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. The 4-benzyl-3, 4-dihydro-2-[3-[[2-(3,4-dimethoxyphenyl)ethyl]amino]propyl]-2H-1, 4-benzoxazine (3c) is the most potent derivative of the series with a ratio of IC50 values against PE (phenylephrine) and K+ of 2.1. Under these test conditions a ratio near 1 indicates potential intracellular calcium activity while a ratio greater than 100 an action on extracellular calcium influx.

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 = 0.82 microM). Similarly to reference drugs, Org 13061 was more selective in reducing vascular compared to cardiac contraction. In concentrations overlapping those exerting vasorelaxant actions, Org 13061 inhibited copper ion-induced human low density lipoprotein (LDL) peroxidation (0.1-1 microM) and inhibited lipid accumulation by rat aortic smooth muscle cells in culture (1-3 microM). Higher concentrations (3 microM) modestly inhibited proliferation of these cells. The (-) enantiomer was ten times more potent than the (+) enantiomer as a vasorelaxant but was equipotent in inhibiting lipid accumulation and LDL peroxidation (eg, lag phase of conjugated dienes formation increased by 29 and 61 min and by 22 and 56 min in response to 0.3 and 1 microM (-) and (+) enantiomers, respectively). The antioxidant probucol was approximately three times more potent than Org 13061 in inhibiting lipid accumulation but was 30 times less potent in antagonizing LDL peroxidation. The classical calcium channel blocking agents were totally ineffective on lipid accumulation (1-10 microM), whereas human LDL peroxidation was slightly reduced by nifedipine (0.1-3 microM) but unaltered by diltiazem (0.1-30 microM) and verapamil (0.1-3 microM). In conclusion, the racemic Org 13061 selectively blocks voltage-operated calcium channels (VOCs) in concentrations that also exert marked antioxidant activity. The (-) enantiomer is largely responsible for calcium channel block but as antioxidants, the enantiomers are equipotent. This mixed pharmacological profile of Org 13061, not shared by known calcium channel blocking agents, may be potentially useful in the treatment of atherosclerosis.

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]. / Phényléthanolamines benzoxazolinoniques antagonistes des récepteurs adrénergiques. Etude chimique et pharmacodynamique.

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. Compound (XXXIV), the most interesting, is a competitive alpha and beta adrenergic antagonist which has been studied for antihypertensive activity.

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. The ratio of chronotropic to inotropic potencies for each agent shows that the physiological mediator. Acetylcholine, differentiates best between the two subtypes, while atropine is the least discriminatory.

[Cardiovascular effects of elliptinium. The mechanism of action]. / Effets cardiovasculaires de l'elliptinium. Approche du mécanisme d'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 (0.375; 0.75; 1.5 mg/kg) elliptinium only induced variations of heart rate. With the dose of 3 mg/kg hypotension and tachycardia appeared. The time-course of these effects was different from that of histamine (5 micrograms/kg): later onset and longer duration. Elliptinium was inactive in isolated guinea-pig atria, as observed in tracheal or digestive isolated smooth muscle. Thus, the cardiovascular activity of this antitumoral agent seems to implicate an indirect mechanism of action. This result is in accordance with the previous results obtained on bronchopulmonary system.

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. All compounds demonstrated antihypertensive properties in spontaneously hypertensive rats. The most active compound was 1-(1,4-benzodioxin-2-yl)-2-[N4-(2-methoxyphenyl)piperazino]ethanol (11), which at 2.5 mg/kg iv lowered blood pressure by 41%.

[Compared efficacies of somes antispasmodic drugs on the digestive tract and the bladder of the anesthetized dog (author's transl)]. / Puissance relative de quelques antispasmodiques au niveau du tractus digestif et de la vessie, chez le chien anesthésié.

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. Five minutes after the intra-venous injection of the drugs, contraction of the smooth musculature was induced by 3 intra-venous injections of BaCl2 (1 mg.kg(-1)) at 3 minutes intervals. The results were expressed as ED50 values (mg.kg(-1)). 2. Tiemonium was the most potent of the 4 antispasmodic drugs. Its ED50 values were very similar for the different organs, ranging from 0.13 +/- 0.022 for the duodenum to 0.31 +/- 0.03 for the bladder. Mebeverine and pitofenone + fenpiverinium association were equipotent but for colon contraction, where mebeverine was more active (ED50 = 0.68 +/- 0.06). Other ED50 relatives to these 2 compounds were ranging from 0.40 +/- 0.02 (duodenum) to 1.32 +/- 0.14 (gall bladder). N-butyl scopolammonium was found to be the weakest antispasmodic drug on this model. Its activity was very weak on colon (ED50 = 5.21 +/- 0.037), gall bladder (ED50 = 5.40 +/- 0.074) and bladder (ED50 = 5.02 +/- 0.059). 3. The strong antispasmodic activity demonstrated on this model with tiemonium seems to be due to its potent inhibition of membrane Ca++ ions, added to its moderate anticholinergic activity.

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 0.00001). Enhancement of the vitamin did not yield any significant improvement. Weight increase after gastrectomy was clear in the three groups of animals treated with Gastropylore or LLGM containing vitamin B12. Vitamin B12 passive diffusion appears to play no important therapeutic role while the intrinsic factor contained in a lyophilised preparation of lamb gastric mucosa seems to prove useful.

[Relation between the electronic structure of a series of 1,4-tetrahydro-oxazines and their p-D2, for the tryptaminergic receptor]. / Relation entre la structure électronique d'une série de 1.4-tétrahydro-oxazines et leur p-D2, vis-à-vis du réceptor tryptaminergique.

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: 9.01 (M), 7.80 (D) and 5.64 (E) with the ileum; 8.06 (M), 7.00 (D) and 6.02 (E) with the trachea. The so called non specific component (at high concentrations) was of comparable intensity in the two organs. The pD'2 values were 5.54-5.66 (M), 4.65-4.38 (D) and 3.82-3.55 (E) with ileal and tracheal muscle, respectively. At low concentrations the equi-active dose-ratio for N/D/E (1/16/2300 on the ileum) became 1/12/110 when the trachea was used as the effector. This is surprising since histaminergic receptors of the two preparations are of the same H1-type. It is suggested that only diphenhydramine and eprozinol are really dualistic, and that the non-specific mechanism of activity differs for each drug with that of eprozinol being effective on tracheal muscle.

[Strict additivity of the antispasmodic effects of papaverine and tiemonium: an example of sequential blockage]. / Additivité des effets antispasmodiques de la papavérine et du tiémonium: un exemple de blocage séquentiel.

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. No such antagonism has been previously described in the case of the interaction with barium chloride with any other combination of two spasmolytic drugs.

[Comparative affinity of several standard anti-secretory agents for the intestinal cholinergic receptors of of rats and dogs]. / Affinités comparées de quelques anti-sécrétoires de référence pour les récepteurs cholinergiques intestinaux du rat et du chien.

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.