Synthesis and central dopaminergic activities of (+/-)-hexahydro-7H-indolo[3,4-gh][1,4]benzoxazine derivatives [(+/-)-9-oxaergolines].

The synthesis and biological activities of a series of (+/-)-hexahydro-7H-indolo[3,4-gh][1,4]benzoxazine derivatives [(+/-)-trans-9-oxaergolines] with central dopamine (DA) agonist properties are described. The compounds were prepared from [2aRS-(2a alpha,4 beta,5 alpha)]-4-amino-1,2,2a,3,4, 5-hexahydro-1-(phenylmethyl)benz[cd]indol-5-ol (6b) by alkaline cyclization of the corresponding N-chloracetamide 7b, followed by reduction of the amido group [5aRS-(5a alpha, 6a beta, 10a alpha)]-4,5,5a,6,6a,7,9, 10a-octahydro-4-(phenylmethyl)-7H-indolo[3,4-gh][1,4]benzoxazin-8-one (8b) with LiAlH4. After debenzylation of the resulting amine 9a, the indoline ring of [5aRS-(5a alpha, 6a beta, 10a alpha)]-4,5,5a,6,6a,8,9, 10a-octahydro-7H-indolo[3,4-gh][1,4 ]benzoxazine (10a) was dehydrogenated with MnO2 to give (+/-)-trans-9-oxaergoline (11a), which can be alkylated on the nitrogen (11b,c and 12) and brominated in position 2 (13a,b). The compounds were examined in vitro for their ability to bind to DA receptors and to inhibit prolactin (PRL) secretion in pituitary cells in culture, in vivo both for their DA stimulant effects at the striatal level (circling in 6-OHDA-lesioned animals, DA turnover, and stereotypy) and inhibitory effects on plasma PRL levels in rats, and for their emetic effects in dogs. Most of the tested compounds were active in these tests, and the potency of (+/-)-trans-6-n-propyl-9-oxaergoline (11c) was comparable to that of pergolide mesylate.

Comparative study of six -adrenoceptive antagonists on airway resistance and heart rate in the guinea-pig.

1. The effects of six beta-adrenoceptive antagonists [(+/-)-propranolol, (+)-propranolol, (+/-)-sotalol, (+/-)-practolol, (+/-)-pindolol and (+/-)-procinolol] were studied on airway resistance and heart rate in guinea-pigs and dose-response curves constructed.2. All beta-adrenoceptive antagonists decreased heart rate and increased airway resistance. A significant correlation was found between the increase in airway resistance and the degree of bradycardia induced by all drugs except practolol. The orders of activity of the six drugs in inducing significant variations of the two parameters were respectively, for airway resistance: (+/-)-procinolol>(+/-)-pindolol>(+/-)-propranolol>(+/-)-sotalol>(+)-propranolol>(+/-)-practolol, and for heart rate: (+/-)-pindolol>(+/-)-procinolol>(+/-)-propranolol>(+/-)-sotalol>(+)-propranolol>(+/-)-practolol.3. (+/-)-Sotalol, (+/-)-pindolol and (+/-)-procinolol-induced changes in airway resistance and heart rate reached plateau values, which were not modified by increasing the dose. Since sotalol and procinolol have only very weak partial agonist and cardiac depressant properties, it appears that these changes can mainly be accounted for by the suppression of sympathetic tone. It is probable that this is also the case with pindolol.4. On the other hand, (+/-)-propranolol and (+)-propranolol induced dose-related changes in airway resistance and heart rate. Thus, a direct and non-specific effect of both drugs on the bronchial muscle, similar to that observed on the heart appears to be implicated, together with sympathetic tone suppression in these variations.5. (+/-)-Practolol-induced effects on airway resistance and heart rate were different from those observed with the five other beta-adrenoceptive antagonists.

The effects of pentobarbitone and urethane on pulmonary airway resistance in guinea-pigs and their interactions with drugs.

1 Propranolol increased pulmonary airway resistance (PAR) in the conscious guinea-pig, whereas atropine had no effect, suggesting the existence of a continual sympathetic bronchodilator tone. 2 The direct bronchoconstrictor effects of histamine, acetylcholine and 5-hydroxytryptamine were modified by autonomic reflexes: a bronchodilator one, abolished by propranolol, and a cholinergic bronchoconstrictor one, seen with histamine. 3 Pentobarbitone increased PAR, an effect which was reduced by propranolol but which was unaffected by atropine. The bronchoconstrictor effects of histamine, acetylcholine and 5-hydroxytryptamine were potentiated by pentobarbitone. 4 Pentobarbitone therefore appears to inhibit the adrenergic bronchodilator tone and to depress adrenergic reflexes, these being the preponderant autonomic influences in these experiments. 5 Like pentobarbitone, urethane increased PAR in the conscious guinea-pig and potentiated the bronchoconstrictor effects of the three amines. These actions are similarly attributed to a reduction in adrenergic influences.

[Effects of antianxiety drugs on the water intake in trained and untrained rats and mice (author's transl)]. / Effets des anxiolytiques sur la prise de boisson en situation nouvelle et familière

In water-deprived rats and mice, animals trained to the test situation spent more time in drinking than naive animals (first exposure to the test situation). The time spent in drinking, either during 5 min or during 10 min was recorded. As compared to controls, benzodiazepines, phenobarbital, meprobamate, and mecloqualone increased drinking time whether the experiments were run on naive or on experienced animals [5 or 10 (in mice) and 9 (in rats) exposures in the test situation]. All drugs were injected i.p. 30 min before testing. This release of the drinking behavior was more pronounced during the last 5 min than during the first 5 min of the 10 min test session. These results suggest that: 1. The inhibition of water intake of naive animals as compared to trained rats and mice, could be related to some emotional factors elicited by the first exposure to an unknown situation. 2. The increase in drinking time induced by the antianxiety drugs in a novel and in a familiar situation seems difficult to correlate only with the antianxiety action of these compounds. 3. Antianxiety drugs could interfere with the regulatory mechanism of thirst.

[Psychopharmacological profile of a new dopaminergic agonist, RU 24213 (author's transl)]. / Profil psychopharmacologique d'un nouvel agoniste dopaminergique, le RU 24213.

The psychopharmacological properties of RU 24213 were compared to those of other dopaminergic agonists (apomorphine, dexamphetamine, bromocriptine and L-dopa) in various behavioural tests. In naive mice the drug reduced the locomotor hyperactivity in the primary exploratory phase and produced stimulation in the subsequent stabilized activity period. In rats it provoked dose-related stereotypies, specially gnawing and sniffing. It delayed the cataleptic state induced by prochlorperazine without affecting its intensity. In animals unilaterally lesioned with 6-OHDA in the nigro-striatal pathway, RU 24213 caused contralateral turning. It exhibited relatively weak emetic and anorexic effects in dogs. Core temperature recordings in rats revealed a biphasic hypo- and hyperthermic activity. In drug interaction studies it was obsers in rats with unilateral electrolytical striatal lesion. The results obtained suggest that RU 24213 stimulates dopamine receptors both directly and indirectly. In this respect it could be compared to bromocriptine but unlike this latter compound it has an immediate effect which is of shorter duration.

Benzodiazepines and behavioral effects of reward (water) omission in the rat.

Two behaviors related to nonreward (omission of water in an enclosure where the rats were habituated to drink) were studied. The time spent licking the bottles during water omission and the time spent drinking during a subsequent 5-min drinking session (water available) were recorded. The drinking session was performed 30 min after the water-omission session. Rats subjected to water omission showed an enhanced drinking time that varied with the length of the water omission session, with the motivational state of the animals, and with the previous number of water-omission sessions. Diazepam, chlordiazepoxide, lorazepam, and meprobamate (i.p., 30 min before water omission), increased the time spent licking the empty bottles, but failed to abolish subsequently enhanced drinking. However, some of our data suggested that minor tranquilizers weakly reduced the increased drinking induced by nonreward, despite their direct stimulation on water drinking. It is proposed that either minor tranquilizers are devoid of general antifrustration activity or nonreward-induced frustration and nonreward-induced drive enhancement may not be correlated.

Age-dependent changes in the beta-endorphin content of discrete rat brain nuclei.

Concentrations of beta-endorphin were measured by radioimmunoassay in discrete brain nuclei of young (3 months) and old (24 months) rats. The beta-endorphin content of all major structures known to contain this peptide with the exception of the eminence, is reduced (50.3 +/- 2.8% of control) in old rats.

Biochemical assessment of the central 5-HT agonist activity of RU 24969 (a piperidinyl indole).

The most potent compound of a series of piperidinyl indole derivatives which decrease 5-hydroxyindole acetic acid (5-HIAA) levels in rat brain-stem was chosen for further study on the neurochemistry of serotonin (5-HT) neurons. This derivative (RU 24969: 5-methoxy 3-(1,2,3,6-tetrahydro-4-pyridinyl) 1 H indole, succinate) exerted a dose-dependent reduction in 5-HIAA concentrations in rat forebrain and brain-stem, which was of rapid onset and lasted for at lest 4 h. The decrease in 5-HIAA was apparently due to a decrease in 5-HT turnover since RU 24969 significantly diminished 5-HTP accumulation after RO 4-4602 administration, and 5-HIAA accumulation after probenecid treatment. Basal or 5-HT-stimulated adenylate cyclase activities in colliculi from new-born rats were unaffected by RU 24969. This compound increased serum prolactin and corticosterone levels in a dose-related manner. Together with previous behavioral observations and the potent displacement of [3H]-5-HT binding obtained with this series, the present data indicate that these new piperdinyl indole derivatives are likely potent 5-HT receptor agonists in rat brain.

Time course of apomorphine-induced circling behaviour after striatal dopamine receptor denervation.

The curve describing the time course of apomophine-induced circling behaviour in rats with a 6-hydroxydopamine-induced lesion of the nigrostriatal dopamine (DA) pathway was studied with a microcomputerized rotometer. Up to a 2-week interval after lesioning, the contralateral circling response was a single bell-shaped curve but this gradually became a double-peaked curve after 4-5 months. At this time the bell-shaped curve was, however, restored by haloperidol pretreatment. It is concluded that the response of striatal DA receptors was modified either by the lesion of another neuronal system and/or that the absence of DA nerve endings induced changes in the striatal DA receptor itself.

Chronic atenolol treatment and hypertension development in spontaneously hypertensive rats.

Changes in systolic blood pressure (SBP), heart rate (HR), heart rate and plasma renin concentration (PRC) have been compared in three different groups of rats between the ages of 5 and 20 weeks. The groups were: spontaneously hypertensive rats (SHRs), atenolol-treated SHRs (200 mg/kg/day orally throughout the 15 weeks) and normotensive rats of the same strain (WKYs). Treatment with atenolol markedly inhibited the onset of genetic hypertension, reduced HR and PRC from the outset and diminished the heart weight/body weight ratio. Comparison of changes in these parameters in atenolol-treated SHRs, control SHRs and WKYs strongly suggests that the mechanism of atenolol's preventive action against hypertension development in SHRs primarily involves its effects on heart and on the renin--angiotensin system.

Beta-adrenergic blockade and atrio--ventricular conduction impairment.

Atrio--ventricular conduction and its modifications induced by six Beta-adrenergic blocking agents have been investigated in the dog. Premature atrial stimuli (St2) were applied at variable intervals following regular stimuli (St1) ensuring atrial pacing; atrial (AERP), nodoventricular (NERP) and global (GERP) effective refractory periods as well as global functional refractory period (GFRP) were determined before and after administration of each of the six drugs. When Beta-blockade was produced with d,1-propranolol which hwas membrane stabilizing effects (MSE) but no intrinsic sympathomimetic activity (ISA) or with sotalol, which has neither MSE nor ISA, all parameters were significantly increased. When Beta-blockade was achieved with pindolol or practolol, which have only a poor Beta-adrenolytic potency and no ISA. Alprenolol showed intermediate effects. Thus, it appears that Beta-blockade and not MSE, is responsible for the onset of A-V conduction impairment but that ISA, probably through a metabolic mechanism, affords protection against this impairment. On the other hand, measurement of ventricular effective refractory period (VERP) has shown that at the Purkinje-free junction, it is MSE which is mainly involved in conduction impairment.

Antagonism by sulpiride of three apomorphine-induced effects in rodents.

Three effects of apomorphine (hypothermia and climbing behavior in mice, stereotyped behavior in rats) were studied. Sulpiride antagonized the two effects in mice but stereotyped behavior in rats remained unchanged. Pimozide and haloperidol antagonized the three effects. These results could be explained by the existence of two types of dopaminergic receptors or by the different accessibility to identical dopaminergic receptors located in different CNS areas.

Isoprenaline and canine cardiac refractory periods.

Atrioventricular refractory periods and their modifications induced by variable doses of sioprenaline have been investigated in dogs. Premature atrial stimuli (St2) were applied at variable intervals following regular stimuli (St1) which ensured atrial pacing. Atrial (AERP), nodoventricular (NERP) and global (GERP) effective refractory periods, as well as the global functional refractory period (GFRP) were determined before, during and after infusion of the drug. In low doses, isoprenaline did not significantly alter these various parameters. This confirms its lack of dromotropic effect on the healthy heart. In contrast, high doses of the drug significantly reduced the refractory periods, probably by simple correction of the negative dromotropic effects resulting from overstimulation. Also when the infusion was stopped, marked but reversible conduction depression was observed. It would appear that this reflects 'exhaustion' of cell metabolism induced by the drug.

Benzamides and classical neuroleptics: comparison of their actions using 6 apomorphine-induced effects.

The effects of 6 benzamides and 8 classical neuroleptics were studied on 6 different apomorphine-induced effects. These drugs did not antagonize all the effects in the same way. The differences are discussed according to the two types of dopaminergic receptor hypothesis. Some apomorphine-induced effects (stereotyped behavior, circling behavior, climbing behavior, and increased motor activity) could be related to stimulation of one type of dopaminergic receptor, other effects (hypothermia and decreased activity) to the other type. Pimozide, sulpiride, thioproperazine, GRI 1665 and TER 1546, could block selectively one type of dopaminergic receptor, at least in a given range of doses. Clozapine, chlorpromazine, levomepromazine, and thioridazine, could block selectively the other type of dopaminergic receptor. Haloperidol, metoclopramide, prochlorperazine, sultopride, and tiapride, could block both types of dopaminergic receptors with equal intensity whatever the dose.

The role of beta-adrenoceptors in coronary blood flow distribution in normal and ischemic canine myocardium.

beta-Adrenoceptor agonists increase myocardial ischemic injury, mainly by elevating myocardial oxygen consumption. Moreover, it has been shown that isoprenaline may "steal" regional myocardial blood flow (RMBF) from ischemic to non ischemic areas and from epicardium to endocardium. The mechanisms of these two isoprenaline-induced redistributions of RMBF have been investigated by the use of radioactive microspheres in an experimental model of canine myocardial ischemia with simultaneous measurement of ST-segment elevation. Isoprenaline increased RMBF in both epi- and endocardial non ischemic areas and in epicardial ischemic areas, leading to a significant decrease in the endo/epi ratio. After atenolol, isoprenaline still increased RMBF but to a lesser extent and the endo/epi ratio was still decreased. Salbutamol, in doses inducing no significant changes in cardiac parameters or myocardial oxygen consumption, produced effects similar to those of isoprenaline. These results indicate a non-homogeneous beta2-stimulation-induced vasodilation in endo- and epicardium, which might be due either to the higher epicardial coronary vasocilatory reserve or to a heterogeneous distribution of transmural beta2-adrenoceptors. Isoprenaline also decreased the ischemic/non ischemic total blood flow ratio (I/NI) and caused further increases in ST-segment elevation. These effects were abolished by atenolol pretreatment, indicating the deleterious effects of isoprenaline-induced tachycardia in this I/NI decrease and in the ischemic injury.

Comparative study of central dopaminergic properties of RU 29717 (N-propyl-9-oxaergoline) and pergolide.

RU 29717, a 9-oxaergoline derivative, has been compared with pergolide in a variety of biochemical and behavioural tests indicative of dopaminergic (DAergic) activity. RU 29717 and pergolide have a similar affinity for DA receptors labelled by [3H]spiroperidol or [3H]dihydroergocryptine ( [3H]DHEC) by using striatal or anterior pituitary membranes respectively. Both compounds stimulate the striatal DA-sensitive adenylate cyclase and inhibit the activity of this enzyme in dispersed cells from the neurointermediate lobe of the pituitary gland. In anterior pituitary cells in primary culture, they decrease prolactin release with the same efficacy. In vivo, they exert a long-lasting inhibition of the reserpine-induced hyperprolactinemia. They equally retard the alpha-MPT-induced disappearance of striatal DA and increase striatal acetylcholine levels. In behavioural models, the similarity between RU 29717 and pergolide is also evident: they induce contralateral circling in animals lesioned unilaterally with 6-OHDA, produce stereotyped behaviour and have emetic activity within the same dose range. Therefore, RU 29717, like pergolide, is a potent direct acting DAergic agonist. In experimental models used to investigate this activity at the striatal or the anterior pituitary levels the compounds present a similar profile of action.

Is dopamine-sensitive adenylate cyclase involved in regulating the activity of striatal cholinergic neurons?

The dopamine (DA)-receptor mediated changes in striatal acetylcholine (ACh) levels have been studied to determine if this effect involves a D1-(adenylate cyclase dependent) or D2-(not linked to an adenylate cyclase) type of DA-receptor, Various DA-agonists (apomorphine, N-diphenethylamine derivatives) increased striatal ACh levels in both intact and 6-OHDA lesioned rats whereas only apomorphine stimulated the adenylate cyclase activity of striatal homogenates. The N-diphenethylamine compounds (RU 24213, RU 24926 and RU 26933) were without effect either on basal or DA-stimulated activities of this enzyme. In contrast, D-LSD (which acts as a partial agonist of the striatal DA-sensitive adenylate cyclase) did not modify the striatal ACh content. More interestingly, an intrastriatal injection of cholera toxin greatly stimulated striatal adenylate cyclase without altering ACh concentrations. Both haloperidol and methergoline antagonized the DA stimulation of adenylate cyclase, but only haloperidol decreased striatal ACh levels. These results indicate that the DA receptor involved in regulating the activity of striatal cholinergic neurons is of the D2-type.