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Biomedical subjects

N Decker

Publications and source records attributed to N Decker.

At least 37 records · Page 2Linked to original sources
PubMed1988

Soft drug derivatives related to perhexiline. Part I: In vitro studies.

A series of cyclohexylaralkylamines derived from perhexiline was synthesized according to the "soft drug" concept. An amide function was introduced as a labile centre to give non-toxic moieties in vivo after the "soft drugs" had attained their therapeutic aims. Compounds were evaluated for their alpha-adrenolytic, calcium antagonist and vasodilator activities in vitro. Some of them, 2, 3, 7 and 15 on rat aorta had alpha-adrenolytic effects comparable to that of perhexiline. Most of them were about 10 times more active calcium antagonists on depolarized pig coronary artery than perhexiline. All derivatives produced concentration-related coronary dilation in the perfused guinea pig heart. Compound 2 was equipotent to perhexiline. The decrease in coronary resistance might, at least partly, be attributable to the alpha-blocking properties of the molecules. In conclusion, the introduction of an amide function into the perhexiline skeleton does not markedly alter the in vitro pharmacological properties.

Adrenergic alpha-Antagonists↗
PubMed1988

Soft drug derivatives related to perhexiline. Part II: In vivo studies.

A series of cyclohexylaralkylamines derived from perhexiline and synthesized according to the "soft drug" concept were evaluated for haemodynamic effects and myocardial oxygen consumption in vivo. In anaesthetized rabbits, the most active compounds, 2, 5, and 11 decreased arterial blood pressure, to a greater extent dp/dtmax and, to a lesser extent heart rate. The decrease in cardiac work and the decrease in cardiac output varied concomitantly. The cardiac effort index decreased in all cases to a greater degree than with perhexiline. In anaesthetized open-chest dogs, the potential antianginal properties of compounds 2, 5 and 11 were due to a decrease in cardiac work via a decrease in cardiac output and myocardial oxygen consumption. None of these compounds reduced arterial blood pressure. Compounds 2 and 5 decreased myocardial oxygen consumption more than perhexiline. Compound 5 was the most promising molecule of this series both as regards cardiac work and myocardial oxygen consumption, being active at a lower dose than perhexiline and having a long active span. These studies suggest that compounds 2, 5 and 11 might be beneficial to patients with angina pectoris.

Animals↗
PubMed1987

Effects of various antianginal drugs on sodium influx in rat brain synaptosomes and in rat heart muscle cells in culture.

This paper describes the inhibitory effects of several antianginal drugs on 22Na uptake of the fast Na+ channel in rat brain synaptosomes and in rat heart muscle cells in culture. Calcium antagonists like verapamil, flunarizine, perhexiline, two perhexiline derivatives IPS 629 and IPS 672, and beta-adrenoceptor antagonists like propranolol and practolol were tested. IPS 672 was the most active compound on synaptosomes and heart muscle cells (IC50 = 2.0 X 10(-6) and 2.4 X 10(-6) M respectively). The relative potencies of the Ca2+ antagonists tested on heart muscle cells were found to be IPS 672 greater than IPS 629 greater than perhexiline greater than flunarizine greater than verapamil. Verapamil was 55 and 10 times less active than IPS 672 on synaptosomes and heart cells respectively. Propranolol had an inhibitory activity comparable to that of flunarizine and was 100 times more active than practolol. It can be concluded that several antianginal drugs seems to interfere with the Na+ fast channel on rat brain and heart.

Angina Pectoris↗
PubMed1987

A novel positive inotropic series. 1st communication: in vitro studies of 3-, 4-, 5-, 6-, 7- and 8-pyridyl-2(1H)-quinolone derivatives.

A series of 3-, 4-, 5-, 6-, 7- and 8-pyridyl-2(1H)-quinolones and related compounds were evaluated for positive inotropic and vasodilatory activities in vitro. Most of them produced dose-related increases in myocardial contractility on guinea pig isolated atria and perfused heart. In guinea pig atria, the 6-pyridyl molecules were more active than the 5-pyridyl ones; the mean ED50 of compounds 14, 32 and 33 was 4.0 x 10(-7) mol/l i.e. 33 times that of sulmazole; that of compounds 6 and 7 was 2.0 x 10(-5) mol/l. The potencies of the 5- and the 6-pyridyl series also differed by 2 log units on perfused guinea pig heart. The 5- and 6-pyridyl series induced relaxation in precontracted pig coronary artery and coronary vasodilation on perfused guinea pig heart. Compounds 14, 32 and 33 also showed alpha-adrenolytic properties, which were by 0.7 log unit lower than that of phentolamine. These results indicate that this novel cardiotonic series exert positive inotropic and coronary vasodilatory effects.

Animals↗
PubMed1987

A novel positive inotropic series. 2nd communication: in vivo studies of 5- and 6-pyridyl-2(1H)-quinolone derivatives.

In the anaesthetized rabbits and dogs, the 6-pyridyl compounds 14, 32 and 33 (0.1-3 mg/kg) and the 5-pyridyl compounds 6 and 7 (1-10 mg/kg), administered i.v., produced dose-related increases in cardiac contractile force lasting more than 30 min. They also produced relatively minor and shorter-lasting increases in heart rate. Only the 6-pyridyl series decreased blood pressure. The effects were not blocked by propranolol. In the normal haemodynamic states, myocardial oxygen consumption did not increase. When the haemodynamic characteristics of heart failure were produced by propranolol in anaesthetized rabbits and dogs, compounds 14, 32 and 33 reversed these effects, increasing in particular cardiac output. These studies suggest that compounds of the 6-pyridyl series might be beneficial in patients with congestive heart failure.

Anesthesia↗
PubMed1986

Cardiotonic agents. 1. Synthesis and structure-activity relationships in a new class of 3-, 4-, and 5-pyridyl-2(1H)-quinolone derivatives.

A series of 3-, 4-, and 5-pyridyl-2(1H)-quinolone derivatives with H or HO or CH3O substituents in the 8-position were prepared and tested for positive inotropic activity. Several derivatives, especially 29, 9b, and 27 with a pyridyl ring in the 5-position, were ca. 2-10 times more potent on left guinea pig atria than sulmazole (ARL-115) and milrinone used as references. Some structure-activity relationships are discussed.

Animals↗
PubMed1986

Cardiotonic agents. 2. Synthesis and structure-activity relationships in a new class of 6-, 7-, and 8-pyridyl-2(1H)-quinolone derivatives.

A series of 6-, 7-, and 8-pyridyl-2(1H)-quinolone derivatives with various quinolone substitutents (CH3, Cl, OH, OCH3) was prepared by arylation of pyridine with quinolone via a diazotized aminoquinolone for positive inotropic activity. Several derivatives, especially those with a pyridyl ring in the 6-position, were from 28 to 50 times more potent on left guinea pig atria than ARL-115 and milrinone used as references. Intrinsic activities of the derivatives were almost equivalent to that of ARL-115. These results indicate that pyridyl-2(1H)-quinolone derivatives are a potent new class of positive inotropic agents.

Animals↗
PubMed1986

The manipulative patient.

"Manipulative" is a popular but often misused description of behavior seen in some patients who come to psychiatric attention. The authors suggest a definition of "manipulation" which can impart helpful information about symptoms, diagnosis, and treatment. They survey the differential diagnosis of manipulative behavior and consider specific treatment strategies.

Antisocial Personality Disorder↗
PubMed1986

Inhibition of some new cardiotonic agents by tetrodotoxin.

The effects of sulmazole, milrinone and 1,5-dihydro-6-chloro-3-methylimidazo[2,1-b]quinazolone-2 on guinea pig left atria were studied, measuring the force of contraction in the absence and in the presence of 1 x 10(-5) mol/l octahydro-12-(hydroxymethyl)-2-imino-5,9: 7,10a-dimethano-10aH-[1,3]-dioxocino[6,5-d]pyrimidine- 4,7,10, 11,12-pentol (tetrodotoxin, TTX). The dihydropyridine derivative methyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-tri-fluoromethylphenyl) pyridine-5-carboxylate, a Ca2+ agonist, was also tested. Protoveratrine B, which prolongs the Na+ current phase, was inhibited by TTX. Isoprenaline, whose activity is mediated by cyclic adenosine monophosphate and consequently by the increase in slow inward Ca2+ current, was not. TTX antagonized competitively sulmazole, milrinone and the quinazolone drug and reduced only the activity of the dihydropyridine derivative. These results suggest an interference of the new cardiotonic drugs with the fast Na+ channel.

Animals↗
PubMed1986

Effect of some new cardiotonic agents on synaptosomal sodium uptake.

The new positive inotropic agents sulmazole, piroximone, milrinone and 1,5-dihydro-6-chloro-3-methy-limidazo [2,1-b]quinazolone-2 enhance 22Na uptake in rat brain synaptosomes. In comparison, theophylline, a cyclic nucleotide phosphodiesterase inhibitor, has no effect on synaptosomal 22Na uptake. Tetrodotoxin inhibits the stimulation induced by the new inotropic agents. The quinazolone is about three times more potent than protoveratrine B and milrinone and ten times more potent than sulmazole and piroximone. There is a direct correlation between the 22Na uptake and the positive inotropic effect on guinea pig left atria of the new cardioactive drugs. The dose-response curves for synaptosomal 22Na uptake and for the inotropic effect on guinea pig left atria are parallel for sulmazole and the quinazolone drug, with first an increase and then a decrease in activity.

Animals↗
PubMed1985

Derivatives related to betaxolol with alpha- and beta-adrenergic activities.

The paper describes the synthesis and the pharmacological evaluation of some derivatives of betaxolol, all with a N-aralkylamine instead of the tertiobutylamine. Their general formulas are: (Formula: see text). These compounds have been tested for beta 1-adrenergic receptors antagonism on guinea pig atria, beta 2-adrenergic receptor antagonism on guinea pig trachea and alpha-adrenergic blocking activity on rat aorta. Compound U12 with a marked alpha-blocking activity and compound R8 with a beta 1/alpha ratio = 1 were selected for a haemodynamic study in the dog. The decrease in cardiac work and the diminution of total peripheral resistance exhibited by U12 are consistent with a dual alpha/beta-blocking agent. Finally, structure-activity relationships are discussed.

Adrenergic alpha-Antagonists↗
PubMed1985

Postjunctional alpha-1 and alpha-2 adrenoceptors in the coronaries of the perfused guinea-pig heart.

Prazosin and yohimbine were used to differentiate postjunctional alpha adrenoceptors in the coronaries of the perfused guinea-pig heart. Two postjunctional alpha adrenoceptor subtypes were distinguished by the affinities of the receptor for yohimbine and prazosin. The pA2 for yohimbine were 8.74 against alpha-methylnorepinephrine and 8.98 against BHT-920, and the pA2 for prazosin was 9.84 against phenylephrine. Yohimbine was not very active against the alpha-1 selective agonist as was prazosin against the alpha-2 selective agonists. Alpha-1 and alpha-2 postjunctional adrenoceptors mediate vasoconstriction in the whole coronary bed of the perfused guinea-pig heart.

Animals↗
PubMed1984

Postjunctional alpha-adrenoceptors. Alpha 1 and alpha 2 subtypes in rat vasculature in vitro and in vivo.

The postsynaptic alpha-adrenoceptors in rat aorta and in pithed rat were investigated according to their sensitivity to nine alpha-adrenergic agonists and to the selective antagonists yohimbine (alpha 2) and prazosin (alpha 1) and the nonselective one, phentolamine. In addition, in radioligand binding studies, the affinity and selectivity of the drugs were determined on rat cerebral cortex using [3H] yohimbine and [3H] prazosin. On rat aorta, prazosin is 1,000 times more potent than yohimbine against each alpha-adrenoceptor agonist, whether alpha 1- or alpha 2-selective. Rat aorta probably contains only alpha 1-adrenoceptors. Pressor effects in pithed rats are mediated by post-junctional alpha 1- and alpha 2-adrenoceptors. The dose-response curve for alpha-methylnorepinephrine in the presence of prazosin, using Hofstee's plots, revealed alpha 1- and alpha 2-adrenoceptors, respective proportions being 80.5 and 19.5%.

Adrenergic alpha-Agonists↗
PubMed1984

Synthesis and beta-adrenergic blocking activity of new aliphatic and alicyclic oxime ethers.

We describe the synthesis and pharmacological properties of two new series of aliphatic and alicyclic beta-adrenergic blockers, most of them containing a cyclopropyl ring. They belong either to 2-hydroxy-3-(tert-butylamino)propyl ether A or 2-hydroxy-3-tert-(butylamino)propyl ketoxime ether B derivatives. The O-[2-hydroxy-3-(tert-butylamino)propyl] dicyclopropyl ketoxime 5 exhibited a beta-adrenergic antagonist activity comparable to that of propranolol. It was found that ketoxime ethers B generally showed higher potency than the corresponding ethers A. We confirm that the presence of an aromatic nucleus is not crucial for the beta-adrenergic activity. Structure-activity relationships among these series are discussed.

Adrenergic beta-Antagonists↗
PubMed1984

Effects of theophylline and isoproterenol on the activity on the isolated guinea pig ureter.

To determine the role of the autonomic nervous system and of cyclic AMP in the control of ureteral peristalsis, isolated guinea pig ureters were placed in a 20-ml organ bath containing modified Krebs solution. Theophylline induced significant dose-dependent reduction in frequency and amplitude of contractions of the ureter hypertonified with barium chloride. No change in frequency or amplitude of contractions was observed with isoproterenol. Besides, our data explain why beta-agonist drugs are of very little value in the treatment of renal colic due to spasms of the pelviureteral tract.

Animals↗
PubMed1983

Study of two alkylating derivatives: the p-isothiocyanato- and the p-methylisothiocyanato-clonidine.

Pharmacological experiments with isolated rat aorta and radioligand binding studies in rat cerebral membranes were performed with the p-isothiocyanato (p-NCS) and p-methylisothiocyanato (p-CH2-NCS) derivatives of clonidine in order to assess their selectivity for alpha 1- and alpha 2-adrenoceptors, and to characterize their ability to alkylate alpha-adrenoceptors. Preincubation of rat aortic strips with both derivatives produced non-parallel rightward shifts in the dose-response curves of noradrenaline and significantly depressed the maximum response in a manner characteristic of irreversible receptor antagonists. The p-CH2-NCS derivative was slightly more potent than the p-NCS derivative. Further analysis of the data indicated that treatment of rat aorta with a 30 microM concentration of the p-CH2-NCS derivative alkylated all but 2.4 percent of the alpha-adrenoceptors, whereas a 100 microM concentration of the p-NCS derivative was required to produce a similar degree of alpha-adrenoceptor alkylation. Radioligand binding studies indicate an apparent 2 fold alpha2-adrenoceptor selectivity for the p-NCS derivative. In contrast, the p-CH2-NCS derivative displayed 7 fold selectivity for alpha 1-adrenoceptors. Interestingly, both alkylating derivatives of clonidine produced dose-dependent contractile responses in rat aorta with pD2 values of 6.30 and 5.56 for the p-NCS and p-CH2-NCS derivatives, respectively, relative to a pD2 of 7.67 for clonidine. The order of potency of the two alkylating derivatives of clonidine for producing contraction of rat aorta is the opposite of that for antagonizing the contractile effects of noradrenaline. The results suggest that the p-NCS and p-CH2-NCS derivatives of clonidine non-competitively antagonize noradrenaline by irreversibly alkylating alpha-adrenoceptors.

Alkylating Agents↗