Design and synthesis of substituted compounds containing the 1, 4-benzodioxin subunit. New potential calcium antagonists.

New compounds possessing 1,4-benzodioxin or its saturated analogous heterocyclic system were synthesized and tested for calcium antagonist activity. Biological differences were seen between the different modifications applied. These compounds have been shown to be representative of a novel series of calcium channel antagonists.

New substituted 1,4-benzoxazine derivatives with potential intracellular calcium activity.

Substituted 1,4-benzoxazines bearing an amino side chain at the 2-position were prepared and were found to have a moderate activity on intracellular calcium. Of the compounds studied it was found that those which possess a homoveratrylamino moiety exhibited superior potency. The chain length and the nature of the amine (4-fluorophenylpiperazine, 4-fluorobenzhydryloxyethylamine, N-substituted homoveratrylamine) is discussed.

In vitro calcium antagonistic and antioxidant effects of Org 13061 and its enantiomers, new potential antiatherosclerotic compounds.

The calcium antagonistic and antioxidant properties of a new potential antiatherosclerotic agent, Org 13061 were compared with those of its (-) and (+) enantiomers (Org 13471 and Org 13581) In vitro and with appropriate reference drugs. Org 13061 antagonized contractions induced by potassium in rabbit aortic rings with an IC50 value of 0.50 microM and reduced the maximum rate of phase 0 depolarization (Vmax) of the 'slow' calcium-mediated transmembrane action potentials in cardiac tissue (IC25 = 0.

Effects of bepridil and of its quaternary derivative on rat tail artery.

The effects of bepridil and its quaternary ammonium derivative (BN+) were compared, showing that: (i) both drugs inhibited K+-induced contractions with similar time courses and potencies, (ii) bepridil blocked the tonic but not the phasic component of contractions elicited by noradrenaline, whereas BN+ had no effect on noradrenaline-elicited contractions. These results, and the relative insensitivity of skinned taenia caeci to bepridil, suggest that this drug and BN+ do not act directly on contractile proteins but affect K+- and noradrenaline-induced calcium channel activities differentially.

[Benzoxazolinone phenylethanolamine antagonists of adrenergic receptors. A chemical and pharmacodynamic study].

Benzoxazolinone can be considered as a bioisosteric analogue of pyrocatechol. This concept has led to the synthesis of benzoxazolinonic phenylethanolamines. The pharmacological study shows that these compounds possess an affinity for adrenergic receptors.

Pharmacological evidence for cardiac muscarinic receptor subtypes.

The chronotropic and inotropic effects of muscarinic receptor agonists (Acetylcholine, Arecoline, Carbachol, Furtrethonium) and antagonists (Atropine, N-methyl and N-butyl scopolammonium, pirenzepine) on isolated guinea-pig atria were studied. All had a greater affinity constants for muscarinic receptors as assessed in terms of inotropic effects than in terms of chronotropic effects. This difference, well correlated with the pharmacological effect, suggests the occurrence of cardiac muscarinic receptor subtypes, one mediating heart rate and the other contractile force.

[Cardiovascular effects of elliptinium. The mechanism of action].

The effects of elliptinium were studied: Firstly, in the dog, in comparison with the effects of histamine, on heart rate and arterial blood pressure. Secondly, in guinea-pig isolated atria. When smaller doses were used (0.

2-Benzodioxinylaminoethanols: a new class of beta-adrenergic blocking and antihypertensive agents.

Various 2-benzodioxinylaminoethanol derivatives were synthetized and investigated for beta-adrenergic blocking activity. Most compounds demonstrated a beta-blocking activity of a competitive type when evaluated in guinea pig atrial and tracheal preparations. Three compounds were more potent than practolol and propranolol.

[Compared efficacies of somes antispasmodic drugs on the digestive tract and the bladder of the anesthetized dog (author's transl)].

The antispasmodic activity of tiemonium, mebeverine, pitofenone + fenpiverinium association and N-butyl scopolammonium was compared in the anesthetized dog. Strain gauges were fixed on the gastric antro-fundic border, on the pylorus, on the descending duodenum and on the terminal colon. Pressure transducers were connected with water filled small balloons inserted into the gall bladder and the bladder.

Vitamin B12 and a lyophilised extract of lamb gastric mucosa in the treatment of two digestive pathological models in the rat and the dog. Clinical and macroscopical observations.

A comparative experimentation between treatment with large amounts of vitamin B12 alone and associations of intrinsic factor with different concentrations of vitamin B12 in the gastrectomised dog and rat subjected to digestive stress induced by phenylbutazone is reported. This study served to examine the possible therapeutic role of vitamin B12 passive diffusion occurring with large amounts of cyanocobalamine in the digestive tract, and to verify the utility and efficacy of the intrinsic factor contained in the marketed Gastropylore, the composition of which associates an original lyophilisate of suckling lamb gastric mucosa (LLGM) with vitamin B12. Treatments with either of the components alone exerted no protective effect against phenylbutazone-induced ulcerations whereas Gastropylore gave very significant protection (p less than 0.

[Relation between the electronic structure of a series of 1,4-tetrahydro-oxazines and their p-D2, for the tryptaminergic receptor].

Certain features of the isopotential maps of morpholine derivatives seem to be related to their ability to bind with tryptaminergic receptors.

Dualist or pseudo-dualist interactions of mepyramine, diphenhydramine and eprozinol with histamine at H1-receptors.

The types of interaction of mepyramine (M), diphenhydramin: (D) and eprozinol (E), with histamine H1-receptors of guinea pig ileal and tracheal smooth muscle, were comparatively studied in vitro. According to the concentrations used, all three substances showed an apparent dualist mechanism of action on both preparations when histamine (dihydrochloride) was used as the agonist. The competitive component of this mechanism (at low concentrations) was characterized by the following pA2 values: 9.

[Strict additivity of the antispasmodic effects of papaverine and tiemonium: an example of sequential blockage].

The interaction of papaverine and tiemonium alone or combined, with BaCL2 and histamine on guinea pig ileum and with acetylcholine on rat jejunum have been studied with the help of molecular pharmacology techniques. The competitive antagonist effects of tiemonium and the non competitive antagonist effects of papaverine are evidenced and shown to be strictly additive when the two drugs are combined. This reflects a sequential blockage of the effects of acetylcholine, histamine and barium ions at the smooth muscle level.

[Comparative affinity of several standard anti-secretory agents for the intestinal cholinergic receptors of of rats and dogs].

Anticholinergic potentialities of four standard anti-secretory drugs (N-methyl-scopolammonium methylsulfate, atropine, diphemanil and prifinium) have been investigated with the help of molecular pharmacology techniques. The results gained with two different agonists (acetylcholine and carbachol) on rat and dog intestinal cholinergic receptors-jejunum and duodenum respectively-show : 1) That relative potentialities of the anticholinergic drugs (pA2) as well as those of the cholinomimetic agonists (pD2) are markedly modified according to which effector is used. 2) The N-methyl scopolammonium methylsulfate remains in any event the most potent anticholinergic drug investigated.

Different membrane mechanisms of action for tiemonium; a comparison with atropine and papaverine.

The effects of tiemonium on various membrane events preceding smooth muscle fibre contraction, have been studied in vitro. Classical molecular pharmacological models and methods were used: stimulation of muscarinic, histamine H1 and alpha-adrenergic receptors; induction of contraction by release of membrane phospholipid bound Ca2+ ions, or by intracytoplasmic influx of this cation in depolarized preparations. At each level of investigation, tiemonium was studied comparatively with two reference antispasmodics, atropine and papaverine.

[Creation, in the dog, of a denervated antral pouche, associated with a Heindenhain's pouche: technical considerations relative to surgical time and postoperative complications].

Overall assessment following the creation of denervated antral and fundic pouches, in 64 mongrel dogs, leads to the recommendation of certain important technical options: surgical intervention carried out in 1 stage; respecting of precise operative timetable; reestablishement of digestive continuity by gastro-jejunostomy with large anastomosis mouth; inutility of scraping the walls of vessels irrigating the pouches.

[Value of the "gastric chamber", new technic performed ex vivo, for the study of the gastric mucosa of the rat].

The "gastric chamber" technique, performed in the anaesthetised rat, enables the study of gastric mucosal fragility induced by doses of phenylbutazone, which do not themselves cause ulceration or exulceration. The perfusion of buffered solution at pH 2-8 into the gastric chamber shows that prior oral administration of phenylbutazone 50 mg/kg increases the fragility of the mucosa. The optimal delay separating this administration from the time of experimentation is 6 hours.