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B Testa

Publications and source records attributed to B Testa.

At least 181 records · Page 10Linked to original sources
PubMed1983

Potent lipophilic substituted benzamide drugs are not selective D-1 dopamine receptor antagonists in the rat.

The substituted benzamide drugs YM 09151-2 and clebopride potently inhibited apomorphine-induced stereotyped behaviour in the rat and caused displacement of the specific binding of [3H]spiperone to D-2 binding sites on striatal membranes in low nanomolar concentrations. Other substituted benzamide drugs including metoclopramide, sultopride and flubepride also inhibited stereotyped behaviour to a greater or lesser degree, but were less potent in displacing [3H]spiperone from D-2 sites. YM 09151-2 and clebopride only weakly displaced specific binding of [3H]piflutixol to D-1 sites on rat striatal membranes, and only weakly inhibited striatal dopamine stimulated adenylate cyclase activity, when compared with cis-flupenthixol. The other substituted benzamide drugs did not displace [3H]piflutixol or inhibit dopamine stimulation of adenylate cyclase activity in the concentration range used. Clebopride and YM 09151-2 were highly lipophilic with apparent partition coefficient (log P') values equivalent to those of classical neuroleptic compounds, such as cis-flupenthixol. In contrast, the other substituted benzamide drugs were markedly less lipophilic. A log P' value of approximately 2 was required before inhibition of adenylate cyclase activity or displacement of [3H]piflutixol binding occurred. However, in excess of this value there was no correlation between either inhibition of adenylate cyclase activity or displacement of [3H]piflutixol binding and the lipophilicity of the various compounds. We conclude that potent lipophilic substituted benzamide drugs, like other members of the substituted benzamide series, are selective D-2 receptor antagonists. Inherent steric factors within the drug series would appear to dictate activity at D-1 and D-2 sites, although lipophilicity may contribute to actions in these environments.

Adenylyl Cyclases↗
PubMed1983

The effect of cianidanol on rat hepatic monooxygenase activities.

The antinecrotic hepatoprotective agent cianidanol ((+)-catechin, (+)-cyanidan-3-ol, Catergen) has been tested for its ability to interfere with rat liver monooxygenase activities. In vitro, the drug was found to inhibit biphenyl 4-hydroxylation in microsomes from uninduced rats, and aminopyrine N-demethylase in microsomes from uninduced and PB-treated rats, with IC50 just below 1 x 10(-3) mol/l. The compound is less active in inhibiting biphenyl 2- and 4-hydroxylation and ethoxyresorufin 0-deethylation in microsomes from 3-methylcholanthrene-treated rats. Kinetically, cianidanol behaves as a non-competitive inhibitor in all reactions investigated. It binds to oxidized cytochrome P-450 as a ligand (modified type II binding spectrum). The drug does not decrease levels of cytochrome P-450, but rather protects the enzyme from lipoperoxidation-mediated destruction. In vivo, a single dose of cianidanol does not inhibit [14C]-aminopyrine metabolism. Only after 5 days administration a weak but statistically significant inhibitory effect is detected. The mechanism of action of cianidanol is discussed.

Aminopyrine↗
PubMed1981

A theoretical conformational study of substituted O-anisamides as models of a class of dopamine antagonists.

The quantum mechanical PCILO method has been used to investigate the conformational behaviour of N-(2-aminoethyl)- and N-(2-dimethylaminoethyl)-o-anisamide, two model molecules of substituted benzamides. The molecules are shown to have only limited conformational freedom due to the presence of two intramolecular hydrogen bonds acting as conformational locks. The molecules in their preferred conformation are characterized by a distance between the centre of the aromatic ring and the nitrogen atom of almost 6 A, i.e. almost 1 A longer than in the fully extended dopamine conformers. Some implications at the receptor level of this topographical dissimilarity are discussed.

Benzamides↗
PubMed1981

Aryl ether O-dealkylase activity in the skin of untreated mice in vitro.

1. O-Dealkylation of p-nitroanisole and p-nitrophenetole in 10 000 g supernatant preparations of mouse skin is detectable and quantifiable. The reaction is NADPH-dependent and is mediated by cytochrome P-450. 2. The rate of p-nitroanisole O-demethylation in mouse skin preparations is 2% of that in mouse liver preparations on a mg protein basis, but only 0.23% on a g of tissue basis. 3. For p-nitrophenetole O-deethylation, the cutaneous Vmax is 3.8% of the hepatic Vmax on a mg protein basis. The Km values for the reaction in these two tissues are in a 3:1 ratio, suggesting that there are no marked qualitative differences between cutaneous and hepatic cytochrome P-450.

Animals↗
PubMed1981

Steric and lipophobic components of the hydrophobic fragmental constant.

Newly calculated increments of molar volumes and surface areas were compared with hydrophobic fragmental constants in an effort to establish a relationship between these parameters. For completely non-polar fragments, the hydrophobicity is directly and linearly related to the volume or surface area. In the case of most fragments, however, the hydrophobicity is found to result from two factors, namely, a) a volume- or surface-related lipophilicity, and b) a lipophobicity effect, designated. The physical meaning of this parameter is unclear at present and may be related to hydration effects. The parameter may be of interest in QSAR studies. This is illustrated by an example in which the combined use of V and discriminates between the steric and lipophobic contributions of the partition coefficient to the biological activity.

Chemical Phenomena↗
PubMed1980

Quantitative structure-activity relationships in drug metabolism and disposition: pharmacokinetics of N-substituted amphetamines in humans.

Pharmacokinetic data of 15 N-alkyl-substituted amphetamines in humans have been the object of a retrospective quantitative structure-activity relationship study. The urinary excretion of amphetamines was shown to decrease with increasing lipophilicity; the correlation equations revealed that, for identical lipophilicities, tertiary amines are excreted faster than secondary amines, which are excreted faster than primary amines. The apparent n-heptane-pH 7.4 buffer partition coefficient correlates better with urinary excretion than does the true n-octanol-water partition coefficient, probably because it includes a pKa term that accounts for the fraction of the drug present in the tubules as nonionic species. The N-dealkylation rate increases with increasing lipophilicity of the substrates (enhanced enyzme affinity) but decreases with increasing bulk of the N-substituent that is split off (steric hindrance of initial C alpha-hydroxylation).

Amphetamines↗
PubMed1980

Deprenyl in the management of response fluctuations in patients with Parkinson's disease on levodopa.

Fluctuations in response to levodopa are a common and serious complication of long-term levodopa therapy. It may be possible to prolong the effect of each dose of levodopa by retarding the breakdown of dopamine. The selective monoamine oxidase type B inhibitor deprenyl, which is extensively metabolised to amphetamine and methamphetamine, has this effect as well as possible actions on dopamine release and re-uptake. In a double-blind crossover trial against placebo, deprenyl prolonged the action of levodopa and produced an objective improvement in mobility in five of 10 patients with dose-related response swings, and a subjective improvement in a further four patients. In another group of seven patients with random fluctuations in symptoms, only two noted subjective improvement, and there was an apparent increase in the severity of response swings in five patients. Deprenyl exacerbated dyskinesias, but had no serious side-effects. We conclude that deprenyl is unlikely to benefit patients with random response swings, and may cause deterioration in such cases. However, it may be a useful adjuvant in the management of dose-related response fluctuations in patients already on optional levodopa therapy.

Aged↗
PubMed1978

An ab initio study of electronic factors in metabolic hydroxylation of aliphatic carbon atoms.

The monooxygenase-mediated hydroxylations of aliphatic carbon atoms are known to be regioselective for positions alpha to heteroatoms or to pi systems (aromatic rings, carbon-carbon double bonds, carbonyl groups). Ab initio calculations (STO-3G and in some cases 4-31G) were performed on model molecules, indicating that the Mulliken overlap populations (taken as indices of electron bond densities) of Calpha-H bonds being regioselectively hydroxylated are larger than Cbeta-H and Cgamma-H overlap populations. These results support the hypothesis that metabolic C-hydroxylations occur by insertion of an activated oxygen species of electrophilic nature, probably oxene.

Carbon↗