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Biomedical subjects

B Testa

Publications and source records attributed to B Testa.

At least 127 records · Page 7Linked to original sources
PubMed1991

Bicarbonate-catalyzed hydrolysis of hexamethylene diisocyanate to 1,6-diaminohexane.

The hydrolysis of hexamethylene diisocyanate (HDI) in water was tested in a dynamic and stationary system. Without catalysts, the reaction was very slow (less than 1% in 10 min at 30 degrees C) while the addition of simple carboxylic-acid-containing neutral buffers markedly catalyses the formation of 1,6-diaminohexane as the known hydrolysis product. The catalytic efficiency of formic acid, oxalic acid, acetic acid, lactic acid, citric acid and carbonic acid increased in this order while phosphate, glycine and glutamate were inactive even at very high concentrations. A 20 mM bicarbonate buffer was the optimal catalyst, but below this concentration the rate of HDI hydrolysis was drastically reduced. It is suggested that the hydrolysis of inhaled HDI in the lungs may be catalysed by bicarbonate in the blood, giving rise to amines found as urinary metabolites following occupational exposure.

Bicarbonates↗
PubMed1991

Morphine 6-glucuronide and morphine 3-glucuronide as molecular chameleons with unexpected lipophilicity.

Morphine 6-glucuronide, but not morphine 3-glucuronide, is a highly potent opiate receptor agonist. In fact, there is converging evidence that much of the analgesic effect occurring after morphine treatment in humans is due to this metabolite rather than to the parent drug. Yet glucuronides as a rule are considered as highly polar metabolites unable to cross the blood-brain barrier and rapidly excreted by the urinary and/or biliary routes. Here, we report that morphine 6-glucuronide, and to a lesser extent morphine 3-glucuronide, are far more lipophilic than predicted, and in fact not much less lipophilic than morphine itself. Force-field and quantum mechanical calculations indicate that the two glucuronides can exist in conformational equilibrium between extended and folded forms. The extended conformers, because they efficiently expose their polar groups, must be highly hydrophilic forms predominating in polar media such as water; in contrast, the folded conformers mask part of their polar groups, thus being more lipophilic and likely to predominate in media of low polarity such as biological membranes.

Calorimetry↗
PubMed1991

Structure-metabolism relationships in the hydrolysis of nicotinate esters by rat liver and brain subcellular fractions.

Rat liver and brain subcellular esterase activities toward nicotinic acid esters were studied, under varying conditions, such as pH, organic solvents, protein concentration, duration of incubation, and substrate concentration. Esterases in each subcellular fraction displayed activities that obey Michaelis-Menten kinetics, although subcellular fractions are heterogeneous. The Km values were of the same magnitude, and the Vmax values were lower in microsomes than in cytosol of the liver. Brain activities normalized to protein concentration, were much lower than liver activities, aromatic nicotinates being the best substrates in both tissues. Myelin and brain mitochondria of nerve-ending and neuroglial origin display esterase activity toward phenyl nicotinate. In contrast to brain esterases, liver esterases appear homogeneous, and esterase activities in both tissues react differently to changes in pH. Qualitative and quantitative structure-metabolism relationships are not suggestive of tissue-specific ester hydrolysis.

Animals↗
PubMed1991

Determination of lipophilicity and hydrogen-bond donor acidity of bioactive sulphonyl-containing compounds by reversed-phase HPLC and centrifugal partition chromatography and their application to structure-activity relations.

The lipophilic character of two large series of substituted benzenesulphonamides (BzSA) and 4-aminodiphenylsulphones (4-ADS) has been assessed by two chromatographic methods, i.e. reversed-phase HPLC using a relatively novel octadecylpolyvinyl packing and centrifugal counter-current chromatography (CPC). The octadecylpolyvinyl stationary phase proved an interesting alternative to the more common octadecylsilane type stationary phase for obtaining retention parameters correlated to partition coefficients (i.e. log P). The CPC method, being far less time-consuming and markedly more precise than the classical shake-flask method, offers a promising alternative for measuring partition coefficients. The parameter delta log Poct-hep, i.e. log Poctanol minus log Pheptane, was also determined for both congeneric series and was indicative of a similar H-bonding capacity for the SO2NH2 and 4-NH2-C6H4-SO2 groups. QSAR analyses of carbonic anhydrase inhibition by BzSA and antimycobacterial activity of 4-ADS show the capacity of the new lipophilicity parameters to express the hydrophobic component of the drug-enzyme interactions and to reveal a possible role of H-bond donor capacity in governing the antimycobacterial activity of 4-ADS.

Carbonic Anhydrase Inhibitors↗
PubMed1990

Toxication of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) and analogs by monoamine oxidase. A structure-reactivity relationship study.

MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) elicits motor deficits similar to those observed in Parkinson's disease. Before exerting its neurotoxic action, MPTP must be activated by brain monoamine oxidase (MAO) to the neurotoxic metabolite MPP+ (1-methyl-4-phenylpyridinium). MPTP derivatives differ in their reactivity as MAO substrates and in their neurotoxicity. A structure-reactivity relationship study based on literature data was undertaken in order to determine the key features in the structure of MPTP and analogs that are responsible for the reactivity towards MAO. Thirty-three MPTP derivatives (including MPTP itself) were included in the study. To explain the reactivity towards MAO of the 33 MPTP analogs, different statistical methods (principal component analysis, multiple linear regression analysis) as well as the CoMFA (Comparative Molecular Field Analysis) approach, a new tool in structure-activity correlations, were used. Linear regression analysis failed to yield any predictive model, but suggested some trends. In contrast, the CoMFA approach was successful in correlating structural features and MAO reactivity. Coefficient contour maps showed where differences in the steric field (van der Waals' interactions) are most highly associated with differences in MAO reactivity. Several positive (in the ortho- and meta-position of the phenyl group) and negative (in the para-position of the phenyl group; beyond the N-methyl group) interaction regions were identified. Some structural features of the MAO active site could be postulated. First, the N-methyl group has the ideal size and elicits ideal interactions within the MAO active pocket, while smaller or larger groups are less favorable; second, para-substituent on the phenyl ring produce steric hindrances and are unfavorable to reactivity; third, ortho- and meta-substituents may have stabilizing interactions within the active pocket and are favorable to the reactivity. Moreover the model derived by CoMFA allowed us to make successful predictions of reactivity towards MAO for several additional tetrahydropyridines.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1990

[Chiral drugs: pharmacological tools and/or therapeutic problems?].

Various issues connected with chiral drugs are discussed. They include definitions, the concept of stereoselectivity in pharmacodynamic and pharmacokinetic processes, the need for a stereochemically informative generic name system, and the debate surrounding eutomers versus racemates in pharmacotherapy.

Humans↗
PubMed1990

Metabolic chiral inversion of ibuprofen in isolated rat hepatocytes.

Ibuprofen was used to demonstrate that isolated rat hepatocytes offer a suitable in vitro model to investigate the metabolic chiral inversion of anti-inflammatory 2-arylpropionic acids (profens). The inversion of the pharmacologically inactive (-)-(R)-ibuprofen to the active (+)-(S)-ibuprofen was shown to obey apparent first-order kinetics during 5 h and to increase linearly with increasing hepatocyte concentration up to 4 x 10(5) cells/ml. No elimination of (R)-ibuprofen by routes other than inversion was seen, whereas the elimination of (S)-ibuprofen appeared to be saturable.

Animals↗
PubMed1990

Behavioural and pharmacokinetic studies on nicotine, cytisine and lobeline.

Previous work has suggested that cytisine and lobeline are of low potency in producing nicotine-like behavioural effects, despite having some nicotine-like peripheral effects and potently inhibiting the binding of tritiated nicotine to the brain of the rat. Rats were trained to discriminate nicotine from saline in a two-bar operant conditioning procedure with food reinforcement. It was confirmed that cytisine had a nicotine-like discriminative effect, but it was much less potent than nicotine itself. Lobeline failed to produce a nicotine-like discriminative effect, even at doses that greatly reduced overall rates of responding. Neither drug attenuated discriminative responses to nicotine. The concentrations of drugs in plasma and brain were determined by HPLC in rats of the same sex, strain and age as those used in the behavioural experiments. The rank order of the ratios of concentrations in brain to plasma was lobeline greater than nicotine greater than cytisine, which was directly proportional to their lipophilicity determined by reversed-phase HPLC. Based on the concentrations in brain and known affinities for high-affinity nicotine binding sites, in vivo tests should show cytisine to be slightly more potent than nicotine and lobeline to have nicotine effects in the doses used. These predictions were not fulfilled and thus, the behavioural effects of cytisine and lobeline cannot be correlated with their effects at the binding site for tritiated nicotine. Since pharmacokinetic factors do not account for this discrepancy, a pharmacodynamic explanation will be necessary.

Alkaloids↗
PubMed1990

Mechanisms of inhibition of xenobiotic-metabolizing enzymes.

1. Various molecular mechanisms underlie the action of inhibitors of xenobiotic-metabolizing enzymes acting upon the enzyme itself and not elsewhere. 2. The activity of directly acting inhibitors is due to the compounds themselves rather than to metabolic intermediates thereof. When the enzyme's ground state is the target, competitive or non-competitive inhibition can be seen, depending on a number of factors. 3. Some inhibitors are transition-state analogues and bind slowly but with high affinity to the enzyme. Inhibition may be due to the compound itself and/or a metabolic intermediate. 4. Mechanism-based inhibitors are those which act via an in situ generated metabolic intermediate that can bind reversibly or irreversibly to the enzyme. 5. These various mechanisms are exemplified and discussed in terms of selectivity and reversibility.

Animals↗
PubMed1989

Histamine 2 antagonists in allergic rhinitis. Relationship of clinical response and serum concentrations of total and specific IgE antibody levels.

During a double-blind clinical trial of a histamine (H2) antagonist (ranitidine) in monitoring allergic rhinitis, the clinical response, total serum IgE levels, and Parietaria IgE antibody levels were measured. Ranitidine induces an improvement in scores of subjective and objective symptoms, a decrease in total serum IgE levels, and no significant variations in Parietaria IgE antibody levels. Since H2 antagonists seem to induce these improvements by acting on suppressor T cells bearing H2 receptor, as shown in our previous studies, it is hypothesized that the lymphocytic subset that regulates the total IgE synthesis is not the same as that governing specific IgE synthesis.

Adolescent↗
PubMed1989

Pattern recognition study of QSAR substituent descriptors.

Parameter values for 59 common substituents and 74 descriptors used in QSAR studies were compiled. This data matrix was analysed by a variety of multivariate techniques. Linear regression confirmed that lipophilicity can be factorized into two terms, one related to molecular bulk and the other to polarity. Principal component analysis (PCA) of parameters revealed 5 significant principal components and a grouping of lipophilic, steric and electronic parameters. The different loadings of parameters with 5 PCA were also explored. The classification of substituents by cluster analysis (CA) proved rather disappointing. In contrast, the SIMCA method classified substituents of increasing bulk into 5 groups of increasing polarity.

Analysis of Variance↗
PubMed1989

Signs of the times: the need for a stereochemically informative generic name system.

'Research and clinical pharmacologists frequently present data on impure drugs.' Because generic drug names often hide the fact that different stereoisomers (possibly with different pharmacological properties) may be present in the 'pure' preparation, this statement is all too frequently true. However, the problem may be overcome by pharmacologists and publishers adopting the user-friendly SIGNS nomenclature devised and explained here by Miklòs Simonyi, Joseph Gal and Bernard Testa. The acronym stands for 'stereochemically informative generic name system'. Seven prefixes are offered to describe the stereochemical nature of any drug. The appropriate prefix would be attached to the generic name. A generic name without prefix would indicate a single agent with no stereoisomers.

Methods↗
PubMed1989

Stereoelectronic study of zetidoline, a dopamine D2 receptor antagonist.

A combination of experimental and theoretical methods were used to investigate the stereoelectronic structure of zetidoline, a dopamine D2 receptor antagonist showing Na+-dependent binding. The solid-state conformation of zetidoline is characterized by synplanarity (coplanarity of the two rings with the chloro substituent and the carbonyl group on the same side). The side chain in the crystal adopts a folded conformation which places the azetidine nitrogen atom at about 8 A from the center of the aromatic ring. Quantum mechanical calculations indicate the synperiplanar and antiperiplanar conformations of the ring system to be of approximately equal energies. The molecular electrostatic potential of zetidoline in a nearly extended conformation shows a remarkable similarity with that of orthopramides (e.g. metoclopramide) and indolones (e.g. piquindone), i.e. two groups of drugs displaying the same D2 selectivity and Na+-dependent binding. We postulate that the close stereoelectronic similarity between zetidoline, orthopramides, and indolones accounts for their identical mechanism of action in the molecular level.

Chemical Phenomena↗