ergoline and etisulergine

Two alpha-aminoergolines with different dopaminergic effects in rats were tried in two groups of Parkinson patients. CQ 32-084 was given in increasing doses up to 10 mg a day for 4 weeks to 10 Parkinson patients, 6 untreated cases and 4 cases with long-term levodopa treatment problems. The patients were checked every week by the Webster rating scale. All patients improved more or less, the earlier untreated patients more than the levodopa-treated patients. Most patients stopped at a dose of 15 mg a day. The side effects were slight. Another group of 10 patients with long-term levodopa treatment problems or insufficient effect of actual treatment were treated in a double-blind crossover trial with another ergoline derivative, CU 32-085. The dose was increased as in the first experiment up to 20 mg a day. Seven of the patients improved during the active drug period. In three cases, the hyperkinesia was increased during the active period, and in two cases it improved. Three patients found an obvious antidepressive effect during the active drug period. Five patients indicated slight decrease of on/off phenomena during the active period of treatment. A more extensive examination of these drugs seems indicated.

Topics: Adult; Aged; Blood Pressure; Clinical Trials as Topic; Disability Evaluation; Ergolines; Female; Humans; Male; Middle Aged; Parkinson Disease; Pilot Projects

CQ 32-084 and CQP 201-403, two ergot derivatives that previous behavioural studies in rats had suggested to be differently active on dopamine (DA) receptors, were IP injected into male chickens. Both compounds strongly modified the animals' behaviour. CQ 32-084 led to sedation, increased yawning, and decreased preening, while CQP 201-403 exerted a biphasic activity: At a low dose, it elicited sedation and yawning; at high doses, however, it induced a state of excitation manifested by diminished sedation and yawning, enhanced preening, and pecking. The sedation, increased yawning, and decreased preening induced by the two DA agonists were reversed by the D2-selective antagonist, sulpiride. The present studies indicate that, from a behavioural point of view, chickens respond similarly to rats to the DA agonists CQ 32-084 and CQP 201-403, which differ in their selectivity of action on the various DA receptor subtypes.

Topics: Animals; Behavior, Animal; Chickens; Dopamine Agents; Ergolines; Grooming; Hypnotics and Sedatives; Male; Receptors, Dopamine; Sulpiride; Yawning

The influence on rat-feeding behaviour of lisuride and CQ 32-084, agonists at dopamine D2 receptors, was examined using two procedures. In a first series of experiments, the apparatus was an X-maze baited with food pellets where individual fasted rats were observed for 5 min. A number of parameters were recorded: latency to tasting and feeding, interval between tasting and feeding, total feeding time, and total grooming time. Lisuride (0.05 and 0.1 mg/kg) and CQ 32-084 (0.05 and 0.5 mg/kg) behaved as stimulants of eating; lisuride (0.4 mg/kg) inhibited the phenomenon. Both drugs always antagonized grooming. Subsequently, when food intake was determined in the home cages of fasted animals lisuride reduced feeding at all doses during the first hour after treatment, while CQ 32-084 had no effect. The data show that the two compounds display different activity on ingestive behaviour according to the dose and experimental model used. Discussion centres on the possible dependence of feeding enhancement in the X-maze on the anxiolytic activity exerted by low D2 autoreceptorial doses.

Topics: Animals; Behavior, Animal; Dopamine Agents; Ergolines; Feeding Behavior; Lisuride; Male; Rats; Rats, Inbred Strains; Receptors, Dopamine; Receptors, Dopamine D2

Topics: Antiparkinson Agents; Bromocriptine; Disability Evaluation; Drug Therapy, Combination; Ergolines; Humans; Levodopa; Lisuride; Long-Term Care; Parkinson Disease; Pergolide; Receptors, Dopamine

The effects of six putative dopamine receptor agonists on exploratory behaviour in rats were assessed: pergolide, (+)- and (-)-3-PPP, bromocriptine, mesulergine and CQ 32-084. Behaviour was automatically recorded in a holeboard apparatus and the data were analysed by the novel multivariate statistical method of partial least squares. All six substances suppressed exploratory behaviour at low doses. Pergolide and (+)-3-PPP-induced stereo-typed behaviour at higher doses. The suppression of exploration induced by pergolide was completely antagonised by sulpiride, partly antagonised by metoclopramide and weakly affected by haloperidol pretreatment. The effects of a low dose of (+)-3-PPP, bromocriptine or CQ 32-084, but not (-)-3-PPP or mesulergine, were antagonised by sulpiride. These findings support the hypotheses that pergolide, (+)-3-PPP, bromocriptine and CQ 32-084 inhibit exploration via stimulation of dopamine receptors. The present data do not substantiate the hypothesis that the suppression of exploration induced by (-)-3-PPP is mediated by stimulation of dopamine autoreceptors. A detailed analysis of the dose curves for pergolide and (+)-3-PPP indicates that the latter compound may have effects in addition to those of a dopamine receptor agonist.

Topics: Animals; Bromocriptine; Ergolines; Exploratory Behavior; Habituation, Psychophysiologic; Male; Motor Activity; Piperidines; Rats; Rats, Inbred Strains; Receptors, Dopamine

The ability of a number of ergot derivatives to inhibit 5-hydroxytryptamine (5-HT)-induced vasoconstriction was examined in the perfused rat mesenteric artery preparation. 5-HT produced an increase in perfusion pressure indicative of vasoconstriction. The ergot derivatives inhibited the 5-HT-induced vasoconstriction in a manner that was predominantly not competitive in nature. As 5-HT2 antagonists the ergot derivatives ranged in potency from CQ 32-084 which abolished the 5-HT2 receptor mediated response at a concentration of 10 nM to LY-141865 which was inactive up to a concentration of 10 microM.

Topics: Animals; Ergolines; Ergot Alkaloids; Female; In Vitro Techniques; Male; Mesenteric Arteries; Perfusion; Rats; Rats, Inbred Strains; Receptors, Serotonin; Serotonin; Serotonin Antagonists; Vasoconstriction

The affinities of several ergot derivatives for 5-HT1 and 5-HT2 receptors were evaluated using [3H]5-HT and [3H]mianserin, and membranes prepared from rat frontal cortex. CQ 32-084, which had a Ki value against the 5-HT2 component of [3H]mianserin binding of 9 nM, had little effect on [3H]5-HT binding and was selective for the 5-HT2 receptor. Lisuride and LY-158A also displayed preferential affinity for the 5-HT2 receptor. Dihydroergocryptine, CM 29-712, lergotrile and LY-062 were more selective for the 5-HT1 receptor. Bromocriptine showed little selectivity for either subtype. Overall, the ergot derivatives displayed markedly different affinities and selectivities for central 5-HT receptors suggesting that their serotonergic actions should be considered when evaluating their pharmacological spectrum of activity.

Topics: Animals; Cerebral Cortex; Ergolines; Ergot Alkaloids; Female; Male; Mianserin; Quinpirole; Rats; Rats, Inbred Strains; Receptors, Serotonin; Serotonin; Structure-Activity Relationship

Clinical responses to bromocriptine and three new ergoline derivatives, CM 29-712, CQ 32-084, and CU 32-085, in the treatment of Parkinson's disease were studied in new, non-levodopa-treated parkinsonian patients. All compounds elicited a significant but mostly only mild or moderate antiparkinsonian efficacy which seems to be less than that of levodopa. The therapeutic profile of the dopaminergic agonists studied was similar, and the improvement in tremor was considerably better than that in rigidity and hypokinesia. All of the compounds elicited clinical side effects typical of dopaminergic agonists but differed both quantitatively and qualitatively in certain respects. Fewer side effects, especially reduced blood pressure or the occurrence of postural hypotension, developed during treatment with CU 32-085. It is evident that more effective, specific, and tolerable dopaminergic agonists are needed before they can be considered a primary treatment of Parkinson's disease. At present, the main indications for dopaminergic agonists seem to be a deteriorating response to levodopa and daily fluctuations in performance.

Topics: Blood Pressure; Bromocriptine; Disability Evaluation; Domperidone; Dopamine; Ergolines; Follow-Up Studies; Humans; Levodopa; Parkinson Disease; Pleural Effusion; Receptors, Neurotransmitter; Time Factors

The affinities of several ergot derivatives for rat cerebral cortex alpha 1- and alpha 2-adrenoceptors were assessed using radioligand binding techniques. In most cases both [3H]prazosin (labelling alpha 1-adrenoceptors) and [3H]rauwolscine (labelling alpha 2-adrenoceptors) binding were displaced by the ergot derivatives tested, but with markedly different potency. Generally compounds displayed selectivity toward the alpha 2-adrenoceptor, particularly CQ 32-084, which had a Ki value against [3H]rauwolscine binding of 35 nM, but had little effect on [3H]prazosin binding at concentrations in excess of 5 microM. Lisuride was the most potent displacer of [3H]rauwolscine binding with a Ki value of 0.54 nM. Only bromocriptine was relatively alpha 1-selective with a Ki against [3H]prazosin binding of 18 nM and against [3H]rauwolscine binding of 120 nM. The results indicate that the ergot derivatives tested display a marked affinity for alpha-adrenoceptors and that their actions at this receptor class should be considered when interpreting their pharmacological activity in vivo.

Topics: Animals; Cerebral Cortex; Ergolines; Ergot Alkaloids; Female; In Vitro Techniques; Kinetics; Lisuride; Male; Membranes; Prazosin; Rats; Rats, Inbred Strains; Receptors, Adrenergic, alpha; Yohimbine

Bromocriptine and the two ergoline derivatives, CQ 32-084 and CM 29-712, exert dopamine-like effects in experimental models and have been shown to possess antiparkinsonian activity. Biochemical investigations indicate that they differ in their specificity towards the different dopamine receptor types and, in addition, interact with other neurotransmitter receptors. Bromocriptine appears to be a potent agonist at D2-receptors. Furthermore, it blocks adenylate cyclase coupled serotonin receptors and antagonizes central alpha-adrenergic receptors. The two ergoline derivatives are multiple agonists. CQ 32-084 stimulates both D1- and D2-, and CM 29-712 only D1-receptors. In addition, both compounds stimulate adenylate cyclase coupled serotonin receptors and antagonize central alpha-adrenergic receptors.

Topics: Acetylcholine; Adenylyl Cyclases; Animals; Antiparkinson Agents; Brain; Bromocriptine; Cerebral Cortex; Corpus Striatum; Cyclic AMP; Dopamine; Ergolines; In Vitro Techniques; Kinetics; Male; Nitriles; Norepinephrine; Rats

The effect of lisuride, bromocriptine, CQ 32-084 and CU 32-085 on the specific binding of radiolabelled spiperone to homogenates of human putamen taken post-mortem has been investigated. In addition, the binding of 3H-lisuride to such preparations has been studied. Lisuride is found to inhibit spiperone binding to the dopamine receptor at very low concentrations and to bind to the beta-adrenergic receptor at somewhat higher levels. Lisuride binding to the dopamine receptor was found to be antagonist-like. A measure of the in vivo effect of lisuride was obtained from investigations of brain tissue taken from a patient treated with the drug before death.

Topics: Brain; Bromocriptine; Ergolines; Humans; Kinetics; Lisuride; Receptors, Dopamine; Spiperone

Dopamine receptors have been characterized by the use of radiolabelled dopamine agonists and antagonists. Using ibotenic acid induced lesions of the striatum, evidence was obtained that 3H-N-propylnorapomorphine (3H-NPA) binding sites and 3H-bromocriptine binding sites are located both on intrastriatal nerve cells and on extrinsic nerve terminals probably mainly originating in the cerebral cortex. Development of dopamine receptor supersensitivity as evaluated in 6-hydroxydopamine lesioned rats was associated with an 50% increase in the number of 3H-NPA binding sites in the striatum. Furthermore, one year following the 6-hydroxydopamine induced lesion of the dopamine pathways two binding sites for 3H-NPA could be demonstrated in the striatum. However, at this time interval the total number of 3H-NPA binding sites was not increased. The functional significance of these two binding sites for 3H-NPA in the striatum is unknown, but they are probably coupled to the biological effector in view of the marked behavioural supersensitivity demonstrated in these old animals. The dopamine receptor agonists and especially the dopaminergic ergot derivatives have been characterized by studying their affinities for 3H-bromocriptine, 3H-spiperone, 3H-ADTN and 3H-NPA binding sites in vitro. It is suggested that the Ki ratios for agonist and antagonist radioligands may be one useful way to characterize the agonist-antagonist character of the drug. Another important method is to study the effects of dopamine receptor agonists on the specific in vivo binding of 3H-spiperone and 3H-NPA. The correlation analysis of DA agonist affinities for the four radioligands of DA receptors used in the present study give evidence for the existence of at least 3 types of DA receptors. Actions of dopaminergic ergot drugs have been evaluated at supersensitive dopamine receptors. The findings suggest that the shift to the left of the threshold dose to activate supersensitive dopamine receptors could be due to a lowering of the stereoselectivity of agonist interaction at the dopamine agonist sites of supersensitive dopamine receptors. Such a change may explain the highly preferential action of CF 25-397 at supersensitive dopamine receptors, since its affinity for 3H-NPA binding sites was not increased in the present experiments. In agreement with previous work, evidence have also been presented that prolonged treatment with a potent dopaminergic drug, pergolide, can produce a down regulation of n

Topics: Animals; Antiparkinson Agents; Apomorphine; Behavior, Animal; Brain; Bromocriptine; Caudate Nucleus; Corpus Striatum; Ergolines; Kinetics; Organ Specificity; Pergolide; Putamen; Rats; Receptors, Dopamine