striatal and tuberculum olfactorium homovanillic acid (HVA) and 3,4-dihydroxyphenylacetic acid (DOPAC) levels. Differences in the pattern of change produced by individual drugs, compared with L-dopa, were observed. Only the phenoxyethyl ester caused elevations of both striatal and tuberculum olfactorium HVA and DOPAC, greater than those measured following L-dopa administration. Overall the m-trifluoromethylbenzyl, phenylethyl, p-chlorophenylethyl and p-methoxyphenylethyl ester prodrugs produced greater elevations of striatal and tuberculum olfactorium HVA, but not DOPAC, compared with L-dopa. The administration of the 2-tetrahydropyranyl-methyl derivative only enhanced striatal HVA and striatal and tuberculum olfactorium DOPAC concentrations. Changes of HVA and DOPAC tissue concentrations following administration of the 2-hydroxypropyl, n-propyl, methyl, ethyl and 2-(1-methoxy)propyl ester prodrugs were comparable with those produced by the administration of L-dopa itself. The alterations in striatal and tuberculum olfactorium HVA and DOPAC levels observed did not correlate with the ability of these compounds to elicit locomotor activity in reserpinized mice.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1987

Multivariate statistical analysis of L-dopa esters as potential anti-parkinsonian prodrugs.

This paper reports a QSAR study of thirteen L-DOPA esters previously synthesised and examined for their physicochemical, biochemical and behavioural properties. Multivariate statistical analysis (principal component analysis, cluster analysis, simple and multiple linear regression) reveals favourable and unfavourable structural features of L-DOPA prodrugs. Some of the many biochemical and behavioural activities investigated are shown to be redundant. These indications may contribute to the design of novel L-DOPA prodrugs.

Analysis of Variance↗
PubMed1986

Dual ligand binding of pyridylalkanamides to microsomal cytochrome P-450.

Twelve homologous and regioisomeric pyridylalkanamides were examined spectrally for their binding affinity to cytochrome P-450 in phenobarbital- and 3-methylcholanthrene-induced rat liver microsomes. The pKs values were calculated by the Lineweaver-Burk method and by non-linear analysis using both a one ligand-one acceptor and a one ligand-two acceptor model. The latter model best fits most of the data, confirming that two pKs values exist for most derivatives in the 3-pyridyl and 4-pyridyl series. Structure-binding relationships are discussed. The two binding constants are hypothesized to arise from a dual mode of binding to the ferric ion. At low ligand concentrations, binding to hexacoordinated cytochrome P-450 occurs and involves displacement of an endogenous 6th ligand; at higher concentrations, the ligands bind to the pentacoordinated P-450, resulting in a high-to-low spin shift.

Animals↗
PubMed1986

Histamine2 antagonists in allergic rhinitis. Possible role in the control of cellular immune reaction.

We studied effects of monoclonal antibodies on lymphocyte subpopulations in patients with allergic rhinitis treated with histamine2 antagonists. The OKT4/OKT8 ratio after treatment showed a statistically significant decrease compared with initial values, the expression of a relative increase in the OKT8 subpopulation containing the suppressor fraction. In control patients no significant variations were observed. These results confirm our hypothesis that histamine2 antagonists act in allergic rhinitis by modulating the activity of T-suppressor lymphocytes reduced in atopic patients.

Adolescent↗
PubMed1986

Molecular electrostatic potential of orthopramides: implications for their interaction with the D-2 dopamine receptor.

The electronic properties of orthopramides, a group of selective D-2 dopamine receptor antagonists, were investigated by calculating molecular electrostatic potentials (MEP) of model compounds with the ab initio STO-3G MO method. The various substitution patterns of the aromatic ring are characterized by a positive region comprising the H-bonded 2-methoxy group and ring positions 2, 3, and 4 and a negative region comprising the CONH group, 5-substituent, and ring positions 5 and 6. The regions of positive and negative potential are separated by a "curtain" running along the longitudinal axis of the molecule. At shorter distances from the plane of the aromatic ring (1.75 and 2.0 A), this "curtain" is quite sinuous, but at greater distances (2.5 and 3.0 A) it tends toward rectilinearity. We postulate that this longitudinal separation, together with the single positive maximum and the three negative minima perceptible at 3.0 A, constitute a distance pharmacophore responsible for the recognition and proper alignment of the ligand. The more complex MEP at 1.75 and 2.0 A are equated with a contact pharmacophore. Comparison of the MEP of orthopramides and dopamine reveals some analogies and suggests a possible mode of binding of these antagonists to the D-2 receptor.

Benzamides↗
PubMed1986

The influence of conformational factors on the metabolic conjugation of aryloxyacetates.

Among p-chlorophenoxyalkanoic acids, the acetate and 2-propionate are essentially inert towards metabolic conjugation, whereas the isobutyrate (clofibric acid) undergoes extensive glucuronidation, as well as amino acid conjugation in carnivores. To try to explain these differences, the conformational behaviour of three model compounds was studied by quantum mechanical calculations (PCILO method). All three compounds prefer syn (folded) conformers, but the isobutyrate, in contrast to its two lower homologues, also has anti (extended) conformers of relatively low energy. Based on these results, a hypothetical topographical model is proposed for the binding site of glucuronyltransferase.

2,4-Dichlorophenoxyacetic Acid↗
PubMed1986

The binding of agonists and antagonists to rat lung beta-adrenergic receptors as investigated by thermodynamics and structure-activity relationships.

Interaction of several agonists and antagonists with the relevant beta receptor were studied in vitro using rat lung membranes as beta-adrenergic receptor source. The influence of temperature, between 4 degrees C and 37 degrees C, on the ability of beta-adrenergic agonists and antagonists to displace (-)-[125I]iodocyanopindolol from beta-adrenergic receptors was checked. Thermodynamic parameters were calculated from the Kj values thus obtained. Lipophilicity of the twenty molecules was also measured using a RP-HPLC method. The results obtained show: the density of receptors was not affected by the temperature but their affinity for the twenty agonists and antagonists increased with decreasing temperature; the binding of agonists is enthalpy driven while that of antagonists is entropy driven, with the exception of the lipophilic agonist dobutamine; a single relationship between entropy and lipophilicity exists for all twenty compounds and would suggest that molecular structure and physicochemical properties account for the thermodynamics of binding.

Adrenergic beta-Agonists↗
PubMed1986

The thermodynamics of agonist and antagonist binding to dopamine D-2 receptors.

The ability of dopamine agonists and antagonists to compete with [3H]spiperone binding to rat striatal membrane preparations at 4, 15, 26, and 37 degrees varied markedly with temperature. Dopamine and the dopamine agonist 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene hydrobromide (ADTN) were more potent at lower temperatures. The ability of the dopamine antagonists, haloperidol, cis-flupenthixol, cis-N-(1-benzyl-1-methypyrrolidin-3-yl)-5-chloro-2-methoxy-9- methylaminobenzamide (YM 09151-2), raclopride, and clozapine, and of the agonists apomorphine and pergolide, to compete with [3H]spiperone binding was little altered by temperature. (+)-Butaclamol was more potent at higher temperatures. In contrast, the antagonists sulpiride, metoclopramide, clebopride, sultopride, tiapride, piquindone, and zetidoline were more potent at lower temperatures. The interaction of the agonists dopamine and ADTN was driven by a decrease in enthalpy, allowing an energetically unfavorable decrease in entropy. The binding of the antagonists, haloperidol, cis-flupenthixol, YM 09151-2, raclopride, (+)-butaclamol, and clozapine, and also of the agonists, apomorphine and pergolide, was entropy driven. The interaction of the antagonists sulpiride, metoclopramide, clebopride, alizapride, sultopride, tiapride, piquindone, and zetidoline differed from that of other antagonists in being enthalpy driven. The observed entropy changes correlated with the lipophilicity of the displacing drugs and not with their intrinsic activity.

Animals↗
PubMed1986

Affinity of pyridylalkylamines for nicotinic, muscarinic and histaminic recognition sites in brain tissue preparations.

The affinity of 15 regioisomeric and homologous pyridylalkylamines was examined in brain preparations for nicotinic, muscarinic, and H1-histaminic binding sites as labeled by [3H]-nicotine, [3H]-dexetimide and [3H]-mepyramine, respectively. Overall, the compounds show a clear selectivity for the nicotinic versus muscarinic binding sites, and a weak affinity for the H1-histaminic sites. Variations in affinity appear to be partly influenced by steric factors (such as position of attachment, length and rigidity of side-chain) and marginally by lipophilicity.

Amines↗
PubMed1986

Inhibiting or potentiating effects of flavonoids on carbon tetrachloride-induced toxicity in isolated rat hepatocytes.

Carbon tetrachloride (CCl4) added to isolated rat hepatocytes produces toxic effects which were assessed by monitoring the release of aspartate aminotransferase (ASAT). CBrCl3 was equitoxic with CCl4, while CHCl3 was inactive, suggesting solvent properties not to be involved. The CCl4-mediated toxicity was markedly decreased by carbon monoxide, indicating possible activation by cytochrome P 450. 55 flavonoid compounds were tested for their ability to interfere with CCl4-induced release of ASAT. The compounds are cianidanol, 3-ethers and 3-esters thereof, flavanones, flavanolols, flavones and flavanols. The more hydrophilic compounds inhibit the CCl4-induced toxicity, while the lipophilic derivatives are potentiators. No other structure-activity relationships are apparent. The results are discussed in terms of the mechanisms of action of the compounds and of the validity of the technique as a screening test for hepatotropic agents.

Animals↗
PubMed1985

The toxic actions of MPTP and its metabolite MPP+ are not mimicked by analogues of MPTP lacking an N-methyl moiety.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), its metabolite 1-methyl-4-phenylpyridine (MPP+) and three analogues of MPTP, lacking an N-methyl moiety, namely, 4-phenylpiperidine (I), 4-phenyl-1,2,3,6-tetrahydropyridine (II) and 4-phenylpyridine (III), were infused continuously for a period of 4 days into the rat substantia nigra. Within 12 h of commencing the bilateral infusion of MPTP or MPP+, rats showed marked motor deficits with reduction in locomotor activity, loss of ability to move the forelimbs and grip with forepaws and, following MPP+ infusions, similar loss of movement in the hindlimbs associated with the development of limb and body rigidity. These motor deficits were not induced by the 3 analogues of MPTP on infusion into the substantia nigra. After 4 days of infusion, the motor deficits caused by MPTP and, in particular, MPP+, were still marked, and for MPP+ these correlated with marked loss of striatal dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid. 4-Phenyl-1,2,3,6-tetrahydropyridine caused a small loss in striatal DA and DOPAC, but the other analogues failed to modify the striatal content of DA or its metabolites. Small alterations of chemical structures related to MPTP and its metabolite can critically alter ability to induce behavioural and neurochemical changes reflecting toxicity on the nigrostriatal DA system.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1984

High-performance liquid chromatographic separation of the enantiomers of anti-inflammatory 2-arylpropionates: suitability of the method for in vitro metabolic studies.

The enantiomers of 2-phenylpropionic acid, 2-(2-naphthyl)propionic acid, 2-(4-biphenyl)propionic acid and six anti-inflammatory congeners were separated by high-performance liquid chromatography via their diastereoisomeric derivatives with (S)-(-)-1-phenylethylamine. In agreement with a general rule, the diastereoisomers derived from the (R)-acids are less polar and elute first. Structural factors influencing the resolution are discussed. Good calibrations were obtained for R/S ratios and total (R + S) concentrations of flurbiprofen and naproxen added to inactivated rat liver preparations. The method is suitable for in vitro metabolic studies of chiral 2-arylpropionates.

Animals↗
PubMed1984

L-Dopa methyl ester--a candidate for chronic systemic delivery of L-Dopa in Parkinson's disease.

Continuous intravenous infusions of L-Dopa as a treatment for response swings in Parkinson's disease are limited by the insolubility and acidity of L-Dopa. Its methyl ester is a soluble neutral derivative that might be of benefit to these patients, and is examined in the present study in behavioural and biochemical animal models. On intraperitoneal or subcutaneous administration to mice L-Dopa methyl ester was equivalent to L-Dopa in reversing reserpine-induced akinesia and producing contraversive circling behaviour in rats with a 6-hydroxydopamine lesion of the medial forebrain bundle. On oral administration the methyl ester was more active. The administration of L-Dopa or the methyl ester produced equivalent changes in striatal and mesolimbic dopamine, homovanillic acid, and 3,4-dihydroxyphenylacetic acid metabolite levels. We suggest that systemic or subcutaneous infusion of L-Dopa methyl ester to patients who experience response fluctuations may provide a means of maintaining mobility.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1984

Objective tinnitus due to peritubal myoclonus. A case report.

A case of bilateral peritubal myoclonia with objective tinnitus in a 5-year-old child, under general anesthesia for phimosis surgery, is reported. After having shown the etiology, pathogeny and symptomatology of the peritubal myoclonic syndrome, the use of impedansometric research consisting of a spontaneous variation of 'compliance' is emphasized. The authors discuss the significance of differential diagnosis with the spontaneous variations of 'compliance' of vascular, respiratory and muscular origin.

Anesthesia, General↗
PubMed1983

Theoretical conformational studies on some dopamine antagonistic benzamide drugs: 3-pyrrolidyl- and 4-piperidyl derivatives.

Model derivatives of 3-pyrrolidyl- and 4-piperidyl-o-methoxybenzamides, as representatives of neuroleptic substituted benzamide drugs, have been investigated by theoretical conformational analysis. Folded conformers of 2-methoxy-N-(1-methyl-3-pyrrolidyl)benzamide have the lowest energy, but extended conformers are only a few kilocalories per mole less stable. As regards to piperidyl derivative, it has been found that folded conformers are of much higher energy than extended ones. These and previous results are discussed in terms of the pharmacologically active conformers of substituted benzamide drugs and of possible modes of interaction with the dopamine receptor.

Animals↗