New benzocycloalkylpiperazines, potent and selective 5-HT1A receptor ligands.

A series of 1-(benzocycloalkyl)-4-(benzamidolkyl)piperazine derivatives was prepared in order to obtain compounds with a high affinity and selectivity for 5-HT1A receptors. The modifications of aromatic substituents, the length of the alkyl chain, and the size of the ring were explored. Most of N-(1,2,3,4-tetrahydronaphthyl)-N'-(benzamidoethyl)piperazines (32-37) were bound to 5-HT1A receptors in a nanomolar range and presented a high degree of selectivity. After resolution, levorotatory enantiomers showed affinity and selectivity higher than those of dextrorotory ones for 5-HT1A sites. The agonist type activity of selected derivatives was also confirmed in vitro on the inhibition of the activation of adenylate cyclase induced by forskolin and, in vivo, on the induction of the lower lip retraction in rats.

Inhibition of mouse-killing behaviour in magnesium-deficient rats: effect of pharmacological doses of magnesium pidolate, magnesium aspartate, magnesium lactate, magnesium gluconate and magnesium chloride.

Magnesium deprivation induced interspecific aggressive behaviour (muricidal behaviour) in rats undoubtedly attributable to magnesium deficiency since magnesium chloride, by correcting magnesium deficiency, suppressed it. Inhibition of magnesium deficiency-induced behaviour by various magnesium salts should enable the classification of the therapeutic effects of these salts. Consequently we compared the effects of various magnesium salts used therapeutically on the inhibition of the acute muricidal behaviour induced by magnesium deficiency. All the magnesium salts used (chloride, pidolate, aspartate, gluconate, lactate) suppressed the muricidal behaviour. There was no significant difference in the duration of the treatment needed to inhibit this comportment for each of the salts studied. In contrast, significant differences appeared, concerning the different phases of muricidal behaviour. Magnesium pidolate significantly increased the attack latency (P < 0.05). By repeating the muricidal assays, we showed that magnesium pidolate treated rats had a muricidal behaviour rate which was lower than that of the other magnesium salt-treated rat groups. Consequently, it can be assumed that all the magnesium salts used had an acute anti-muricidal, perhaps anti-stress, effect and that magnesium pidolate presented, on this experimental model the greatest efficacy.

[Psychopharmacological properties of three magnesium salts: pidolate, lactate and aspartate]. / Propriétés psychopharmacologiques de trois sels de magnésium: pidolate, lactate et aspartate.

The psychopharmacological activities of three organic magnesium salts were estimated on the spontaneous and amphetamine-induced motility, the barbital-induced sleep and the NMDA toxicity of Swiss mice fed with a normal diet, rich in magnesium. Magnesium aspartate had a stimulant effect whereas lactate did not clearly modify the animal behaviour and pidolate induced a clear cut neurosedative effect. None of these salts afforded protection against NMDA toxicity, moreover, aspartate and lactate increased NMDA toxicity. These results indicate that depending on the anion, magnesium salts do not have the same psychopharmacological activities and that pidolate only seems to respect and enhance magnesium basic pharmacological properties.

Anti-immobility activity of different antidepressant drugs using the tail suspension test in normal or reserpinized mice.

The tail suspension test is a screening procedure recently used in mice to detect antidepressant activity of drugs. The ability of amine re-uptake inhibitors to decrease immobility in non-reserpinized and in reserpinized mice was studied. Reserpine (4 mg/kg ip) was injected 4 h previously. Anti-depressants were administered ip, 60 min before tail suspension. Animal activity was recorded for 6 min. Preferential serotonin re-uptake blockers (fluoxetine, fluvoxamine, clomipramine) were poorly active in non-reserpinized mice and inactive in reserpine-treated mice. Noradrenergic drugs (desipramine, demexiptiline, viloxazine) were more efficient in reserpinized than in non-reserpinized mice. The mixed serotonin-noradrenaline re-uptake inhibitor (imipramine) shows an activity which should be considered between serotonin re-uptake inhibitors and noradrenaline re-uptake inhibitors. DA re-uptake inhibitors (amineptine, GBR 12909) exhibited the highest anti-immobility effect in non reserpinized animals but were of low efficacy after reserpine treatment. Amphetamine differed from dopamine re-uptake inhibitors by its better activity in reserpinized animals. Moreover, it was the only drug showing an equal anti-immobility effect in non reserpinized and reserpinized mice because the dose of 8 mg/kg of amphetamine reduced immobility in reserpinized mice with the same intensity as the dose of 4 mg/kg in non reserpinized mice whereas no other drugs tested in this study achieved the same effect. Comparison of anti-immobility activities of putative anti-depressants in non-pre-treated and in reserpine-pre-treated mice, using the tail suspension test, may be useful to discriminate amphetamines from antidepressant drugs and to differentiate between categories of amine re-uptake blockers.

Electrotherapy in mice: dopaminergic and noradrenergic effects in the Tail Suspension Test.

The Tail Suspension Test (TST) is a psychotropic screening test which is used principally to detect antidepressant activity. Electrotherapy (ECT) is used to treat depressions which are resistant to the usual antidepressant drugs and has proved to have a profile in the TST approaching that of antidepressants after treating mice at the rate of 2 shocks per day for 5 days. The results of a single treatment were not statistically different from those of the control group, whereas single daily treatment for 5 days showed a reduction in immobility which did not differ significantly from the control group. The reduction in immobility, induced by 5 days of ECT treatment twice daily, was antagonized by sulpiride and prazosin but not by yohimbine, methysergide, metergoline and DL propranolol. The results suggest that electrotherapy leads to an increase in noradrenergic and dopaminergic activities expressed by a reduction in immobility in the TST.

Participation of vascular H1-receptors in histaminergic relaxation of rabbit middle cerebral artery in vitro.

4-Methylhistamine relaxed potassium-constricted perfused rabbit middle cerebral arteries at low concentrations (3 X 10(-11) - 3 X 10(-8) M) and constricted them at high concentrations (3 X 10(-7) - 10(-4) M). The relaxation was antagonized by either cimetidine (3 X 10(-7) or 10(-6) M) or mepyramine (3 X 10(-8) M) given 20 min before testing a series of increasing concentrations of 4-methylhistamine, whereas the constriction was slightly potentiated by cimetidine and reversed by mepyramine. The reduction of relaxation was enhanced by a combination of both blockers. These results suggest the involvement of both H1- and H2-receptors in the 4-methylhistamine-induced relaxation. When dimaprit was compared with 4-methylhistamine, it acted only as a relaxing agent, not as a constricting agent. The dimaprit-induced relaxation was antagonized by either cimetidine (3 X 10(-7) M) or mepyramine (3 X 10(-8) M). The inhibition of relaxation was enhanced with a combination of both blockers. This supports the hypothesis that the dimaprit-induced relaxation in the rabbit cerebral artery is also mediated through both H1- and H2-receptors. The H1-agonists 2-methylhistamine and 2-pyridyl ethylamine induced two kinds of responses: an initial relaxation at low concentrations which was reversed by mepyramine (3 X 10(-8) or 10(-6) M) but not by cimetidine (10(-6) or 10(-5) M); this relaxation was followed at higher concentrations by a vasoconstriction which was antagonized by mepyramine (3 X 10(-8), 3 X 10(-7) or 10(-6) M) but not by cimetidine (10(-6) or 10(-5) M). Relaxation by these agents therefore seems to involve the participation of H1-receptors. The pharmacological effects of the histaminergic agonists and antagonists used could be explained by assuming that a distinction exists in the rabbit middle cerebral artery between the receptors concerned in H1-mediated relaxation and H1-mediated constriction.

[Effect of an acidic sulfated polysaccharide on whole blood coagulability. In vivo study in rats]. / Action d'un polysaccharide sulfaté acide sur la coagulabilité globale du sang. Etude in vivo chez le rat.

Armatan, an acid sulphated polysaccharide isolated from a red marine seaweed Asparagopsis armata (Harv.), increases the coagulation time of the rat plasma in vivo assays. This property presents, with administration, time and dose, some variations. Among the three ways studied, subcutaneous injection gives more interesting results than the others. At high concentrations (10, 20 and 50 mg/kg), intravenous administration induces plasma and organic (liver-spleen) diseases.

[Characteristics of the action of an acidic sulfated polysaccharide on global blood coagulation in vitro. Preliminary study in various species of mammals and in man]. / Particularités de l'action d'un polysaccharide sulfaté acide sur la coagulation globale du sang in vitro. Etude préliminaire chez différentes espèces de Mammifères dont l'Homme.

An acid sulphated polysaccharide, isolated from a red marine seaweed, Asparagopsis armata ( Harv .), increases the coagulation time of the plasma in vitro studies. This property, compared with the anticoagulant activity of pentosan polysulphate and heparin, pr esents , with concentration and temperature, some variations in man and other mammals . The rat and human plasma seem to behave in the same way with this substance.

[Effects of a polysaccharide extracted from a red alga (Bonnemaisonales) on mononucleate phagocytes in several rodents]. / Effects d'un polysaccharide extrait d'une algue rouge (Bonnemaisionaile) sur les phagocytes mononuclees de quelques rongeurs.

"Armatan" an acidic sulfated polysaccharide isolated from a red algae (Asparagopsis Armata), has a marked affinity for the Mononuclear Phagocytes System. Its activity seems fairly well established. Indeed, it sets off a series of evolutionary cellular processes beginning with an accumulation of monocytes at the inflammatory injection site; these cells are then replaced by macrophages over several weeks which are progressively substituted by fibroblasts, thereby inducing a final fibro-cicatricial reaction. The inductive effect of Armatan in this cellular evolution is discussed.

Side chain-hydroxylated sterols of the red alga Asparagopsis armata: significant products or artifacts due to autoxidation?

Sterols characterized by an allylic hydroxyl group in the side chain, such as stigmasta-5,28-diene-3 beta, 24 epsilon-diol (1), cholesta-5,23-diene-3 beta,25-diol (2) and cholesta-5,25-diene-3 beta,24 epsilon-diol (3), have been identified several times in various marine algae. Their origin was considered as doubtful: they could have been bona fide constituents of the alga, or be artifacts caused by autoxidation during the isolation process. We have shown that the dihydroxy steroids 2 and 3 can indeed be produced by the autoxidation of cholesta-5,24-dien-3 beta-ol (desmosterol) (5), but that they are nevertheless present in the taxonomic significance.

[Study fo sterols from brown seaweeds of the genus Cytoseira. Identification by gas-liquid chromatography coupled with mass spectrometry (author's transl)]. / Etude des sterols d'algues brunes du genre Cystoseira. Identification par chromatographie gaz-liquide couplée à la spectrométrie de masse

All the samples of brown seaweeds (Cystoseria) that we have studied present the same deltas sterols fucosterol, 22 trans-dehydrocholesterol, brassicasterol, 24-methylene cholesterol as well as cystosterol, a new C27 sterol. This sterol has been submitted to gas-liquid chromatographic-mass spectrometric analysis.