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%.

Cardiovascular and central nervous system effects of rilmenidine (S 3341) in rats.

Rilmenidine (S 3341) is a new alpha 2 agonist, with antihypertensive properties. Pharmacologic data concerning its hemodynamic and central nervous system effects in the rat are described in this report. In the anesthetized or conscious spontaneously hypertensive rat, rilmenidine was found effective and potent as an antihypertensive agent, lowering blood pressure in a dose-dependent manner after intravenous and oral administration. These effects are related to a reduction in sympathetic tone as seen by the decrease in plasma catecholamines induced by rilmenidine in the spontaneously hypertensive rat. Studies in the normotensive pithed rat (electrical stimulation and adrenalectomization) confirmed the presynaptic alpha 2-stimulating properties of rilmenidine and suggested that a component of the antihypertensive activity of rilmenidine could be exerted through these peripheral receptors. A study of the central effects of rilmenidine was performed using classic neuropharmacologic tests. No effect was observed on the pentobarbitone-induced sleeping time in the rat. Rilmenidine caused only a minimal and non-dose-dependent inhibition of the righting reflex in the chick. In the rat, rilmenidine did not decrease the motor activity at concentrations up to 50 times higher than the antihypertensive dose. These results confirmed the contrast between rilmenidine and clonidine and suggest that a dissociation between sedative and antihypertensive effects could occur with rilmenidine.

Electrophysiologic effects of bepridil in the anesthetized dog studied by endocardiac electrodes.

The electrophysiologic effects of bepridil in the anesthetized closed-chest dog were studied with intracardiac electrodes using the extrastimulus technique to measure the refractory periods of atria, atrioventricular (AV) junction and ventricles. Intravenous administration of 5 mg/kg of bepridil caused a reduction in sinus node rate and prolonged the sinus node recovery time. Refractory periods in the atrium, especially the effective refractory period, increased. Anterograde AV nodal conduction was slowed and refractoriness increased, often resulting in AV nodal Wenckebach periods, during atrial pacing, and retrograde conduction was always completely abolished. Refractory periods of the AV junction were altered in a comparable fashion to conduction through the AV node. No significant actions on conduction or the refractory period were noticed in the His-Purkinje system or the ventricle. The mechanism of action of bepridil seems to be correlated to its membrane effects, namely, inhibition of pathways responsible for the slow inward current, which explains its selective action on myocardial sites where this current is particularly involved.

Studies on the bradycardia induced by bepridil.

Bepridil, a novel active compound for prophylactic treatment of anginal attacks, induced persistent bradycardia and a non-specific anti-tachycardial effect, the mechanisms of which were investigated in vitro and in vivo. In vitro perfusion of bepridil in the life-support medium for isolated sino-atrial tissue from rabbit heart, caused a reduction in action potential (AP) spike frequency (recorded by KCl microelectrodes) starting at doses of 5 X 10(-6) M. This effect was dose-dependent up to concentrations of 5 X 10(-5) M, whereupon blockade of sinus activity set in. Bepridil at a dose of 5 X 10(-6) M, induced a concomitant reduction in AP amplitude (falling from 71 +/- 8 mV to 47 +/- 6 mV), maximum systolic depolarization velocity (phase 0) which fell from 1.85 +/- 0.35 V/s to 0.84 +/- 0.28 V/s, together with maximum diastolic depolarization velocity (phase 4) which fell from 38 +/- 3 mV/s to 24 +/- 5 mV/s. In vivo injection of bepridil at a dose of 5 mg/kg (i.v.) into 6 anaesthetized dogs which had undergone ablation of all the extrinsic cardiac afferent nerve supply, together with a bilateral medullo-adrenalectomy, caused a marked reduction in heart rate which fell from 98.7 +/- 4.2 beats/min to 76 +/- 5.3 beats/min sustained for more than 45 min. It is concluded that bepridil reduces heart rate by acting directly on the sinus node. This effect, which results in a flattening of the phase 0 and phase 4 slope, together with a longer AP duration, may be due to an increase in the time constants of slow inward ionic currents (already demonstrated elsewhere), but also to an increased time constant for deactivation of the outward potassium current (Ip).

Structure-activity relationships as a response to the pharmacological differences in beta-receptor ligands.

With a few notable exceptions, beta-receptor ligands (agonists and antagonists) belong to the aryl- or heteroaryl-ethanolamine series and to the aryl- or heteroaryl-oxypropanolamine series. Structure-activity relationships for beta-adrenergic agonists show that a secondary amine in the phenylethanolamine side chain ending is essential for receptor stimulation. The 3,4-dihydroxyphenyl groups may be replaced by "phenol equivalents" (-CH2OH, -NHCONH2, -CHOH, -NHSO2CH3). In contrast, substitution at carbon alpha of the phenyl-ethanolamine side chain decreases or suppresses beta-adrenergic activity. The general requirements for beta-adrenergic blocking activity in the aryl- or heteroaryl-oxypropanolamine are as follows: (1) the potency of beta-blockade is conferred by a branched alkyl group (isopropyl or tert-butyl) grafted on the terminal amino N, and by the nature and position of a substituent on the aromatic ring: ortho-substituted compounds (especially when they have an hetero-atom in alpha) are the most potent ones. (2) The cardioselectivity is improved by the attachment of 3,4-dimethoxyphenylethyl,4-amide-substituted phenoxyethyl or acylamino-alkyl moieties to the terminal amino N of the side chain. Para substitution on the aromatic ring (particularly 4-acylamido substitution) has also yielded cardioselective drugs. Finally, the beta 1-selectivity is strongly and negatively correlated with lipophilicity. (3) Intrinsic sympathomimetic activity can be modulated by aromatic nucleus variations, particularly by hydroxyl-equivalents (electron withdrawing groups) on meta- and para-positions (3,4-substitutions).

Structure-activity relationships of tricyclic antidepressants, with special reference to tianeptine.

Structure-activity relationships in the classical antidepressant (imipramine-like) series show a relative lack of specificities: Compounds should simply have a nucleus consisting of two phenyl rings and a third, seven-member central ring. This central ring may have one, several, or no heteroatoms, and it may or may not be saturated. The side chain may be attached to any one of the atoms of the central ring, but it must be short (two or three carbon atoms), and have a terminal amine group (secondary, tertiary, or included in a ring). We investigated the structure-activity relationships of 22 new tricyclic tianeptine derivatives exhibiting reserpine-induced ptosis reversal potency in the mouse. Tianeptine is an antidepressant characterized by a 3-chlorodibenzothiazepin nucleus and an aminoheptanoic side chain. Our results indicate highly specific structural requirements for the tianeptine-like series. In order to be active, compounds must have an aminocarboxylic chain (with an optimal length of six methylene links), a tricyclic system with an electron-donor heteroatom in position 5, and an aromatic substitution with a moderate electron-acceptor atom in position 3. These specificities in the tianeptine series are in sharp contrast with the lack of specific requirements that characterize the classical tricyclic series.

A lymphatic function of Daflon 500 mg.

UNLABELLED: The lymphagogue activity of a micronized, purified flavonoidic fraction, Daflon 500 mg (D) (diosmin 90%+ hesperidin 10%) was tested in dogs and rats. METHODS: In the anaesthetized mongrel dog measurement of lymphatic flow was carried out in a thoracic duct fistula inserted 30 min prior to I.V. injection of D (3.125; 6.250 and 12.500 mg/kg-1). Lymph was collected every 10 min for 200 min. Using the same experimental model 14C-diosmin transfer from blood to lymph was studied after I.V. infusion (5 min) of 14C-diosmin (50 muCi)+D(12.5 mg/kg-1) in the saphenous vein. Similar experiments were performed in the rat after oral treatment. RESULTS: D induced an important lymphatic flow increase which was correlated with the administered doses. The maximal 10 min period flow after I.V. injection of D (12.500 mg/kg-1) was 191% higher than the corresponding one in the control group. A correlation between lymphatic flow increase and pulsatility was demonstrated. Infusion of 14C-labelled-D evidenced a clear blood-lymph transfer of the drug: an active transport into the lymph was suggested during a 15 min-100 min period from the concentration curves. CONCLUSIONS: The improvement of lymphatic drainage displayed by D seems to be an important component of its beneficial effect on perivascular edema.

Pharmacologic properties of Daflon 500 mg.

AIMS AND METHODS: Some pharmacologic activities of a micronized flavonoid complex consisting of 90% diosmin + 10% hesperidin (Daflon 500 mg*) have been investigated by use of various experimental models: (1) interference with mechanisms of edema (synthesis of arachidonic acid derivatives, microvascular hyperpermeability induced by bradykinin, ischemia, or streptozotocin), (2) interference with lymphatic drainage (thoracic duct fistula in the dog). RESULTS: Daflon 500 mg inhibited prostaglandin E2 (PGE2) and thromboxane A2 (TxA2) synthesis during a one-month oral daily treatment (100 mg.kg-1.day-1) in the rat, after induction of chronic inflammation by subcutaneous implantation of sponge fragments. Microvascular hyperpermeability induced by bradykinin or ischemia in the rat cremaster muscle was reduced after an oral treatment with Daflon 500 mg (100 mg.kg-1 twice daily). Microvascular hyperpermeability of the streptozotocin-induced diabetic rat was antagonized when Daflon 500 mg (300 mg.kg-1 once daily) was given orally as a preventive treatment. In the anesthetized dog, an increase in lymphatic flow, correlated with administered doses, was observed after IV injection of Daflon 500 mg. Lymphatic flow was maximal twenty minutes after injection of the drug (12.5 mg.kg-1) and was three times higher than the basal flow. CONCLUSION: The protective effect of Daflon 500 mg against the formation of perivascular edema and its therapeutic value in the treatment of venous stasis could be explained by its inhibitory activity on the inflammatory process or ischemia-induced hyperpermeability and by its stimulatory effect on the pulsatile activity of lymphatic vessels.

Neurochemical and pharmacological properties of tianeptine, a novel antidepressant.

Tianeptine is a tricyclic antidepressant with an unusual chemical structure (a long lateral chain grafted on to a substituted dibenzothiazepin nucleus), and with biochemical and animal-behavioural properties which are strikingly different from those of classical tricyclics. Unlike the latter, which decrease serotonin (5-HT) uptake, acute and chronic tianeptine treatment enhances 5-HT uptake in rat brain and in rat and human platelets ex vivo. In vivo, tianeptine potentiates the depletion of rat brain 5-HT by 4-methyl-alpha-ethyl metatyramine and increases rat hippocampal 5-HIAA; 5-HT uptake inhibitors (e.g. fluoxetine) have opposite effects. On iontophoretic injection into CA1 pyramidal cells, tianeptine shortens the period of neuronal hypoactivity caused by GABA or 5-HT, whereas other tricyclics prolong it, and it enhances attention, learning, and memory in laboratory animals, while classical tricyclics have opposite effects. However, the relationships between these effects of tianeptine in animal experiments and their relevance to clinical findings remain to be determined.

[Tianeptine, an uncommon psychotropic drug]. / La tianeptine, un psychotrope original.

The pharmacological studies show that tianeptine (Stablon) is an original psychotropic drug. In classical and behavioural pharmacology, tianeptine has a novel antidepressant profile, different from other molecules and an anxiolytic effect but different from the benzodiazepines. Tianeptine does not cause sedation and sleeping troubles. In mice, tianeptine does not impair spatial memory but have facilitating effects on both working and reference memory. Tianeptine also increased the focalization of attention in cat and is active on comportmental adaptation models in stress. The electrophysiological data showed that tianeptine increases activity of the hippocampus pyramidal cells and decreases the recovery time after inhibitory substances application. Neurobiochemical studies showed that tianeptine increases serotonin uptake, in rat brain and in rat and human platelets, after acute and chronic treatment. Neuroendocrinology data showed that tianeptine decreases CRF and ACTH levels. Current research on the effect of tianeptine on acetylcholine could explain its anti-stress and memory facilitation activity.

[Cellular disorders induced by ischemia. The effect of trimetazidine]. / Pertubations cellulaires induites par l'ischémie. L'action de la trimétazidine.

In contrast with the classical anti-anginal drugs, trimetazidine appears to be a very specific treatment, especially to the ischaemic cell. Whereas beta-blockers, nitrates and calcium antagonists all act outside the real ischaemic area (on peripheral veins or arteries, coronary vessels, whole heart muscle contractility, sinus node, endo-epicardial blood flow ratio, etc...) trimetazidine is only efficient on the ischaemia-induced loss of membrane functions and its consequences. The disturbance of tissue oxygen supply during ischaemia decreases mitochondrial ATP production and increases the generation of free radicals (O2-., OH-.). By diminishing the bioavailability of free radicals, trimetazidine lessens all their toxic effects: trimetazidine acts on the inactivation of enzymatic membrane proteins (which induces ATP over-reduction, creatine phosphokinase and lactate release outside the cell and electrolyte shifts); trimetazidine corrects the elevation of passive membrane permeability (increased by free radical-induced peroxidation of unsaturated membrane lipids); it antagonises free radical-induced stimulations of phospholipase A2 and thromboxane synthetase. In conclusion, trimetazidine restores energy-producing processes in the ischaemic heart cell by lessening the toxic effects of oxygenated free radicals.

[The almitrine dimesylate molecule. Various structure-activity relationship aspects]. / La molécule de bismésilate d'almitrine. Quelques aspects des relations structure-activité.

The improvement in PaO2 induced by almitrine bismesylate is due to better adjustment between alveolar ventilation and lung perfusion (VA/Q ratio). Experimental studies and clinical pharmacology suggest that this improvement involves changes in both alveolar ventilation and pulmonary circulation. By synthesizing and testing compounds with different structures in a series of trisubstituted triazines, it has been possible to determine qualitative structure-activity relationships and to select almitrine bismesylate is due to better adjustment between the greatest, most rapid and longest lasting increase in PaO2. Almitrine bismesylate is a molecule with three components: a di-allylamino-triazine group, a piperazine ring and a bis-parafluoro-benzhydryl fraction. The di-allylamino-triazine group may be regarded as responsible for the effects on blood gases and ventilation. The presence of two allyl-amino substituents is an absolute prerequisite, and the triazine ring can possibly be replaced by a very similar pyrimidine ring. The piperazine ring is mainly responsible for dissociation between the effects on blood gases and on ventilation as well as for the general kinetics of the biological action of the drug. Molecules of this series which have a pyrrolidine ring or an azetidine ring instead of a piperazine ring do increase PaO2 but much more slowly than almitrine bismesilate. Finally, the bis-parafluoro-benzhydryl group modulates the intensity and duration of the effects on blood gases. Other constituents, such as the cinnamylamino, alpha-cyclohexyl-parafluorobenzyl, beta-naphthyl methyl or 5-fluoro-benzofluranyl-methyl groups also exert favourable biological activities comparable to those of the bis-parafluorobenzhydryl group characteristic of almitrine bismesylate.