Dopamine Agonist Activity Research Articles

Potent dopamine agonist activity of a novel ergoline, 6-Ethyl-9-oxaergoline (EOE)

6-Ethyl-9-oxaergoline (EOE) and its enantiomers were compared with apomorphine in a number of tests designed to measure dopamine (DA) agonist activity within the central nervous system. In rats, the tests were: interaction with DA receptors labeled with 3H-apomorphine or 3H-spiroperidol; the effects on DA synthesis as assessed by the ▪-butyrolactone procedure; turning in 6-OHDA lesioned animals; stereotypy; and, slowing of DA cell firing rates. In the mouse, locomotor activity, hypothermia and postural asymmetry in Caudectomized animals were studied. Emesis in the beagle was also examined. The (-)-enantiomer of EOE was more potent than either the (+)-enantiomer or the racemate in all tests. With the exception of inducing stereotypy and the displacement of 3H-apomorphine from rat striatal membranes, (-)-EOE was equi- or more potent than apomorphine in all test procedures. (-)-EOE was effective following oral administration and exhibited a longer duration of action than apomorphine. The results indicate EOE is a potent DA agonist.

Dopaminergic mechanisms in the nucleus tractus solitarius and effects on blood pressure

The actions of dopamine (DA) agonists and antagonists upon spontaneously active neurons in the nucleus tractus solitarius (NTS), dorsal motor nucleus of the vagus (nX), and nucleus nervi hypoglossi (nXII) were studied. DA was applied microiontophoretically to 42 neurons within the NTS and nX. Sixteen of these cells were stimulated by DA and 9 neurons were depressed. In neurons localized in the nXII nucleus, DA inhibited 19 cells out of 23. Noradrenaline (NA) excited 11 out of 30 cells in the NTS and nX. In the area of nXII nucleus, NA inhibited 6 out of 19 cells and did not modify 11 cells. Acetylcholine (ACh) stimulated the firing of 18 out of 22 neurons. The effects on NA and DA were directly compared on 21 neurons in the NTS. On 16 cells of this group the responses to DA were quantitatively or qualitatively different from those to NA. The DA receptor blockers sulpiride and fluphenazine antagonized the effects of DA but not those due to NA or ACh. Bilateral microinjections of DA (50 nmole) in the area of the NTS induced an increase in systemic blood pressure and heart rate. ACh induced similar effects. NA in the NTS decreased blood pressure and produced bradycardia. The effects of DA on heart rate and blood pressure were blocked by sulpiride or fluphenazine. The cardiovascular role played by DA in the NTS is discussed.

Mouse neuroblastoma clone N1E-115: A suitable model for studying the action of dopamine agonists on tyrosine hydroxylase activity

The DOPA-content in neuroblastoma clone N1E-115 is higher than the dopamine or noradrenaline content. Blockade of tyrosine hydroxylase by ifα-methyl-p-tyrosine (1 × 10 su−3 M) resulted in a decrease of cellular DOPA-content to 24.9% after 4 hr. The accumulation of DOPA in these cells which is probably due to limited activity of l-aromatic amino acid decarboxylase led us to use DOPA-content as a measure of tyrosine hydroxylase (TH) activity. Dopamine and especially apomorphine were effective at low concentrations (dopamine ic 501 × 10 −5 M, apomorphine 2 × 10 −7 M); lisuride had no effect on TH-activity. The low effective dose of apomorphine and the failure of lisuride to influence TH-activity are comparable to the observations in striatal synaptosomal preparations and make the N1E-115 clone a suitable model for studying the mechanism of TH-regulation. However, since haloperidol (1 × 10 −5 M) did not reverse the apomorphine-induced blockade of TH, a receptor-mediated blockade of TH seems to be improbable.

Dynamic tests of prolactin secretion in hyperprolactinemic states: carbidopa-L-dopa and indirectly acting dopamine agonists.

In normal subjects, similar degrees of PRL suppression have been reported after L-dopa alone and after a lower dose of L-dopa given in combination with carbidopa (CD), a peripheral inhibitor of L-dopa decarboxylase. In patients bearing PRL-secreting pituitary adenomas, CD-L-dopa induces a minimal suppression of plasma PRL, which is significantly less than after L-dopa alone. Similarly, indirectly acting dopamine (DA) agonists (IADAs), i.e. drugs which release DA and /or block DA reuptake without directly stimulating DA receptors, while capable of suppressing plasma PRL in normal subjects and subjects with puerperal hyperprolactinemia, fail to do so in patients with PRL-secreting adenomas. In the present study, to determine whether in puerperal subjects central nervous system (CNS) dopaminergic function is actually preserved and to elucidate the mechanism (s) underlying the defective CNS dopaminergic function of patients with prolactinomas, we have investigated: 1) whether, like IADA, CDL- dopa suppresses ...

Structure-anti-Parkinson activity relationships in the aminoadamantanes. Influence of bridgehead substitution.

A limited series of bridgehead alkyl-, dialkyl-, and trialkyl-substituted amantadines was synthesized and tested for potential anti-Parkinson activity as dopamine (DA) agonists. The compounds were evaluated using a battery of three murine bioassays, including stimulation of locomotor activity, induction of circling in animals with unilateral striatal lesions, and reversal of reserpine/alpha-methyltyrosine induced akinesia. Apparent mechanistic differences were seen between the methyl-substituted series and the ethyl-substituted series. While activities in both series increase with increasing liphophilicity, the methyl series (1b--d), as well as amantadine itself (1a), exhibit only indirect DA agonist activity, as evidenced by ipsilateral rotation in the circling model and no significant difference from control in reversal of akinesia. The ethyl series (1e,f) exhibits weak but reproducible direct DA agonist activity, as shown by contralateral rotation in the circling assay for 1e and reversal of akinesia by 1e and 1f. The 3-n-propyl derivative (1g) was devoid of any DA agonist activity.

The effect of 6-hydroxydopamine on the antinociceptive action of oxotremorine

Mice received intraventricular 6-hydroxydopamine (6-OHDA) to deplete brain noradrenaline (NA) and dopamine (DA). 6-OHDA reduced the reaction time of mice to nociceptive stimulus (hot plate) and attenuated the antinociceptive action of oxotremorine. The administration of 6-OHDA to desipramine treated mice prevented both the loss of cerebral NA and the antagonism of oxotremorine's antinociceptive action. The administration of 6-OHDA to pargyline-treated mice increased the depletion of cerebral DA, but the antagonism of oxotremorine's antinociceptive action persisted. Catecholamines were measured in mouse brain at intervals from 1 h to 3 days after administration of 6-OHDA. DA levels failed to correlate with either the reduction in the hot plate reaction time or the antagonism of oxotremorine analgesia, whereas these effects were usually accompanied by a loss of brain NA. Centrally acting DA agonists failed to restore oxotremorine's antinociceptive action in 6-OHDA-treated mice. Intraventricular administration of the acetylcholine synthesis inhibitor triethylcholine to mice did not effect the antinociceptive action of oxotremorine. It is concluded that the antinociceptive action of oxotremorine in mice is initiated by stimulation of muscarinic receptors and involves noradrenergic neurones.

A dopamine agonist stimulates progesterone secretion from adrenal gland

Administration of either progesterone (P) or a dopamine agonist, Legrotrile mesylate (LM), have been shown to induce the ovulatory release of LH in rats. In order to elucidate the mode of action of dopamine agonists we studied the effects of LM on P secretion by the adrenals. A subcutaneous injection of LM, in doses which induce ovulation, stimulated adrenal P secretion in ovariectomized, estrogen-primed rats and in castrate male rats. Peak plasma P concentrations were found at 2 h with a gradual return to pre-injection levels at 6 hrs following LM injection. These results raise the possibility that P increments following LM administration may be responsible for inducing ovulation in young and old rats. There is considerable evidence to show that modification of hypothalamic monoamine metabolism by pharmacologic agents results in markedly altered pituitary gonadotropin secretion [1]. Lergotrile mesylate (LM), a dopamine agonist, has been shown to advance the ovulatory release of LH on proestrus and induce ovulation and cyclicity in anovulatory aged rats [2,3]. Everett [4] observed that progesterone (P) administration induced ovulation in rats rendered anovulatory under constant light and also advanced ovulation by one day if administered to 5-day cycling rats. A similar effect of LM on ovulation advancement has been noted (Clemens, personal communication). These similarities in action of P and LM on ovulation in young and aged rats, led us to speculate that LM may stimulate P secretion which in turn may elicit the discharge of ovulatory hormones. To test this hypothesis we examined the effects of LM on progesterone secretion in gonadectomized rats.

Effects of electrolytic and 6-hydroxydopamine lesions of the lateral hypothalamus on rotation evoked by electrical stimulation of the substantia nigra in rats

Contralateral rotation evoked by electrical stimulation of the left substantia nigra was studied in rats before and after electrolytic or 6-hydroxydopamine (6-OHDA) lesions of the lateral hypothalamus. Electrolytic lesions (2 mA DC, 15 sec) which produced mean ipsilateral striatal dopamine depletion of 58% significantly reduced the rotation at 2 h to 14 days postlesion. 6-OHDA (8 μg in 4 μl) which produced mean ipsilateral striatal dopamine depletion of 93% significantly increased the rotation at 3 to 14 days postlesion. Haloperidol 0.1 and 0.5 mg/kg i.p. partially reduced rotation in both control and lesioned rats in a dose-related manner. Control and lesioned rats showed no sognificant differences in haloperidol sensitivity. If stimulus induced rotation were mediated by activation of dopaminergic neurons, one would have expected lesion effects in the present experiments to parallel those on rotation caused by pharmacologically evoked release of dopamine. The lesion effects we obtained on stimulus induced rotation, however, parallel those on rotation evoked by the predominantly directly acting dopamine agonist, apomorphine, rather than those on rotation evoked by the indirect (presynaptic) action of amphetamine. We suggest that contralateral rotation evoked by electrical stimulation of the substantia nigra may reflect direct activation of neurons postsynaptic to the dopaminergic nigrostriatal neurons.

Tests of Prolactin Secretion in the Diagnosis of Hyperprolactinemic States: Nomifensine and Domperidone

Forty-one subjects with hyperprolactinemia underwent testing on separate occasions with nomifensine, an indirectly acting dopamine agonist, and domperidone, a dopamine receptor-blocking agent. Nomifensine (200 mg orally) did not significantly modify plasma levels of prolactin (PRL) in 17 subjects in whom the existence of a pituitary tumor had been established at surgery (12 subjects) or was highly probable (5 subjects). Of the remaining 24 patients with hyperprolactinemia of uncertain etiology, 6 had PRL responsiveness to nomifensine (decrease of baseline PRL levels greater than or equal to 30%) and 18 had PRL unresponsiveness to the drug. The administration of domperidone (4-mg bolus injected intravenously) showed in 36 of the 41 patients the existence of a homogeneity between PRL responsiveness to nomifensine and PRL responsiveness to domperidone. In only five patients was failure of nomifensine to lower plasma PRL levels associated with an increase in plasma PRL levels after domperidone administration (at least doubling of baseline PRL levels). The combined application of nomifensine and domperidone tests holds promise of being a useful method for distinguishing among hyperprolactinemic subjects those with a prolactinoma.

Dopaminergic activity of some simplified ergoline derivatives

AbstractThe dopamine (DA) agonist activity of new simplified ergoline derivatives (RU 27849, RU 28251, and RU 28306) was studied in comparison with bromocriptine. In contrast to bromocriptine, the three compounds were weak displacers of 3H‐dihydroergocriptine or 3H‐spiroperidol binding from bovine anterior pituitary or rat striatal membrane sites and weak inhibitors of prolactin secretion in anterior pituitary cells in culture. Similarly to bromocriptine, they did not induce changes in either the basal or the DA‐induced stimulation of the adenylate cyclase activities. In vivo, the three derivatives, at a low dose, increased plasma prolactin levels, decreased striatal DA turnover, and increased striatal acetylcholine content, as did bromocriptine. Furthermore, in 6‐OHDA‐lesioned rats, these molecules, like bromocriptine, induced an intense contralateral circling behavior. From their effectiveness in these different tests, the potencies of these new ergoline derivatives can be ranked in the following order : N‐propyl > N‐methyl > N‐H.

Dopamine antagonist properties of atypical neuroleptics may be revealed following mesolimbic denervation.

A mesolimbic denervation, caused by bilateral intra-accumbens 6-hydroxydopamine, increased the potency of apomorphine in two behavioural tests of dopamine agonist activity, climbing behaviour and circling (combinations of the accumbens denervation with unilateral electrolesion of the striatum). Of a number of neuroleptics tested, haloperidol, fluphenazine, sultopride, tiapride, sulpiride and thioridazine, only the latter two showed greater effectiveness than normal to antagonize the apomorphine responses after mesolimbic denervation. Sulpiride and thioridazine cause remarkably little change in 'normal' tests for antipsychotic activity; their effectiveness in the clinic may reflect a more unique ability to act on dopamine receptor mechanisms of changed sensitivity.

ChemInform Abstract: CONVERSION OF ERGOLINES TO HEXAHYDRO‐ AND OCTAHYDROBENZO(F)QUINOLINES (DEPYRROLOERGOLINES)

AbstractErgonovin (Ia), Agroclavin (Ib) und Pergolidmesylat (Ic) werden zu den Ketoformamiden (II) gespalten, die über die Aminoketone (III) in die Ketone (IV) umgewandelt werden.

Apparent tolerance to some aspects of amphetamine stereotypy with long-term treatment

Previous reports have demonstrated that long-term amphetamine treatment results in a progressive augmentation of locomotion and focused stereotypy in the rat. A series of experiments were conducted to determine whether an increase in dopamine receptor sensitivity is the primary mechanism underlying the behavioral alterations associated with multiple amphetamine injections. Detailed observations of the focused stereotyped behaviors produced by amphetamine revealed that although some components were enhanced with long-term treatment, others were reduced. Thus, whereas repeated administration of 2.5 mg/kg d-amphetamine produced a progressive increase in repetitive head and limb movements, long-term treatment with 5.5 mg/kg d-amphetamine resulted in a reduction of licking and biting behaviors (oral stereotypies). These results, which suggest that different mechanisms mediate the various components of focused stereotypy, argue against the supersensitivity hypothesis. In fact, the apparent tolerance that develops to oral stereotypies may reflect a decrease in dopamine receptor sensitivity since repeated amphetamine administration also reduces the oral stereotypies produced by 0.5 or 2.0 mg/kg apomorphine, a direct acting dopamine agonist. Thus, the behavioral alterations produced by repeated amphetamine injections cannot be explained solely by an increase in receptor sensitivity.

ChemInform Abstract: BICYCLIC AND TRICYCLIC ERGOLINE PARTIAL STRUCTURES. RIGID 3‐(2‐AMINOETHYL)PYRROLES AND 3‐ AND 4‐(2‐AMINOETHYL)PYRAZOLES AS DOPAMINE AGONISTS

AbstractGemäß dem Formelschema werden die bi‐ und tricyclischen Partialergoline (IV), (XIII), (XIX) und (XXI) sowie verschiedene Pyrazole wie (XXII) und (XXIII) dargestellt.

Separation of potent central and renal dopamine agonist activity in substituted 6-chloro-2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepines

Separation of potent central and renal dopamine agonist activity in substituted 6-chloro-2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepines

Congeners of the .alpha. conformer of dopamine derived from octahydrobenz[h]isoquinoline

Two synthetic paths have been investigated for the preparation of cis and trans 8,9-dioxygenated octahydrobenz[h]isoquinoline ring systems. A sequence involving intramolecular Diels--Alder cyclization of a ring-opened intermediate product of a benzocyclobutene derivative was more satisfactory. The trans-fused isomers of the title compounds are frozen congeners of the alpha conformer of dopamine, isomeric with certain other tricyclic heterocycles which elicit a high degree of dopamine agonist activity. However, the present series of compounds exhibited a very low potency in an assay for dopamine-like actions. A possible reason for this inactivity has been suggested.

Bicyclic and tricyclic ergoline partial structures. Rigid 3-(2-aminoethyl)pyrroles and 3- and 4-(2-aminoethyl)pyrazoles as dopamine agonists.

It is proposed, based upon comparisons with apomorphine, that the rigid pyrroleethylamine moiety of the ergolines is the portion of the molecule responsible for dopamine agonist activity. In support of this hypothesis, bicyclic and tricyclic ergoline partial structures 6, 11, 25, and 35 have been synthesized. In addition, some pyrazole isosters (37, 38, 40, and 45) of these rigid pyrroleethylamines have been made. All of the classes show dopaminergic activity in prolactin inhibition and in lesioned rat turning assays. The most potent drugs, the linear tricyclic pyrazoles 38 (R = Pr) and 40 (R = Pr), are comparable in potency with the highly active ergoline pergolide (41).

The role of dopaminergic mechanisms in naloxone-induced inhibition of apomorphine-induced stereotyped behavior

Although a number of reports has recently suggested naloxone (NX) might affect dopamine (DA) agonist-elicited behavior, the effect of NX on apomorphine-induced sterotyped behavior (AISB) has not yet been systematically investigated. Doses of NX varying from 0.20 to 20.0 mg/kg were administered prior to the injection of apomorphine (0.5 mg/kg), a directly acting DA agonist, and the effect of NX on AISB was subsequently assessed. A sequential doubling of the dose of NX administered from 0.20 to 3.20 mg/kg generated a partial antagonist curve for AISB which fell in a linear manner from 0.20 to 0.40 mg/kg NX and thereafter became essentially asymptotic with 20 mg/kg producing the same effect on AISB as 0.4 mg/kg. Pretreatment with 0.4 mg/kg NX produced a sigmoidal inhibition of the stereotypy induced by successive doses of apomorphine (0.10–0.25 mg/kg). In a subsequent study, a low dose of NX (0.05 mg/kg) was combined with the specific DA receptor antagonist haloperidol (0.01 or 0.05 mg/kg) to determine if extremely low doses of the two antagonists could act synergistically. This was subsequently confirmed. Moreover, while a low dose of haloperidol (0.20 mg/kg) completely abolished AISB, 100 × this dose of NX (20.0 mg/kg) was only partially effective in this respect, indicating that NX, unlike haloperidol, exerts a partial antagonist effect relative to AISB. Furthermore, the marked synergistic effect of the very low doses of NX and haloperidol on blocking AISB was greater than their additive postsynaptic effects, suggesting that the effect of NX on AISB may in part be presynaptic.

Differential behavioral responses of spontaneously hypertensive (SHR) and normotensive (WKY) rats to d-amphetamine

A comparison was made in the behavioral responses of spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) normotensive rats to d-amphetamine. Animals were tested at a young age (6 weeks) to minimize the effects of elevated blood pressure on drug responsiveness. SHR rats were more active than WKY rats after injections of 1.0, 2.0, and 4.0 mg/kg d-amphetamine. A significant strain difference in stereotypy was also noted; rearing occurred in SHR rats while lateral or vertical head movements (head waving) occurred in WKY rats. The lack of significant strain differences in the behavioral responses of rats to apomorphine, a direct acting dopamine agonist, suggested that the differential behavioral responses to d-amphetamine were not a result of differences between strains in receptor sensitivity. Pretreatment of rats with reserpine eliminated the strain differences in behavioral responses to d-amphetamine. Pretreatment of rats with alpha-methyl-p-tyrosine prior to administration of d-amphetamine eliminated the strain differences in stereotyped behavior; however, WKY rats remained less active than SHR rats. Pretreatment of SHR rats with parachlorophenylalanine had no effect on the behavioral responses to d-amphetamine. In contrast, pretreatment of WKY rats with parachlorophenylalanine resulted in an increase in rearing and a decrease in head waving following an injection of d-amphetamine. These findings suggest that the differences in responses to d-amphetamine of SHR and WKY rats are due in part to variations in the activities of central catecholaminergic and serotonergic neurons.

Dopamine neurons: Effect of lergotrile on unit activity and transmitter synthesis

Intravenous administration of increasing doses of the ergoline, lergotrile mesylate, caused a rapid, dose-dependent and haloperidol-reversible inhibition of unit activity of dopamine cells in the pars compacta of the rat substantia nigra. 6 μg/kg caused significant depression of dopamine cell firing rates; 50% inhibition was achieved with a cumulative dose of 100 μg/kg. 60% of the cells were completely inhibited by increasing doses of the drug, the remainder became resistant to further inhibition after reaching rates 25–50% of baseline. Pretreatment with reserpine and α-methylparatyrosine did not significantly attenuate the lergotrile-induced inhibition. Lergotrile had no consistent effect on firing rates of cells in the pars reticulata of the substantia nigra. The ergoline reduced the apparent activation of striatal dopamine synthesis associated with complete cessation of impulse flow in nigral-striatal dopamine neurons induced by γ-butyrolactone treatment. These effects are compared with those of apomorphine and amphetamine. The results are consistent with the idea that lergotrile is a direct acting dopamine agonist.