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We linked 2-aminothiazoloazepane scaffolds with phenylpiperazine pharmacophores to generate bitopic dopamine receptor ligands. Highest D2R/D3R binding affinities up to pKi values of 7.74 were observed for compounds containing a 1-(2,3-dichlorophenyl)piperazinoyl moiety, maintaining affinity with deaminated 5,6,7,8-tetrahydro-4H-thiazoloazepine derivatives.

Although 6-hydroxydopamine-induced (6-OHDA-induced) rats are a well-known Parkinson's disease model, the effects of dopamine D2 agonists in mice with 6-OHDA-induced lesions are not completely understood. We produced mice with 6-OHDA-induced lesions and measured their total locomotion counts following administration of several dopamine D2 agonists (pramipexole, ropinirole, cabergoline, rotigotine, apomorphine, talipexole, and quinelorane). Cabergoline showed the longest duration of drug action, which was in agreement with its long-lived anti-Parkinson effects in rats and humans. In contrast, pramipexole and ropinirole had notably short durations of drug action. We demonstrated that mice with 6-OHDA-induced lesions accompanied with significant lesions in the striatum may be reasonable models to predict the action duration of anti-Parkinson drug candidates in humans.

We measured the functional agonist potencies of dopamine agonists including antiparkinson drugs, and functional antagonist potencies of antipsychotics at human dopamine D2 and D3 receptors. In vitro pharmacological assessment included inhibition of forskolin-stimulated cAMP accumulation and the reversal of dopamine-induced inhibition in clonal Chinese hamster ovary cells expressing low and high densities of human dopamine D2L and D2S receptors (hD2L-Low, hD2L-High, hD2S-Low and hD2S-High, respectively) and human dopamine D3 Ser-9 and D3 Gly-9 receptors (hD3-Ser-9 and hD3-Gly-9, respectively). Cabergoline, bromocriptine, pergolide, (±)-7-hydroxy-N,N-di-n-propyl-2-aminotetralin (7-OH-DPAT), talipexole, pramipexole, R-(+)-trans-3,4,4a,10b-tetrahydro-4-propyl-2H,5H-[1]benzopyrano[4,3-b]-1,4-oxazin-9-olhydrochloride (PD128907) and ropinirole behaved as dopamine D2 and D3 receptor full agonists and showed higher potencies in hD2L-High and hD2S-High compared to hD2L-Low and hD2S-Low. In hD3-Ser-9 and hD3-Gly-9 compared to hD2L-Low and hD2S-Low, dopamine, ropinirole, PD128907, and pramipexole potencies were clearly higher; talipexole and 7-OH-DPAT showed slightly higher potencies; pergolide showed slightly lower potency; and, cabergoline and bromocriptine potencies were lower. Aripiprazole acted as an antagonist in hD2L-Low; a low intrinsic activity partial agonist in hD2S-Low; a moderate partial agonist in hD3-Ser-9 and hD3-Gly-9; a robust partial agonist in hD2L-High; and a full agonist in hD2S-High. Amisulpride, sulpiride and perphenazine behaved as preferential antagonists; and chlorpromazine and asenapine behaved as modest preferential antagonists; whereas fluphenazine, haloperidol, and blonanserin behaved as non-preferential antagonists in hD2S-Low and hD2S-High compared to hD3-Ser-9 and hD3-Gly-9. These findings may help to elucidate the basis of therapeutic benefit observed with these drugs, with varying mechanisms of action, in the treatment of Parkinson's disease, depression and schizophrenia.

Non-ergot-type dopamine receptor agonists such as ropinirole are used for the treatment of Parkinson disease, but they occasionally show serious side effects including sleep attacks and daytime sleepiness. These symptoms are reminiscent of narcolepsy, a major sleep disorder. Because narcolepsy is thought to result from deficiency of a hypothalamic neuropeptide orexin, we examined whether ropinirole affected the integrity of orexin-containing neurons, using organotypic slice culture of rat hypothalamus. Application of ropinirole induced a significant decrease in the number of orexin-immunoreactive neurons. The same treatment showed no significant effect on the number of melanin-concentrating hormone-immunoreactive neurons. The decrease of orexin-immunoreactive neurons was reversible after washout of ropinirole and was not accompanied by induction of cell death. Antagonism of dopamine D(2) receptors and of serotonin 5-HT(1A) receptors attenuated the effect of ropinirole, suggesting involvement of these receptors in depletion of orexin. On the other hand, a moderate concentration of N-methyl-d-aspartate that excited orexin neurons counteracted the effect of ropinirole on the number of orexin-immunoreactive neurons. These results suggest that ropinirole can cause deficiency of orexin by inhibiting excitatory activities of orexin neurons, which may be relevant to the adverse actions of this drug on sleep and wakefulness.

B-HT 920 at low doses inhibited the accumulation of DOPA following treatment with reserpine and a DOPA decarboxylase inhibitor in the dopamine-, but not in the noradrenaline-predominant regions of the rat brain. B-HT 933 selectively inhibited this DOPA accumulation in the noradrenaline-predominant regions. These effects of B-HT 920 and B-HT 933 were completely antagonized by haloperidol and yohimbine, respectively. The rat motor activity was reduced by B-HT 920 and it was restored following apomorphine. B-HT 933 decreased the motor activity by a yohimbine-sensitive mechanism. The results indicate that B-HT 920 can selectively and potently stimulate the dopamine autoreceptors whereas B-HT 933 can selectively stimulate the noradrenaline autoreceptors.

Parkinson's disease (PD) is characterized by loss of nigral dopaminergic (DAergic) neurons and presence of Lewy bodies, whose major component is alpha-synuclein. We had previously generated transgenic mice termed Syn130m that express truncated human alpha-synuclein (amino acid residues 1-130) in DAergic neurons. Syn130m mice showed significant loss of DAergic neurons in the substantia nigra pars compacta. Subsequently, the striatal DA level and spontaneous locomotor activity of the mice were decreased significantly. In the present study, we investigated behavioral responses of Syn130m mice to L-DOPA and DA receptor agonists. Administration of L-DOPA dose dependently ameliorated the reduction of spontaneous locomotor activity of Syn130m mice. Similarly, D(2) agonists, quinpirole and talipexole, and a D1/D2 agonist, pergolide, were effective against the reduction. Syn130m mice also showed significant reduction in exploratory behavior compared with non-Tg littermates when they were placed in a novel environment, but this abnormality was ameliorated by treatment with pergolide. These results strongly suggest that the behavioral abnormalities of Syn130m mice were caused by low striatal DA content. On the other hand, the expression of postsynaptic D(2)-like receptors (DRD2) in the striatum was not increased in Syn130m mice, although the low striatal DA level is known to induce compensatory expression of DRD2. Because the abnormalities could be rectified by treatment with DA receptor agonists, it is likely that Syn130m mice provide a useful tool to explore therapeutic possibilities for PD as a new animal model of the disease.

We have investigated the ability of pramipexole, a dopamine agonist used in the symptomatic treatment of Parkinson's disease (PD), to protect against cell death induced by 1-methyl-4-phenylpyridinium (MPP+) and rotenone in dopaminergic and non-dopaminergic cells. Pre-incubation with either the active (-)- or inactive (+)-enantiomer forms of pramipexole (10 muM) decreased cell death in response to MPP+ and rotenone in dopaminergic SHSY-5Y cells and in non-dopaminergic JK cells. The protective effect was not prevented by dopamine receptor blockade using sulpiride or clozapine. Protection occurred at concentrations at which pramipexole did not demonstrate antioxidant activity, as shown by the failure to maintain aconitase activity. However, pramipexole reduced caspase-3 activation, decreased the release of cytochrome c and prevented the fall in the mitochondrial membrane potential induced by MPP+ and rotenone. This suggests that pramipexole has anti-apoptotic actions. The results extend the evidence for the neuroprotective effects of pramipexole and indicate that this is not dependent on dopamine receptor occupation or antioxidant activity. Further evaluation is required to determine whether the neuroprotective action of pramipexole is translated to a disease-modifying effect in PD patients.

We investigated by means of behavioral and neurochemical studies the effects of either D 1 or D 2 agonist on excessive dopamine release and hyperactivity induced by the microinjection of Bay K 8644, and an L-type Ca 2+ channel stimulant, into the rat caudate putamen under a novel environmental condition. Hyperactivity (locomotor activity and rearing counts) and significant increases in extracellular dopamine levels induced by Bay K 8644 were concomitantly observed. D 1 agonist, SKF81297, administered into the caudate putamen did not block Bay K 8644-induced hyperactivity measured by monitoring both animal activity and increases in extracellular dopamine levels detected by microdialysis. Pretreatment with the D 2 agonists, bromocriptine, talipexole and pramipexole, into the caudate putamen significantly blocked Bay K 8644-induced hyperactivity for 45 min after Bay K 8644 administration, although the single administration of these agonists significantly potentiated locomotor activity and rearing behavior. Furthermore, these agonists significantly suppressed Bay K 8644-induced extracellular dopamine levels. Our results indicate that these D 2 agonists (1) act on postsynaptic neuronal D 2 receptors under conditions of normal or low dopamine release in the caudate putamen, and (2) act on presynaptic D 2 receptors (autoreceptors) when excessive levels of dopamine are released or hyperdopamine neuronal activity is induced. Consequently, the effect of D 2 agonists in the clinical treatment of Parkinson’s disease may be due to stimulation of postsynaptic D 2 receptors rather than presynaptic autoreceptors.

Because little comparative information is available concerning receptor profiles of antiparkinson drugs, affinities of 14 agents were determined at diverse receptors implicated in the etiology and/or treatment of Parkinson's disease: human (h)D(1), hD(2S), hD(2L), hD(3), hD(4), and hD(5) receptors; human 5-hydroxytryptamine (5-HT)(1A), h5-HT(1B), h5-HT(1D), h5-HT(2A), h5-HT(2B), and h5-HT(2C) receptors; halpha(1A)-, halpha(1B)-, halpha(1D)-, halpha(2A)-, halpha(2B)-, halpha(2C)-, rat alpha(2D)-, hbeta(1)-, and hbeta(2)-adrenoceptors (ARs); and native histamine(1) receptors. A correlation matrix (294 pK(i) values) demonstrated substantial "covariance". Correspondingly, principal components analysis revealed that axis 1, which accounted for 76% variance, was associated with the majority of receptor types: drugs displaying overall high versus modest affinities migrated at opposite extremities. Axis 2 (7% of variance) differentiated drugs with high affinity for hD(4) and H(1) receptors versus halpha(1)-AR subtypes. Five percent of variance was attributable to axis 3, which distinguished drugs with marked affinity for hbeta(1)- and hbeta(2)-ARs versus hD(5) and 5-HT(2A) receptors. Hierarchical (cluster) analysis of global homology generated a dendrogram differentiating two major groups possessing low versus high affinity, respectively, for multiple serotonergic and hD(5) receptors. Within the first group, quinpirole, quinerolane, ropinirole, and pramipexole interacted principally with hD(2), hD(3), and hD(4) receptors, whereas piribedil and talipexole recognized dopaminergic receptors and halpha(2)-ARs. Within the second group, lisuride and terguride manifested high affinities for all sites, with roxindole/bromocriptine, cabergoline/pergolide, and 6,7-dihydroxy-N,N-dimethyl-2-ammotetralin (TL99)/apomorphine comprising three additional subclusters of closely related ligands. In conclusion, an innovative multivariate analysis revealed marked heterogeneity in binding profiles of antiparkinson agents. Actions at sites other than hD(2) receptors likely participate in their (contrasting) functional profiles.

Activation of the recombinant human α2C-adrenoceptor (α2C AR) by (−)-adrenaline in CHO-K1 cells transiently co-expressing a chimeric Gαq/i1 protein induced a rapid, transient Ca2+ response with a high-magnitude followed by a low-magnitude phase which continued throughout the recorded time period (15 min). Activation of the α2C AR by various α2 AR agonists revealed the following rank order of high-magnitude Ca2+ response [Emax (%) versus 10 μM (−)-adrenaline]: UK 14304 (102±4)=talipexole (101±3)=(−)-adrenaline (100)=d-medetomidine (98±1)>oxymetazoline (81±4)⋍clonidine (75±5). The methoxy- (RX 821002) and ethoxy-derivatives (RX 811059) of idazoxan and the dexefaroxan analogue atipamezole were fully effective as antagonists of both the high- and the low-magnitude Ca2+ response. However, though acting as full antagonists of the high-magnitude response, the further putative α2 AR antagonists idazoxan (27%), SKF 86466 (29%) and dexefaroxan (59%) reversed the low-magnitude response only partially. In conclusion, kinetic analyses of agonist : antagonist interactions at the α2C AR demonstrate a wide spectrum of partial to complete antagonism of the low-magnitude Ca2+ response for structurally related α2 AR ligands. British Journal of Pharmacology (2000) 131, 1385–1390; doi:10.1038/sj.bjp.0703726

Ligand : receptor interactions were analysed at wt, mutant Ser(200)Ala and Ser(204)Ala alpha(2A) ARs by measuring Ca(2+) responses in CHO-K1 cells either by co-expression with a G(alpha15) protein or at a receptor : G(alpha15) protein stoichiometry of 1.0 using fusion proteins. The magnitude of the UK 14304-mediated Ca(2+) response as elicited by a G(alpha15) protein was largest with both mutant Ser(200)Ala and Ser(204)Ala alpha(2A)ARs compared to the wt alpha(2A) AR in the co-expression and fusion protein experiments. The activation profiles of the wt and both mutant alpha(2A) ARs as analysed by a series of alpha(2) AR agonists differed. d-Medetomidine and clonidine appeared most efficacious at the Ser(204)Ala alpha(2A) AR, whereas oxymetazoline was also partially active at the Ser(200)Ala alpha(2A) AR. Talipexole was silent at both mutant alpha(2A) ARs. The intrinsic activity of (-)-adrenaline was either absent or partial at the Ser(204)Ala and Ser(200)Ala alpha(2A) AR, respectively. This latter observation is related to its lower binding affinity for both mutant alpha(2A) ARs. Ligands characterized as antagonists at wt and Ser(200)Ala alpha(2A) ARs demonstrated either no intrinsic activity (i.e., RX 811059) or positive efficacy with a different rank order of maximal response at the Ser(204)Ala alpha(2A) AR (atipamezole=SKF 86466=idazoxan>dexefaroxan) than Asp(79)Asn alpha(2A) AR (atipamezole>idazoxan approximately SKF 86466>dexefaroxan) and Thr(373)Lys alpha(2A) AR (SKF 86466>atipamezole approximately idazoxan>dexefaroxan). These effects were only observed in the co-expression experiments at concentrations in line with their binding affinities. In conclusion, these Ca(2+) data suggest that multiple activation binding sites exist for these ligands at the alpha(2A) AR, and that their activation may be affected in different ways by the mutations being investigated.

The atypical antipsychotic olanzapine (2.5-20 mg/kg) produced hypothermia in rats. The decrease in rectal temperature caused by olanzapine (2.5-20 mg/kg) was blocked by the selective dopamine D 2 receptor antagonist pimozide (0.5 and I mg/kg) but not by the dopamine D 1 receptor antagonist SCH 23390 (0.5 and I mg/kg). The dopamine D 1 /D 2 receptor agonist apomorphine (3 mg/kg) and the selective dopamine D 2 receptor agonist talipexole (0.5 mg/kg) produced hypothermia in rats. Olanzapine (10 and 20 mg/kg) significantly blocked hypothermia produced by both apomorphine and talipexole while the lower doses (2.5 and 5 mg/kg) of olanzapine failed to block it. The present results demonstrate that olanzapine behaves as a partial agonist at brain DA D 2 receptor populations involved in thermoregulation in the rat.

1. The aim of the present study was to characterize functional responses to ropinirole, its major metabolites in man (SKF-104557 (4-[2-(propylamino)ethyl]-2-(3H) indolone), SKF-97930 (4-carboxy-2-(3H) indolone)) and other dopamine receptor agonists at human dopamine D2(long) (hD2), D3 (hD3) and D4.4 (hD4) receptors separately expressed in Chinese hamster ovary cells using microphysiometry. 2. All the receptor agonists tested (ropinirole, SKF-104557, SKF-97930, bromocriptine, lisuride, pergolide, pramipexole, talipexole, dopamine) increased extracellular acidification rate in Chinese hamster ovary clones expressing the human D2, D3 or D4 receptor. The pEC50s of ropinirole at hD2, hD3 and hD4 receptors were 7.4, 8.4 and 6.8, respectively. Ropinirole is therefore at least 10 fold selective for the human dopamine D3 receptor over the other D2 receptor family members. 3. At the hD2 and hD3 dopamine receptors all the compounds tested were full agonists as compared to quinpirole. Talipexole and the ropinirole metabolite, SKF-104557, were partial agonists at the hD4 receptor. 4. Bromocriptine and lisuride had a slow onset of agonist action which precluded determination of EC50s. 5. The rank order of agonist potencies was dissimilar to the rank order of radioligand binding affinities at each of the dopamine receptor subtypes. Functional selectivities of the dopamine receptor agonists, as measured in the microphysiometer, were less than radioligand binding selectivities. 6. The results show that ropinirole is a full agonist at human D2, D3 and D4 dopamine receptors. SKF-104557 the major human metabolite of ropinirole, had similar radioligand binding affinities to, but lower functional potencies than, the parent compound.

1. Effects of anti-Parkinsonian drugs on neurobehavioural changes induced by bilateral lesions of dopaminergic neurons were investigated in rats. 2. Dopaminergic neurons in rats were lesioned bilaterally by injection of 6-hydroxydopamine (6-OHDA; 8 μg) into the medial forebrain bundle at the level of the posterolateral hypothalamus. As a result, a decrease in locomotor activity and marked catalepsy and prolongation of grasping time were observed. 3. Levodopa, talipexole, bromocriptine and theophylline dose-dependently antagonized the decrease in locomotor activity induced by bilateral 6-OHDA lesions. These drugs also showed antagonistic effects on the appearance of catalepsy and prolongation of grasping time induced by bilateral 6-OHDA lesions. In contrast, trihexyphenidyl showed no antagonizing effect on the neurobehavioural changes induced by 6-OHDA lesions at any concentration tested. 4. Combined treatment with levodopa and talipexole antagonized the neurobehavioural changes induced by bilateral 6-OHDA lesions, whereas no marked changes were observed when either drug was administered separately. The same findings were noted with the simultaneous use of either levodopa (2 mg/kg) and theophylline (2 mg/kg) or talipexole (0.005 mg/kg) and theophylline (2 mg/kg). 5. These results indicate that this model may be useful for estimating the effects of drugs in the treatment of Parkinson's disease.

The activities of a range of agonists at D2(long) dopamine receptors expressed in CHO cells have been determined in ligand binding and in a functional assay, the stimulation of [35S]-GTPγS binding. For several agonists (apomorphine, dopamine, pergolide, quinpirole, NPA, ropinirole, talipexole) binding in the absence of added guanine nucleotides was best described in terms of interaction at higher and lower affinity states, whereas for other agonists (bromocriptine, DHEC, lisuride, 3-PPP) a one binding site model was a good description of the data. In the presence of GTP (100 μM) all agonist binding data were best described by a one site model. All of the agonists tested increased [35S]-GTPγS binding above the basal level and the maximal effects and potencies of the agonists in this test were different. There was no clear relation betwen the ability of an agonist to stabilize the formation of the ternary complex of agonist/receptor/G-protein and the maximal activity of the agonist or the amplification factor (ratio of dissociation constant for binding to receptor to EC50 in functional assay). A comparison was made between the profiles of the D2(short) and D2(long) receptor isoforms in these assays.

The effect of protection of dopaminergic neurons by talipexole, a dopamine (DA) agonist, is investigated on a methamphetamine (MA)-induced parkinsonism model of mice (C57BL/6N). The reduction of tyrosine hydroxylase activity in the striatum 72 h after MA (5 mg/kg every 2 h, four times) treatment was attenuated by the administration of talipexole (0.25 mg/kg or 1.0 mg/kg) prior to the administration of MA. In an in vitro experiment, talipexole inhibited the adduction reaction of hydroxyl radicals to salicylate. Taken together, these data suggest that the protective effect of talipexole on DA neurons is, in part, caused by the hydroxyl radical-scavenging action of the drug.

The anxiolytic-like properties of dopamine agonists and antagonists with different receptor profiles were investigated in the ultrasonic vocalization test in rats after subcutaneous administration. Only dopamine D2 receptor agonists inhibited ultrasonic vocalization with the following ED50 values: apomorphine (0.07 mg kg ), quinelorane (0.01 mg kg ), quinpirole (0.04 mg kg ), pramipexole (0.09 mg kg ), roxindole (0.04 mg kg ), talipexole (0.04 mg kg ), (±)-7-OH-DPAT (0.05 mg kg ), (±)-PPHT (0.03 mg kg ), (−)-TNPA (0.06 mg kg ), PD128907 (0.13 mg kg ). The D2 antagonists haloperidol, mazapertine, raclopride, remoxipride, L745870, U99194A, U101958 and S(−)-DS121, the partial agonists PD143188 and preclamol, the selective D1 agonist R(+)-SKF38393 and the D1 antagonist SCH23390, and the uptake inhibitors GBR12909, GBR12935 and indatraline lacked significant inhibitory effects on ultrasonic vocalization. Because at least some of the D2 receptor agonists investigated have selectivity for dopamine autoreceptors, it is speculated that the dopamine autoreceptor may be a target for the development of new antianxiety drugs.

The stimulating effect of antiparkinsonian drugs, talipexole and bromocriptine, on the striatal postsynaptic dopamine receptors were studied by measuring contralateral rotational behavior in rats. The nigro-striatal dopamine system of rats was degenerated by unilateral injection of 6-hydroxydopamine (6-OHDA, 8 micrograms/rat) into substantia nigra. By subcutaneous administration, talipexole at 0.16 mg/kg and bromocriptine at 10.24 mg/kg induced significantly increased rotational behavior to the contralateral direction to the lesioned side. The onset of the effect was 30 min for talipexole and 90 min for bromocriptine. By intragastric administration, talipexole at 0.4 mg/kg and bromocriptine at 20.48 mg/kg significantly increased the rotational behavior, and the onset of the effect was 60 min for talipexole and 180 min for bromocriptine. Rotational behavior induced by talipexole was suppressed by a D2 antagonist, sulpiride (40 mg/kg, s.c.), but not by a D1 antagonist, SCH23390 (1 mg/kg, s.c.). In contrast, rotational behavior induced by bromocriptine was suppressed by both sulpiride and SCH23390. These results indicated that when the nigrostriatal dopaminergic functions are disrupted, talipexole stimulates the striatal postsynaptic dopamine receptors at much lower doses than bromocriptine. Also it was indicated that the stimulating effect of talipexole is solely mediated by dopamine D2 receptors, whereas the effect of bromocriptine is mediated by both D1 and D2 receptors.

Drug interaction of fleroxacin, new qunolone antibiotics, and talipexole, an antiparkinsonian drug, was studied in rats. When talipexole was administered orally before the oral administrations of fleroxacin, the plasma concentrations of fleroxacin and its metabolite, fleroxacin Noxide, decreased. The maximum plasma concentrations (Cmax) of fleroxacin and fleroxacin Noxide decreased and the time needed to reach Cmax.(Tmax) was also delayed significantly (p< 0.05) as compared to the control. This finding suggests that the pretreatment with talipexole thus decreases the rate of absorption of fleroxacin from the gastro-intestinal tract in rats. On the other hand, when fleroxacin and talipexole were administered simultaneously, the plasma concentrations of fleroxacin and fleroxacin N-oxide increased. Regarding the absorption rate constant, the Cmax and area under the plasma concentration-time curve from 0 to 24 hours (AUCo-24) of fleroxacin increased whereas Tm decreased significantly (p

The effects of two predominant dopamine D2-like receptor agonists, talipexole (6-allyl-2-amino-5,6,7,8-tetrahydro-4H-thiazolo [4,5-d]-azepine dihydrochloride, B-HT 920 CL2) and pramipexole (S(-)2-amino-4,5,6,7-tetrahydro-6-propyl-aminobenzothiazole dihydrochloride, SND 919 CL2Y), were studied alone and in combination with the selective dopamine D1-like receptor agonist chloro-APB ((+/-)6-chloro-7-8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-benz azepine hydrobromide, SKF 82958) in five chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) lesioned hemiparkinsonian Macaca nemestrina monkeys. Talipexole induced contraversive rotation in a dose-dependent manner up to 32 microg/kg, i.m. Talipexole was more potent than pramipexole (10 vs. 32 microg/kg, i.m.), but pramipexole was more efficacious in producing contraversive rotational behavior and significant hand movements in the afflicted limb. Larger doses of chloro-APB also produced contraversive rotation. Combinations of each dopamine D2-like receptor agonist in a median effective dose with chloro-APB (23.4 and 74.8 microg/kg, i.m.) had synergistic effects, producing either addition or potentiation, depending upon the dose used. The effects noted with these combinations were less than the effect of a large dose (100 microg/kg) of pramipexole. Talipexole, in the largest dose studied (100 microg/kg, i.m.), produced sedation which was not seen with the same dose of pramipexole. No significant extrapyramidal side effects were noted with either agent.

▲ Talipexole is a dopamine D2 receptor agonist, with activity at both pre- and postsynaptic D2 receptors. The drug also has α2-adrenoceptor agonist activity. ▲ In a primate model of Parkinson’s disease, talipexole dose-dependently improved motor activity and parkinsonian symptoms, and beneficial effects were additive when combined with levodopa. ▲ Clinical trials with talipexole in patients with Parkinson’s disease demonstrated statistically significant improvements from baseline for parkinsonian symptoms including akinesia, rigidity, tremor and gait disturbances. ▲ In a large comparative trial in patients with Parkinson’s disease, talipexole was associated with a higher response rate and a lower incidence of gastrointestinal adverse events than bromocriptine, although drowsiness was more common among talipexole recipients. ▲ The most frequently reported adverse events associated with talipexole are drowsiness, dizziness, hallucinations and minor gastrointestinal complaints such as nausea, gastrointestinal discomfort and loss of appetite.

Aripiprazole (OPC-14597) is a novel antipsychotic agent with an unusual pharmacological profile that is atypical of compounds affecting the dopaminergic system. This agent is a quinolinone derivative related to OPC-4392 (Fig. 1). OPC-4392 acts on dopamine (DA) neurons and their nerve terminals as an autoreceptor agonist, eliciting inhibitory effects on ventral tegmental and nigral DA neurons (14,20). OPC-4392 has no postsynaptic DA receptor blocking activities (20). In clinical trials OPC-4392 improved the negative and the positive symptoms of chronic schizophrenic patients, such as hallucination, delusion, and psychiatric excitement. Similar effects on negative symptoms were observed with other DA autoreceptor agonists, such as EMD 49980, talipexole and terguride (8,20,17). Further attempts to develop a useful antipsychotic drug that displays both presynaptic DA agonistic and postsynaptic DA antagonistic activities and improves negative as well as positive symptoms in schizophrenic patients resulted in the discovery of aripiprazole. An early phase 11 clinical study on aripiprazole was recently performed in 56 schizophrenic patients by M. Toru et al. in Japan (24). According to the assessment by BPRS in this study, significant global improvement of negative symptoms (emotional withdrawal, motor retardation, blunted affect) and positive signs (suspiciousness, unusual thoughts, hallucinatory behaviors) was achieved. Negligible side effects, including mild extrapyramidal symptoms, were encountered. Aripiprazole may be considered a useful antipsychotic agent with a unique pharmacological profile.

The anti-tremor activity of talipexole (6-allyl-2-amino-5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]azepine dihydrochloride, B-HT 920 CL2, Domin), a non-ergot dopamine D2 receptor agonist which possesses alpha 2-adrenoceptor agonistic and 5-HT3 receptor antagonistic properties, was examined in monkeys with a unilateral lesion in the ventromedial tegmentum. Talipexole dose dependently suppressed the tremor and had ED50 values of 34 micrograms/kg s.c. and 84 micrograms/kg p.o. The anti-tremor effect of talipexole occurred at much lower doses than that of an ergot dopamine receptor agonist, bromocriptine (2-bromo-alpha-ergocryptine mesilate, ED50; 2.5 mg/kg s.c.), and talipexole acted synergistically in combination with L-DOPA (3,4-dihydroxyphenylalanine). In ventromedial tegmentum-lesioned monkeys, anti-tremor doses of talipexole did not cause emetic behavior, but had sedative effects. Conversely, monkeys given bromocriptine exhibited oral movement, salivation and vomiting when anti-tremor effects were observed, but not marked sedative behavior at any of the doses investigated. During repeated administration of talipexole (a daily dose of 50 micrograms/kg s.c. for 21 days), the extent and duration of the anti-tremor effect did not change, but those of the sedative effect decreased gradually. The anti-tremor effect of talipexole was significantly suppressed by sulpiride, but not by SCH 23390 (7-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepine-7-ol) or yohimbine, while the sedative effect was inhibited by sulpiride and yohimbine. The main metabolites of talipexole had no anti-tremor or sedative effects. These results indicate that talipexole exerts its anti-tremor activity via selective dopamine D2 receptor stimulation.

1. 1. Talipexole showed moderate displacement activity of 3 H-GR 65630 binding to 5-HT 3 receptors in both rat cortical and intestinal membrane fractions with Ki values of 0.35 μM and 0.22 μM, respectively. 2. 2. Bromocriptine failed to displace the binding activity in either experimental system even at a concentration of 10 μM. 3. 3. Both talipexole and tropisetron were found to significantly inhibit 5-HT 3 receptor-mediated effects of 5-HT in isolated guinea-pig ileum or atrium; however, the effect of talipexole was weaker than that of tropisetron. 4. 4. Bromocriptine, in contrast, had no antagonistic effects on 5-HT 3 receptor-mediated activity in guinea-pig ileum or atrium. 5. 5. It was concluded that talipexole might act as an antagonist on 5-HT 3 receptors in both brain and intestinal tissues.

Possible involvement of catecholamine receptor activities in modulating the incidence of yawning, which involves activation of dopaminergic-cholinergic linked neuronal mechanism, was investigated in rats. Subcutaneous injection of talipexole (B-HT 920), a selective dopamine D2-receptor-agonist, elicited yawning behavior. This behavior was increased by prazosin and bunazosin, alpha 1-adrenoceptor antagonists, and by pindolol, a beta-adrenoceptor antagonist. The yawning induced by physostigmine, an anticholinesterase agent, and pilocarpine, a direct muscarinic receptor agonist, was increased by pindolol, but was unaffected by prazosin and bunazosin. In addition, the yawning induced by the dopaminergic agonists, but not by the cholinergic agonists, was markedly suppressed by ST587, an alpha 1-adrenoceptor agonist. All the yawning responses to dopaminergic and cholinergic agents were reduced not only by scopolamine, a muscarinic receptor antagonist, but also by idazoxan, rauwolscine, and yohimbine, alpha 2-adrenoceptor antagonists. The results suggest that catecholamine receptor activities seem to play different roles in inhibitory modulation of the occurrence of yawning caused by dopaminergic and cholinergic stimulation.

The present experiments were performed to examine the behavioral effects of OPC-14597, which acts on dopamine receptors in rats. OPC-14597 administered subcutaneously (SC) at doses of 0.1–5 mg/kg elicited yawning, as did OPC-4392 (0.5–2 mg/kg, SC) and (−)-3-PPP (2.5–10 mg/kg, SC). These yawning responses were blocked by intraperitoneal (IP) pretreatment with haloperidol (0.5 mg/kg) but were increased by pindolol (20 mg/kg, IP) or reserpine (5 mg/kg, IP), which per se did not elicit yawning. The yawning induced by talipexole, a selective dopamine D 2 receptor agonist, was inhibited by OPC-14597 (0.5–5 mg/kg, SC) and (−)-3-PPP (10 mg/kg, SC). Apomorphine (0.5 mg/kg, SC), a dopamine D 1 D 2 receptor agonist, elicited stereotypy such as sniffing and licking but OPC-14597 (5–20 mg/kg, SC) did not induce this behavior. The stereotypy induced by apomorphine was inhibited not only by haloperidol (0.5 mg/kg, IP) and (−)-3-PPP (10 mg/kg, SC) but also by OPC-14597 (5–20 mg/kg, SC), without being affected by OPC-4392 (2 mg/kg, SC). In 6-hydroxydopamine (6-OHDA)-treated rats, apomorphine (0.5 mg/kg, SC) elicited rotation behavior whereas OPC-14597, OPC-4392 and (−)-3-PPP did not produce this behavior. These findings suggest that OPC-14597 provokes yawning without causing stereotypy and rotation but markedly antagonizes the talipexole-induced yawning and apomorphine-induced stereotypy, and that OPC-14597 thus exerts partial agonistic effects on yawning behavior but antagonistic effects on stereotypy in rats.

In order to investigate the novel treatment for neuro-psychiatric diseases which are caused by the neuronal dysfunctions, we newly developed an animal model which striatal dopaminergic (DA) neuronal system was markedly potentiated by a Ca2+ channel activator After administration of Bay K 8644 (BAY), a L-type Ca2+ channel activator, into rat caudate putamen, the increases of spontaneous locomotor activity (SLMA) and rearing appearences induced by a novel circumstance were significantly enhanced. These increases were due to the extraordinary efflux of DA in caudate putamen after administration of BAY. Pre-treatment of D1 and D2 antagonists markedly inhibited these increases of SLMA and rearing, although these treatments did not effect on the magnificent increase of DA efflux. Pre-treatment of D1 agonist, a dosage of larger 50 nmol of SKF 81297 (SKF), killed BAY treated rats. The smaller dosages of SKF, however, did not influence to the behavioral and biochemical changes seen after the treatment of BAY. Meanwhile, pre-treatments of bromocriptine and talipexole, significantly blocked BAY induced behavioral and biochemical changes, although single administration of each D2 agonist increased SLMA and rearing number, but not the DA efflux. These results suggest that the antagonistic mechanisms of D2 agonists on BAY-induced DA efflux and SLMA potentiation is due to their stimulating to autoreceptor. In conclusion, this animal model is useful for screening D2 agonists which have the anti-Parkinson, anti-schizophrenia and/or neuroprotective action.

Objectives: Hypothermia is still unproven as beneficial treatment in human stroke, although in animal models, conditioning the brain with hypothermia has induced tolerance to insults. Here, we delineate the feasibility of drug-induced mild hypothermia in reducing ischemic brain damage when conditioning before (preconditioning) and after (postconditioning) experimental stroke. Methods: Hypothermia was induced in rats with a bolus of 6 mg/kg talipexole followed by 20 h continuous talipexole infusion of 6 mg/kg in total. Controls received similar treatment with saline. The core body temperature was continuously monitored. In preconditioning, hypothermia was terminated before either reversible occlusion of the middle cerebral artery (MCAO) for 60 min or global ischemia for 10 min with 2-vessel occlusion and hypotension. In postconditioning, rats experienced 60 min of MCAO before hypothermia was induced either immediately or with 3 h delay. Rats survived ischemia for 2, 7 or 90 days. Infarct volumes were quantified by stereology. Additional experiments of methodological relevance were included in the study. Results: Talipexole induced mild hypothermia (35.1 ± 1.1 to 36.0 ± 0.5°C) for Conclusion: Talipexole is registered for use as a dopamine substitute in humans with Parkinson's disease. Although dosages cannot be directly translated to patients, our study exemplifies in an animal model that drug-induced hypothermia in a clinical setting might reduce cerebral ischemic damage before neuro- and cardiac surgical procedures and after stroke.

Electrophysiological studies using rats anesthetized with chloral hydrate were performed to elucidate whether or not intravenously injected talipexole acted as a D2 receptor agonist on the striatal neurons in comparison with the action of bromocriptine. The activities of the striatal neurons were extracellularly recorded using a glass microelectrode attached along a seven-barreled micropipette, each barrel of which was filled with talipexole, bromocriptine, SCH23390 (D1 antagonist), domperidone (D2 antagonist), glutamate or 2 M NaCl. These drugs were iontophoretically applied to the immediate vicinity of the target neuron being recorded. The effects of talipexole and bromocriptine were examined on the neurons, whose spikes (induced by the stimulation of the substantia nigra pars compacta) were inhibited by the iontophoretic application of domperidone. Iontophoretic application of talipexole or bromocriptine increased spontaneous firing of these neurons and this increase in firing was also inhibited by iontophoretically applied domperidone. In the same neurons, intravenously administered talipexole (0.01, 0.02 and 0.04 mg/kg) dose-dependently increased firing, and this increase was inhibited by microiontophoretically applied domperidone, but not by SCH23390. On the other hand, the intravenous injection of bromocriptine (0.1, 0.2 and 0.4 mg/kg) also increased the firing rate. However, the increase was not dose-dependent and fluctuated; the firing transiently decreased during the increase in firing with intravenously administered bromocriptine. However, the bromocriptine-induced increase in firing was also suppressed by domperidone, and decrease in firing was inhibited by SCH23390. These findings suggest that talipexole acts as a D2 agonist on the striatal neurons receiving input from substantia nigra pars compacta and increases firing when intravenously applied. However, intravenously administered bromocriptine appears to act as both a D2 agonist and probably as a D1 agonist on the striatal neurons to increase and decrease firing, respectively.

Transfection of a human dopamine D3 receptor cDNA in a neuroblastoma-glioma hybrid cell line (NG 108-15) provided clonal cell lines stably expressing up to 600 fmol per mg protein of [125I]iodosulpiride binding sites. Dopamine and several agonists distinguished two receptor-affinity states in membranes. In the case of dopamine, the high-affinity state (Ki = 0.9 nM, 30% of total binding) was completely converted into a low-affinity state (Ki = 57 nM) in the presence of 10 microM guanosine-5'-O-(3-thiotriphosphate). In addition to these two sites, a site with a very low affinity for dopamine was evidenced in whole cells. The dopamine D3 receptor mediated two responses: c-fos activation, as measured by the appearance of Fos-like immunoreactivity, and increased mitogenesis, as measured by incorporation of [3H]thymidine. The Fos-like immunoreactivity appeared within 30 min, lasted 2 h and was blocked by the partially selective dopamine D3 receptor compound (+)-UH 232 (cis-(+)-5-methoxy-1-methyl-2-(di-n-propylamino)tetralin). The mitogenic effect, which occurred after a lag time (over 2 h stimulation), was produced with subnanomolar potency and full intrinsic activity by several compounds previously identified as dopamine D2 receptor agonists, e.g. quinpirole, (+)-7-OH-DPAT ((+)-7-hydroxy-2-(di-n-propylamino)tetralin) and RU 24926 (N-n-propyl-di-beta(3-hydroxyphenyl)-ethylamine), and was reversibly blocked by (+)-UH 232 (Ki = 9 nM). Talipexole (B-HT 920, 5-allyl-2-amino-5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]azepin) was identified as a partial agonist at the dopamine D3 receptor. Dopamine D3 receptor-mediated mitogenesis was potentiated by a phorbol ester and was abolished by pretreatment with pertussis toxin. A mitogenic effect of same amplitude was elicited by bradykinin or carbachol, both acting through constitutive receptors. Bradykinin markedly activated inositol phosphate turnover, and had no effect on forskolin-stimulated cyclic AMP accumulation. Carbachol inhibited forskolin-stimulated cyclic AMP accumulation and had no effect on inositol-phosphate turnover. Quinpirole had no effect on any of these second messenger pathways. Thus, in transfected NG 108-15 cells, the dopamine D3 receptor is coupled to a pertussis toxin-sensitive G protein and mediates two possibly unrelated biological effects, through initial biochemical events that remain to be identified.

An electrophysiological study using cats anesthetized with α-chloralose was performed to elucidate whether or not talipexole (B-HT 920 CL 2 : 6-allyl-2-amino -5, 6, 7, 8-tetrahydro-4H-thiazolo [4, 5 -d] -azepinedihydrochroride), a dopamine D 2 agonist, acts on postsynaptic dopamine receptors in the caudate nucleus (CN) neurons receiving excitatory input from the pars compacta of substantia nigra (SN). Extracellular neuron activities were recorded in the CN using a glass-insulated silver wire microelectrode attached along a seven-barreled micropipette, each of which was filled with talipexole, quinpirole (dopamine D 2 agonist), domperidone (dopamine D 2 antagonist), glutamate and 2M NaCl. These drugs were microiontophoretically applied to the immediate vicinity of the target neuron. In the same neurons in which the spikes elicited by the SN stimulation were blocked by microiontophoretically applied domperidone, microiontophoretic application of talipexole and quinpirole induced a dose-dependent increase in spontaneous firing. This increase in firing by talipexole and quinpirole was blocked during simultaneous application of domperidone, although glutamate-induced firing remained unaffected by domperidone. In the CN neurons, in which the SN stimulation-induced spikes were not blocked by domperidone, spontaneous firing was not affected by talipexole or quinpirole. These findings suggest that talipexole activates CN neurons receiving a dopaminergic input from SN via D 2 receptors, as does quinpirole.

Based on molecular modeling studies on the electronic properties of dopamine and dopamine agorusts the pyraz.o10(1,5-alpyridine structure has been evaluated as a catechol surrogate. The azaergoline analogue 6, including this moiety has been synthesized via 1,3-dipolar cycloaddition, anionic ring closure and electrophilic amination. The target compounds (6) exhibit DA autoreceptor agonistic activity. Presynaptic dopamine receptors serve an inhibitory feed back function on dopaminergic neurotransmissi0n.l Functionally, stimulation of the D-2 autoreceptor inhibits dopamine (DA) synthesis, release and DA neuronal firing. Since schizophrenia is associated with hyperactivity in the mesolimbic system (A 10 system) application of selective DA autoreceptor agonists is a very promising approach to a new class of neuroleptic drugs. * These atypical neuroleptics may offer a more subtle neurotransmitter regulation than the classical neuroleptics with D-2 antagonistic properties. As a consequence, considerable efforts have been dedicated to the design and synthesis of DA autoreceptor agonists without appreciable activity at the postsynaptic DA receptors resulting in compounds as (-)-3-PPP,3 EMD 2344g4 BHT 920 (talipexole) 5 and SND 919 (pramipexole).6 Since it is assumed that the binding sites of the postsynaptic D-2 receptor and its presynaptic analogues are very similar,7 it seemed to be a valuable strategy to modify the structure of known D-2 receptor agonists. We have previously reported that the (S)-enantiomer of the aminotetrahydroindolizine 1 strongly reduces DA synthesis, causes sedation in mice and reveals strong and selective affinity to the D-2 receptor, labeled with the selective autoreceptor agonist SND 919.* On the other hand the regioisomer 2 exhibits only a low order of dopaminergic effects. Thus, structural manipulation of the aromatic moiety seems to be very promising but also very sensitive. 1 and 2 are structurally related to the DA agonistic isoindole derivative 3, which is assumed to be the pharmacophoric core-structure of the ergolines (4).9 Based on these observations, we here report on molecular design, synthesis and tricyclic ergolines 5.9 pharmacological investigations of analogues of the DA active

Administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, 0.5 mg/animal i.v. once or twice) to common marmosets induced persistent parkinsonian motor deficits. The postsynaptic dopamine D2 receptor agonist properties of talipexole (B-HT 920, 2-amino-6-allyl-5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]-azepine), which is believed to be a dopamine autoreceptor agonist, were examined using normal and MPTP-treated marmosets and were compared to these properties of bromocriptine, a selective dopamine D2 receptor agonist. Talipexole (20-160 micrograms/kg i.p.) dose dependently increased motor activity and reversed the akinesia and incoordination of movement in MPTP-treated marmosets. In normal marmosets, higher doses of talipexole (80-160 micrograms/kg i.p.) produced a dose-dependent increase in motor activity, while the lowest dose (20 micrograms/kg i.p.) depressed this activity. These data for talipexole were very similar to those for bromocriptine. Talipexole had, however, several properties different from those of bromocriptine; it had a rapid onset of antiparkinsonian activity compared to bromocriptine; it had more than 25 times as much activity potency as bromocriptine; a dose of talipexole (80 micrograms/kg i.p.) sufficient to produce the activity did not induce emesis as strongly as an insufficient dose of bromocriptine (0.5 mg/kg i.p.). These results suggest that talipexole has postsynaptic dopamine D2 receptor agonist properties and that these properties of talipexole may be favorable in the treatment of Parkinson's disease.

1. Synthesis and release of dopamine as well as firing rates of dopaminergic neurons are controlled by stimulation of autoreceptors via a negative feedback regulation, investigations on therapeutic effects of autoreceptor-nonselective dopamine agonists in schizophrenia have yielded inconsistent results. 2. With respect to the dopamine hypothesis of schizophrenia, dopamine autoreceptor agonists have been tested in positive schizophrenic symptomatology in order to reduce the postulated excess of central dopaminergic activity. However, administration of selective dopamine autoreceptor agonists like talipexole or roxindole did not result in a significant improvement of psychopathological symptoms. 3. In negative schizophrenic symptomatology, a dopamine deficit rather than an excess has been hypothesized. Current evidence from open clinical trials suggests that dopamine autoreceptor agonists may produce a minor to moderate improvement of symptoms like affective flattening, depressed mood, alogia and avolition.

A prospective, nonblind 8-week trial of talipexole dihydrochloride (B-HT 920), a dopamine D2 agonist, was conducted in 15 schizophrenic patients with predominantly negative symptoms. B-HT 920 was initiated at 0.15 mg/day and then adjusted at 0.15-2.4 mg/day on the basis of clinical response and side effects. Dosage of concurrent neuroleptics was fixed at least 3 weeks prior to the trial and was unchanged throughout the study period. In addition to clinical assessment, levels of plasma homovanillic acid (pHVA), a potential index of central dopamine turnover, were measured. There was a small but significant (p0.01, Wilcoxon test) reduction in total scores of the Scale for the Assessment of Negative Symptoms or in a cluster score of three negative items (Emotional Withdrawal, Blunted Affect, and Psychomotor Retardation) of the Brief Psychiatric Rating Scale (BPRS). No change was observed in cluster scores of positive items of BPRS. There was a weak negative correlation between pHVA levels and the cluster scores of negative items of BPRS both at weeks 0 and 8 of the trial. The clinical results suggest that activation of D2 receptors was related to partial amelioration of the negative symptoms. The clinical and biochemical findings are consistent with a hypothesis that decreased dopaminergic activity may be related to the etiology of negative symptoms of schizophrenia.

The therapeutic efficacy of a new partial dopamine receptor agonist, B-HT 920 (talipexole hydrochloride) is discussed. B-HT 920 is primarily a presynaptic dopamine receptor agonist that inhibits the release of dopamine from the synaptic terminals. However, with degenerated dopaminergic terminals, it acts as a postsynaptic dopamine receptor agonist. This drug is therefore expected to possess antiparkinsonian properties with fewer emetic side effects. This hypothesis was examined in 56 patients with Parkinson’s disease. The clinical efficacy of B-HT 920 was comparable with that of the conventional agonists, whereas the incidence of epigastric discomfort was 10.7%, of anorexia was 7.1%, and of nausea was 7.1%, which appeared lower than the incidences reported with the conventional agonists. B-HT 920 seems to be a useful drug for Parkinson’s disease, and our results warrant further studies including double-blind trials.

Talipexole is a non-ergot dopamine (DA) agonist that has been used in the treatment of Parkinson's disease. In the present study, we examined the effect of talipexole on paraquat (PQ)-induced N27 cell death and the intracellular pathways involved in this effect. Pretreatment of N27 cells with talipexole (1 mM) resulted in significant protection against paraquat-induced cell death. In N27 cells, talipexole inhibited paraquat-induced apoptotic hallmarks such as cytochrome c release, caspase-3 activation, chromatin condensation and externalization of phosphatidilserine. Talipexole pretreatment prevents the reduction in the anti-apoptotic Bcl-xL protein and increases in the pro-apoptotic form of Bak and p-Bad, both induced by PQ. Finally, we also observed that talipexole abrogates the activation of cell death pathways JNK1/2 and p38 produced by PQ, and increases the phosphorylated (active) forms of the pro-survival pathways ERK1/2 and Akt. These results reveal that talipexole exerts a neuroprotective effect in a mesencephalic cell line exposed to the neurotoxin PQ, which is related to the etiology of Parkinson's disease.

The present experiments were performed to investigate the potential role of central adrenergic neurons in regulating occurrence of yawning in rats. Intraperitoneal injection of tacrine (THA) or 9-amino-2,3,5,6,7,8-hexahydro-1H-cyclopenta(b)-quinoline monohydrate HCl (NIK-247), cholinesterase inhibitors, induced yawning, which was markedly increased by pretreatment with the beta-adrenoceptor antagonist, pindolol. The yawning evoked by tacrine or NIK-247 given alone or in combination with pindolol was inhibited by pretreatment with scopolamine but not by mecamylamine or spiperone. Treatment with tacrine or NIK-247 increased acetylcholine content of the striatum, but this effect was not enhanced by pindolol, which per se did not affect basal acetylcholine content. Moreover, pretreatment with the central adrenaline synthesis inhibitors, (+-)-2,3-dichloro-alpha-methylbenzylamine HCl (LY-78335) and 2-cyclooctyl-2-hydroxyethylamine HCl (UK-1187A), increased tacrine-induced yawning. Subcutaneous injection of talipexole (B-HT 920), a dopamine D2 receptor agonist, evoked yawning, which was also increased by pindolol, LY-78335, and UK-1187A. These receptors antagonists and synthesis inhibitors per se did not cause yawning responses. The results suggest that the beta-adrenoceptor blockade and the inhibition of adrenaline synthesis facilitate the occurrence of yawning induced by cholinergic and dopaminergic agonists, and thus the central adrenergic neuronal systems may be implicated in the regulation of yawning responses.

Alterations in cortical EEG activity in male rats produced by putative agonists at dopamine (DA) autoreceptors and by antagonists at postsynaptic DA receptors were compared in order to study, whether an impairment in dopaminergic neurotransmission via two different mechanisms might result in similar or different effects. Simultaneously to the EEG recordings, gross behaviour was observed. Putative agonists at DA autoreceptors (apomorphine 0.05 mg/kg, quinpirole 0.05 mg/kg, or talipexole 0.02 mg/kg s.c.) produced increases in the power iin all of the frequency bands, except beta-2, with the most pronounced increase in the delta band. These EEG alterations were accompanied by hypokinesia, ptosis and yawning. In contrast, antagonists at DA receptors (haloperidol 0.1 mg/kg i.p., D2 blocker) or SCH 23390 (0.2 mg/kg i.p., D1 blocker) led to little increases in the delta band, but more pronounced increases in the alpha-2 band. Behavioural signs were hypokinesia, but little ptosis and yawning. The combination of both blockers produced, in addition, strong increases in the delta band and behavioural signs of ptosis and yawning. These results suggest that activation of putative dopamine autoreceptors produced EEG patterns and behavioural patterns different from those produced by blockade of either D1 or D2 postsynaptic dopamine receptors. In contrast, the effects following a stimulation of putative DA autoreceptors, which are expected to decrease the release of the agonist and its action at postsynaptic D1 and D2 receptors, were very similar to those found after a combined blockade of both types of postsynaptic dopamine receptors.

The present experiments were performed to investigate the effects of dopamine D1 receptor agonists given alone or in combination with dopamine D2 receptor agonists on body temperature in rats. The selective dopamine D1 receptor agonist, 1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol (SK&F38393), produced hyperthermia. However, the dopamine D2 receptor agonist, B-HT 920 (talipexole), and the newly synthesized dopamine D2 receptor agonist, (S)-2-amino-4,5,6,7-tetrahydro-6-propylamino-benzothiazole (SND 919), did not change the temperature. Interestingly, the SK&F38393-induced hyperthermia was enhanced by talipexole and SND 919. The drastic hyperthermia induced by combined administration of dopamine D1 and D2 receptor agonists was blocked by either the dopamine D1 receptor antagonist, SCH23390, or the dopamine D2 receptor antagonist, spiperone. On the other hand, treatment with prazosin, yohimbine, propranolol, scopolamine, or methysergide failed to affect the marked hyperthermia. The present results suggest that a functional link between dopamine D1 and D2 receptors may be synergistic in the regulation of body temperature and that concurrent stimulation of both dopamine D1 and D2 receptors thereby produces marked hyperthermia in the rat.

Dopamine autoreceptor agonists reduce the firing rate, synthesis, and release of dopamine in dopaminergic neurons by means of a negative feedback mechanism via stimulation of autoreceptors. Moreover, dopamine autoreceptor agonists are able to stimulate supersensitive but not normosensitive postsynaptic receptors. For dopamine autoreceptor agonists, therapeutic effects by readjustment of excessive or deficient dopaminergic function have been postulated for positive and negative schizophrenic symptomatology as well as for subtypes of depressive disorders. Investigations on the therapeutic effects of autoreceptor-nonselective dopamine agonists in schizophrenia or depression have yielded inconsistent results. In order to reduce the excess of central dopaminergic activity postulated by the dopamine hypothesis of schizophrenia, dopamine autoreceptor agonists have been tested in open clinical trials in positive schizophrenic symptomatology. However, administration of selective dopamine autoreceptor agonists like talipexole or roxindole did not result in a significant improvement of positive psychotic symptoms. In negative schizophrenic symptomatology, a dopamine deficit rather than an excess has been hypothesized. Current evidence from pilot studies suggests that dopamine autoreceptor agonists like roxindole may produce a minor to moderate improvement of symptoms like affective flattening, depressed mood, alogia, and avolition, possibly by stimulation of supersensitive postsynaptic dopamine receptors. For certain subgroups of depression, a reduction of functional dopamine activity has been postulated. In an open pilot study in patients with a major depression, roxindole demonstrated antidepressive properties comparable to those of standard antidepressants, justifying further double-blind controlled trials against reference drugs.

Mouse brain cortex slices preincubated with3H-noradrenaline were superfused and the effect of histamine on the electrically (0.3 or 3 Hz) evoked tritium overflow was examined. The evoked overflow was inhibited by histamine and R-(−)-α-methylhistamine but not by 2-(2-thiazolyl)ethylamine and dimaprit. The effect of histamine was antagonized by thioperamide but not by dimethindene and ranitidine. The degree of inhibition produced by histamine was more marked at 0.3 than at 3 Hz and was attenuated by the α2-adrenoceptor agonist talipexole (the former B-HT 920) but increased by phentolamine and the α2-adrenoceptor antagonist rauwolscine. Pre-exposure of slices toN-ethylmaleimide attenuated the inhibitory effect of histamine. The results suggest that histamine inhibits nordrenaline release in the mouse brain cortex via H3 receptors which interact with presynaptic α2-adrenoceptor and may be coupled to a G (e.g. Gi or Go) protein. The extent of H3 receptor-mediated inhibition of nordrenaline release in the mouse brain is more marked than that in the rat brain.

Brain cortex slices were preincubated with 3H-noradrenaline and superfused with physiological salt solution containing desipramine. We studied the inhibition of the electrically evoked tritium overflow caused by histamine in the presence of α-adrenoceptor ligands (mouse and rat brain cortex), and the inhibition caused by talipexole (the former B-HT 920) in the presence of H3-receptor ligands (mouse brain cortex). In mouse brain cortex slices, the inhibitory effect of histamine on the tritium overflow evoked by 36 pulses, 0.3 Hz was not changed by the α1-adrenoceptor antagonist prazosin, but increased by the α2-adrenoceptor antagonist rauwolscine. When the current strength or the duration of electrical pulses was reduced to compensate for the increase in evoked tritium overflow produced by rauwolscine, the latter still. enhanced the effect of histamine. The histamine-induced inhibition of tritium overflow evoked by 360 pulses, 3 Hz was not affected by the α1-adrenoceptor agonist phenylephrine but attenuated by the α2-adrenoceptor- agonist talipexole. Finally, the inhibition by histamine of the tritium overflow evoked by 3 pulses, 100 Hz was attenuated by talipexole but not affected by rauwolscine. Conversely,. the inhibitory effect of talipexole on tritium overflow elicited by 360 pulses, 3 Hz was slightly attenuated by the H3-receptor agonist R-(−)-α-methylhistamine but not, affected by the H3- receptor antagonist thioperamide. In rat brain cortex slices, histamine only tended to inhibit tritium overflow evoked by 360 pulses, 3 Hz, both in the absence of α-adrenoceptor antagonists and in the presence of prazosin. However, histamine markedly inhibited the evoked overflow in the presence of rauwolscine. Again, enhancement of the histamine-induced inhibition also occurred when the current strength or the duration of pulses was reduced in order to compensate for the increase in evoked tritium overflow produced by rauwolscine. The results suggest that the α2-autoreceptors and the H3-heteroreceptors at the noradrenergic nerve endings in the brain of mouse and rat interact with each other. Activation of the α2-autoreceptors decreases, whereas blockade of the activated (but not of the non-activated) α2-autoreceptors increases, the inhibitory effect of histamine. Activation of the H3-heteroreceptors slightly decreases, whereas blockade of the H3-receptors fails to affect, the inhibitory effect of talipexole.

Summary Objectives: To investigate the pharmacokinetics of talipexole hydrochloride tablets and the potential influence of Madopar (benserazide and levodopa combination; co-beneldopa) tablets on talipexole’s pharmacokinetics when the two tablets are co-administered orally to healthy Chinese volunteers. Methods: A sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed to measure talipexole concentration in human plasma in an open-label, randomized, two-way crossover, single-dose study, with 1-week washout period. Healthy Chinese volunteers were randomized to receive talipexole tablets either alone or together with Madopar tablets by oral administration after an overnight fast. Serial blood samples were collected for a period of 36 h after the administration. Pharmacokinetic parameters Cmax, tmax, t1/2z, mean residence time (MRT), AUC0−τ, AUC0−∞, CLz/F and Vz/F were determined under the non-compartmental model. Pharmacokinetic values of talipexole administered alone to the subjects were compared with those administered simultaneously with Madopar to determine whether or not the differences were statistically significant. Results: The subjects experienced mild gastrointestinal irritation when talipexole was administered alone as well as together with Madopar. For talipexole hydrochloride, there were no significant differences in the pharmacokinetic values between the two administrations. No pharmacokinetic differences based on gender were observed either. Conclusion: A single oral dose of Madopar co-administered with talipexole does not significantly change talipexole’s pharmacokinetics in human.

The aim of the present investigation was to study, taking into account both quantitative and qualitative differences, the influence of full and partial α-adrenoceptor agonists on spontaneous myogenic activity in the rat portal vein. We found that the α-adrenoceptor agonists cirazoline, adrenaline, noradrenaline, phenylephrine, St 587, Sgd 101/75, B-HT 920 and UK-14,304 could increase the amplitude of the phasic myogenic contractions in the rat portal vein with apparent differences in EC50and E(max) values. In addition to an increase in phasic myogenic activity, the α-adrenoceptor agonists cirazoline, adrenaline, noradrenaline, and phenylephrine were also able (in higher concentrations) to increase the basal tone of the rat portal vein preparation, again with apparent differences in EC50and E(max) values. Changing the extracellular Ca2+concentration from 0.9 mmol/l to 2.5 mmol/l had no influence on the phasic character and the concentration range in which St 587 and UK-14,304 increased spontaneous myogenic activity, although changes in amplitude and frequency of the spontaneous myogenic contractions were less pronounced at a higher extracellular Ca2+concentration (2.5 mmol/l). By the use of Schild analysis with the competitive α-adrenoceptor antagonists prazosin (pA2= 8.74) and 5-methyl-urapidil (pA2= 8.37), it was established that the contractile responses to St 587 were mediated by the same α1-adrenoceptor subtype as the phasic and tonic type of contraction elicited by phenylephrine as described in a previous study. The concentration-response curve of UK-14,304 was significantly shifted to the right by low concentrations of prazosin (3 nmol/l-30 nmol/l), indicating stimulation of α1-adrenoceptors by UK-14,304 in the rat portal vein. The α-adrenoceptor antagonists phenoxybenzamine and chloroethylclonidine irreversibly blocked the contractile responses to St 587. Based on the method of receptor alkylation with phenoxybenzamine an affinity constant was calculated for St 587 (pK(a) = 5.91). Phenoxybenzamine was approximately 1000-fold more potent in inactivating α1-adrenoceptors than chloroethylclonidine. In conclusion there appeared to be a divergence in the excitation-contraction coupling of α1-adrenoceptors in the rat portal vein, which is reflected by two types of contraction (phasic versus tonic). The extent to which both the phasic and tonic types of contraction are stimulated by agonists depends on the affinity and intrinsic efficacy for each of the receptor-coupled effector pathways. Thus, partial and full agonism can only meaningfully be discussed if confined to one particular effector pathway.

The aim of the present investigation was to study, taking into account both quantitative and qualitative differences, the influence of full and partial α-adrenoceptor agonists on spontaneous myogenic activity in the rat portal vein. We found that the α-adrenoceptor agonists cirazoline, adrenaline, noradrenaline, phenylephrine, St 587, Sgd 101/75, B-HT 920 and UK-14,304 could increase the amplitude of the phasic myogenic contractions in the rat portal vein with apparent differences in EC50and E(max) values. In addition to an increase in phasic myogenic activity, the α-adrenoceptor agonists cirazoline, adrenaline, noradrenaline, and phenylephrine were also able (in higher concentrations) to increase the basal tone of the rat portal vein preparation, again with apparent differences in EC50and E(max) values. Changing the extracellular Ca2+concentration from 0.9 mmol/l to 2.5 mmol/l had no influence on the phasic character and the concentration range in which St 587 and UK-14,304 increased spontaneous myogenic activity, although changes in amplitude and frequency of the spontaneous myogenic contractions were less pronounced at a higher extracellular Ca2+concentration (2.5 mmol/l). By the use of Schild analysis with the competitive α-adrenoceptor antagonists prazosin (pA2= 8.74) and 5-methyl-urapidil (pA2= 8.37), it was established that the contractile responses to St 587 were mediated by the same α1-adrenoceptor subtype as the phasic and tonic type of contraction elicited by phenylephrine as described in a previous study. The concentration-response curve of UK-14,304 was significantly shifted to the right by low concentrations of prazosin (3 nmol/l-30 nmol/l), indicating stimulation of α1-adrenoceptors by UK-14,304 in the rat portal vein. The α-adrenoceptor antagonists phenoxybenzamine and chloroethylclonidine irreversibly blocked the contractile responses to St 587. Based on the method of receptor alkylation with phenoxybenzamine an affinity constant was calculated for St 587 (pK(a) = 5.91). Phenoxybenzamine was approximately 1000-fold more potent in inactivating α1-adrenoceptors than chloroethylclonidine. In conclusion there appeared to be a divergence in the excitation-contraction coupling of α1-adrenoceptors in the rat portal vein, which is reflected by two types of contraction (phasic versus tonic). The extent to which both the phasic and tonic types of contraction are stimulated by agonists depends on the affinity and intrinsic efficacy for each of the receptor-coupled effector pathways. Thus, partial and full agonism can only meaningfully be discussed if confined to one particular effector pathway.

A microiontophoretic study using rats anesthetized with chloral hydrate and immobilized with gallamine triethiodide was carried out to compare the effect of talipexole (B-HT 920 CL 2 :2-amino-6-allyl-5,6,7,8-tetrahydro-4H-thiazolo [4,5-d]-azepine-dihydrochloride), a dopamine autoreceptor agonist, on dopaminergic neurons in the ventral tegmental area (VTA) to non-dopaminergic neurons in the VTA. VTA neurons were classified into two types according to the responses to antidromic stimulation of the nucleus accumbens (Acc) : type I neurons with a long spike latency (8.69 ± 0.24 msec) upon Acc stimulation and low spontaneous firing rate (6.80 ± 1.34 /sec), and type II neurons with a short latency (2.76 ± 0.20 msec) and high spontaneous firing rate (26.77 ± 7.05 /sec), probably corresponding to dopaminergic and non-dopaminergic neurons, respectively. In type I neurons, microiontophoretic application of talipexole and dopamine inhibited antidromic spike generation elicited by Acc stimulation, and talipexole-induced inhibition was antagonized by domperidone (dopamine D-2 antagonist). In type II neurons, however, the antidromic spikes were not affected by either talipexole or dopamine. Furthermore, spontaneous firing was also inhibited by iontophoretically applied talipexole and dopamine in most type I neurons, but rarely affected by either drug. Inhibitory effects of talipexole were antagonized by domperidone. These results suggest that talipexole acts on dopamine D-2 receptors, thereby inhibiting the dopaminergic neurons in the VTA.

In order to investigate the bedtime dose of talipexole, a D2 and alpha2 stimulant, on patients with periodic leg movement disorder (PLMD) and restless leg syndrome (RLS), we made a comparison of polysomnographic findings and subjective symptom ratings before and during 4 weeks of the treatment on five cases with RLS and PLMD. A significant decrease in both the frequencies of periodic leg movements and subjective symptom ratings and significant improvement of sleep composition were recognized during the treatment. We speculate that the combination of the agonistic action of D2 and alpha2 receptor with the drug might not only suppress PLMD and RLS but also improve sleep quality.

To investigate whether dopamine agonists induce neurite outgrowth, we examined the effects of dopamine D2 receptor agonists such as bromocriptine, talipexole, and pramipexole in PC12 cells, a well-studied model of neurite outgrowth. Bromocriptine significantly induced neurite outgrowth in a concentration-dependent manner. Neither talipexole nor pramipexole induced neurite outgrowth. Domperidone and sulpiride, dopamine D2 receptor antagonists, did not have any effect on the bromocriptine-induced neurite outgrowth. These results suggest that the stimulation of dopamine D2 receptors would not affect neurite outgrowth in nerve regeneration. Next, we investigated how bromocriptine-induced neurite outgrowth. Bromocriptine is not only a dopamine D2 receptor agonist but also an ergot alkaloid. We examined the involvement of the structure of ergot alkaloids in the effect of bromocriptine. Ergot alkaloids have been divided into two groups: amino acid ergot alkaloids, including bromocriptine, and amine ergot alkaloids. Amino acid ergot alkaloids, such as ergocornine and ergotamine, induced neurite outgrowth, but amine ergot alkaloids, including ergometrine and methylergometrine, did not. These results indicate that the structure of amino acid ergot alkaloids is important for the effect of bromocriptine. Moreover, the effect of bromocriptine was inhibited by a src inhibitor and a mitogen-activated protein kinase kinase (MEK) inhibitor. Taken together, bromocriptine-induced neurite outgrowth via src and the MEK/extracellular signal-regulated kinase 1/2 signaling pathway in PC12 cells.