UMLS:C0030567 - FACTA Search

Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Target Concepts:

Query: UMLS:C0030567 (Parkinson's disease)
63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
...
PMID:Differential actions of antiparkinson agents at multiple classes of monoaminergic receptor. I. A multivariate analysis of the binding profiles of 14 drugs at 21 native and cloned human receptor subtypes. 1238 66

Monoamine reuptake inhibitors that do not discriminate between the transporters for dopamine (DA), norepinephrine (NE), or 5-hydroxytryptamine (5-HT, serotonin) can reverse locomotor deficits and motor disability in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated common marmosets. DA reuptake inhibition is presumed to be primarily responsible, but the role played by inhibition of NE and 5-HT reuptake is unknown. We now evaluate the efficacy of a range of monoamine reuptake inhibitors either alone or in combination in MPTP-treated common marmosets to determine the actions required for effective antiparkinsonian activity. Monoamine reuptake inhibitors not discriminating between the DA, NE, and 5-HT transporters [1-[1-(3,4-dichlororphenyl)cyclobutyl]-2-(3-diaminethylaminopropylthio)ethanone monocitrate (BTS 74 398) and nomifensine] reversed locomotor deficits and motor disability in MPTP-treated marmosets but bupropion was without effect. The selective DA reuptake inhibitor 1-(2-(bis-(4-fluorophenyl)-methoxy)ethyl)-4-(3-phenylpropyl) piperazine) dihydrochloride (GBR 12909) also reversed these motor deficits. The relative efficacy of the compounds (BTS 74 398 > GBR 12909 > nomifensine >> bupropion) paralleled their potency in inhibiting DA uptake in vitro and in vivo. In contrast, the selective NE reuptake inhibitor nisoxetine and the 5-HT reuptake inhibitor sertraline administered alone failed to improve motor function and tended to worsen the deficits. Coadministration of nisoxetine attenuated the improvement in motor deficits produced by GBR 12909. Coadministration of sertraline also abolished the reversal of motor deficits produced by GBR 12909. Coadministration of both sertraline and nisoxetine similarly abolished the improvement of motor deficits produced by GBR 12909. Molecules possessing potent DA reuptake inhibitory activity may be useful in the treatment of the motor symptoms of Parkinson's disease. In contrast, there seems to be no role for NE or 5-HT reuptake inhibitors, and they may impair antiparkinsonian activity mediated through dopaminergic mechanisms.
...
PMID:Dopamine, but not norepinephrine or serotonin, reuptake inhibition reverses motor deficits in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated primates. 1243 14

While Parkinson's disease is undoubtedly a disorder with a primary pathology of dopamine neuronal loss, that loss of dopamine and subsequent dopamine replacement therapy leads to imbalances in many non-dopaminergic transmitter systems, including 5-hydroxytryptamine (5-HT). Recent advances in understanding the role of 5-HT in parkinsonism and the generation of side-effects of dopamine replacement therapy (e.g. wearing-off and levodopa-induced dyskinesia) have identified 5-HT1A, 5-HT1B and 5-HT2C receptors as potential therapeutic targets in Parkinson's disease.
...
PMID:5-hydroxytryptamine (5-HT, serotonin) and Parkinson's disease - opportunities for novel therapeutics to reduce the problems of levodopa therapy. 1246 15

Rasagiline [N-propargyl-1R(+)-aminoindan; TVP1012] is a potent irreversible monoamine oxidase (MAO) inhibitor with selectivity for type B of the enzyme, which is being developed for treatment of Parkinson's disease. In this study we examined effects of rasagiline on CNS monoamine levels, modification of behavioural response to L-tryptophan, fluoxetine and L-DOPA, and reversal of reserpine syndrome. Reserpine-induced ptosis was reversed by rasagiline at doses above 2 mg x kg(-1) i.p., which inhibit MAO-A as well as MAO-B, but not at MAO-B-selective doses. However, combination of rasagiline (10 mg x kg(-1) i.p.) with L-DOPA or L-tryptophan (50 mg x kg(-1) i.p.), or rasagiline (10 mg x kg(-1) p.o.) with fluoxetine (10 mg x kg(-1) p.o.), did not induce the behavioural hyperactivity syndrome which is seen following inhibition of both MAO-A and MAO-B by tranylcypromine together with the monoamine precursors. Following oral administration, levels of noradrenaline (NA), 5-hydroxytryptamine (5-HT) and dopamine (DA) were unaffected in hippocampus and striatum after single doses of rasagiline up to 2 mg x kg(-1). Following chronic oral administration (21 days, one dose daily), levels of NA, 5-HT and DA in hippocampus and striatum were unaffected by rasagiline at doses up to 1 mg x kg(-1). Rasagiline does not modify CNS monoamine tissue levels or monoamine-induced behavioural syndromes at doses which selectively inhibit MAO-B but not MAO-A.
...
PMID:Pharmacological properties of the anti-Parkinson drug rasagiline; modification of endogenous brain amines, reserpine reversal, serotonergic and dopaminergic behaviours. 1250 17

Apoptosis and glutamate-mediated excitotoxicity may play a role in the pathogenesis of many neurodegenerative disorders, including Parkinson's disease (PD). In the present study, we investigated whether stimulation of the 5-hydroxytryptamine 1A (5-HT1A) receptor attenuates N-methyl-D-aspartate- (NMDA) and 1-methyl-4-phenylpyridinium (MPP(+))-induced apoptotic cell death in cell culture models. A brief exposure (20 min) of M213-2O striatal cells to NMDA and glutamate produced a delayed increase in caspase-3 activity and DNA fragmentation in a dose- and time-dependent manner. NMDA-induced caspase-3 activity and DNA fragmentation were almost completely blocked by the 5-HT1A agonists 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) and (R)-5-fluoro-8 hydroxy-2-(dipropylamino)-tetralin (R-UH-301). Additionally, the protective effects of 8-OH-DPAT and R-UH-301 on NMDA-induced caspase-3 activation and apoptosis were reversed by pretreatment with the 5-HT1A antagonists N-[2-[4-(2-methoxyphenyl)-1-piperazinyl] ethyl]-N-(2-pyridinyl) cyclohexane carboxamide (WAY 100635) and S-UH-301, respectively. Similarly, dose- and time-dependent increases in caspase-3 activity and DNA fragmentation were observed in rat primary mesencephalic neurons after a brief exposure to NMDA and glutamate. Caspase-3 activation and DNA fragmentation in primary mesencephalic neurons were almost completely inhibited by 8-OH-DPAT. This neuroprotective effect of 8-OH-DPAT was reversed by WAY 100635. Additionally, 8-OH-DPAT blocked tyrosine hydroxylase (TH)-positive cell death after NMDA exposure and also almost completely attenuated the NMDA-induced Ca(2+) influx in primary mesencephalic cultures. Furthermore, 8-OH-DPAT and R-UH-301 blocked apoptotic cell death in the primary mesencephalic neurons that were exposed to the Parkinsonian toxin MPP(+). Together, these results suggest that 5-HT1A receptor stimulation may be a promising pharmacological approach in the development of neuroprotective agents for PD.
...
PMID:5-hydroxytryptamine 1A receptor activation protects against N-methyl-D-aspartate-induced apoptotic cell death in striatal and mesencephalic cultures. 1260 65

Parkinson's disease is characterized not only by a progressive loss of dopaminergic neurons in the substantia nigra but also by a degeneration of locus coeruleus noradrenergic neurons. The present study addresses the question of whether a partial neurodegeneration of dopaminergic neurons using 6-hydroxydopamine in rat, not sufficient to produce motor disturbances, is potentiated by prior selective denervation of locus coeruleus noradrenergic terminal fields using N-ethyl-2-bromobenzylamine. Two types of denervations, one causing dopamine deficiency alone and the other causing noradrenaline and dopamine deficiency, were performed. Noradrenaline, 5-hydroxytryptamine, 5-hydroxyindole acetic acid, dopamine and its metabolites were analysed in various brain regions. Behaviour was evaluated by catalepsy tests and activity box. N-ethyl-2-bromobenzylamine selectively depleted noradrenaline from neurons of locus coeruleus origin. Decreased dopamine content in the striatum, substantia nigra and pre-frontal cortex was observed after dopaminergic lesion with 6-hydroxydopamine (42.9%). Additional locus coeruleus noradrenaline depletion with N-ethyl-2-bromobenzylamine aggravated the dopamine depletion (61.2%). The lesion in the noradrenergic and dopaminergic neurodegenerated group was not sufficient to induce consistent catalepsy and akinesia. However, after a subthreshold dose of haloperidol (0.1 mg/kg), the expression of catalepsy and akinesia was strong in the dual-lesioned group and less in the 6-hydroxydopamine-lesioned group. These results indicate that denervation of locus coeruleus noradrenergic terminals with N-ethyl-2-bromobenzylamine potentiates the 6-hydroxydopamine-induced partial dopaminergic neurodegeneration and parkinsonian symptoms. Based on the present findings and existing reports, it can be concluded that noradrenergic neurons of locus coeruleus have neuromodulatory and neuroprotective properties on the dopaminergic neurons of basal ganglia and that noradrenergic degeneration may contribute to the aetiology and pathophysiology of Parkinson's disease.
...
PMID:Potentiation of parkinsonian symptoms by depletion of locus coeruleus noradrenaline in 6-hydroxydopamine-induced partial degeneration of substantia nigra in rats. 1282 65

Several hypotheses regarding physiopathology of major psychiatric diseases exist. Attention has been focused on cerebral monoaminergic systems, the dysfunction of which is thought to underlie various aspects of their symptomatology. There are reports describing the involvement of serotonergic and dopaminergic systems in the mechanism of action of psychotropic drugs. This article reviews current knowledge on interaction between 5-hydroxytryptamine (5-HT), acting at 5-HT2C receptors in the central dopamine (DA) systems. Since 90s, a growing body of behavioural, neurochemical and electrophysiological evidence from animal studies have demonstrated a clear role for 5-HT2C receptors in modulation of activity of dopamine neurones. This evidence has led to the suggestion that drugs acting on 5-HT2C receptors have potential as novel antipsychotic and antidepressant agents and may also be used in the treatment of other neuropsychiatric disorders such as Parkinson's disease and psychoactive substance abuse.
...
PMID:Serotonin/dopamine interaction--focus on 5-HT2C receptor, a new target of psychotropic drugs. 1297 95

It has been proposed that DT-diaphorase plays a strategic role as a neuroprotective enzyme for monoamine neurons, perhaps together with monoamine oxidase (MAO). Thus, we investigated the long-term effects produced by DT-diaphorase inhibition with dicumarol injected unilaterally into the medial forebrain bundle (MFB) on monoamine and metabolite levels, alone, or following dopamine loading with 3,4-dihydroxyphenyl-L-alanine (L-DOPA) or MAO inhibition with L-deprenyl. Monoamine levels were assayed in aliquots from tissue samples from right and left striatum, including both dorsal and ventral regions. Dicumarol alone produced increases in 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA), but not in dopamine and metabolite levels when assayed two weeks later. However, following preloading with L-DOPA (3 x 25 mg/kg s.c. 7, 4 and 1 h before surgery), a long-lasting bilateral increase in dopamine and metabolite levels was observed after dicumarol. No effect was observed on dopamine, 5-HT and metabolite levels after L-deprenyl (3 x 10 mg/kg, s.c.) alone, but the levels were unilaterally increased when L-deprenyl was followed by dicumarol. The same result was produced when both L-deprenyl and dicumarol were injected simultaneously into the same brain region. In conclusion, the present study shows that intracerebral inhibition of DT-diaphorase produces long-term changes in 5-HT, but also in dopamine metabolism when DT-diaphorase inhibition is combined with MAO inhibition by systemic or intracerebral treatment with L-deprenyl. It is suggested that both MAO and DT-diaphorase have to be inhibited for inducing long-term changes in monoamine metabolism. Thus, DT-diaphorase is an enzyme to be taken into account when L-DOPA is used to treat Parkinson's disease, or when an MAO-inhibitor is used to treat depression.
...
PMID:Effects of the DT-diaphorase inhibitor dicumarol on striatal monoamine levels in L-DOPA and L-deprenyl pre-treated rats. 1511 Dec 34

SL25.1131 [3(S),3a(S)-3-methoxymethyl-7-[4,4,4-trifluorobutoxy]-3,3a,4,5-tetrahydro-1,3-oxazolo[3,4-a]quinolin-1-one] is a new, nonselective, and reversible monoamine oxidase (MAO) inhibitor, belonging to a oxazoloquinolinone series. In vitro studies showed that SL25.1131 inhibits rat brain MAO-A and MAO-B with IC50 values of 6.7 and 16.8 nM and substrate-dependent Ki values of 3.3 and 4.2 nM, respectively. In ex vivo conditions, the oral administration of SL25.1131 induced a dose-dependent inhibition of MAO-A and MAO-B activities in the rat brain with ED50 values of 0.67 and 0.52 mg/kg, respectively. In the rat brain, duodenum, and liver, the inhibition of MAO-A and MAO-B by SL25.1131 (3.5 mg/kg p.o.) was reversible, and the recovery of MAO-A and MAO-B activities was complete 16 h after administration. SL25.1131 (3.5 mg/kg p.o.) increased tissue levels of dopamine (DA), norepinephrine, and 5-hydroxytryptamine and decreased levels of their deaminated metabolites 3,4-dihydroxyphenylacetic acid, homovanillic acid, and 5-hydroxyindolacetic acid. In mice, SL25.1131 induced a dose-dependent potentiation of 5-hydroxytryptophan-induced tremors and phenylethylamine-induced stereotypies with ED50 values of 0.60 and 2.8 mg/kg p.o., respectively. SL25.1131 was able to reestablish normal striatal dopaminergic tone and locomotor activity in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned mice. In addition, when coadministered with L-DOPA, SL25.1131 increased the available DA in the striatum and the duration of L-DOPA-induced hyperactivity. The duration of the effect of L-DOPA on circling behavior in 6-hydroxydopamine-lesioned rats was also increased. The neurochemical profile of SL25.1131 demonstrates that this compound is a mixed, potent, and reversible MAO-A/B inhibitor in vitro, in vivo, and ex vivo. SL25.1131 has therapeutic potential as a symptomatic treatment during the early phase of Parkinson's disease and as an adjunct to L-DOPA therapy during the early and late phases of the disease.
...
PMID:SL25.1131 [3(S),3a(S)-3-methoxymethyl-7-[4,4,4-trifluorobutoxy]-3,3a,4,5-tetrahydro-1,3-oxazolo[3,4-a]quinolin-1-one], a new, reversible, and mixed inhibitor of monoamine oxidase-A and monoamine oxidase-B: biochemical and behavioral profile. 1517 94

Pharmacological treatment of Parkinson's disease (PD) is entering a new and exciting era. Real promise now exists for the clinical application of a large range of molecules in development that will combat different aspects and stages of the condition. These include methyl- and ethyl-esterified forms of L-dopa (etilevodopa and melevodopa), inhibitors of enzymes such as monoamine oxidase type-B (eg, rasagiline), catechol-O-methyl transferase (eg, BIA-3202) and the monoamine re-uptake mechanism (eg, brasofensine). In addition, a range of full and partial dopamine agonists (eg, sumanirole, piribedil and BP-897) and their new formulations, for example, patch delivery systems (eg, rotigotine) are being developed. We also highlight non-dopaminergic treatments that will have wide ranging applications in the treatment of PD and L-dopa-induced dyskinesia. These include alpha2 adrenergic receptor antagonists (eg, fipamezole), adenosine A2A receptor antagonists (eg, istradefylline), AMPA receptor antagonists (eg, talampanel), neuronal synchronization modulators (eg, levetiracetam) and agents that interact with serotonergic systems such as 5-hydroxytryptamine (5-HT)1A agonists (eg, sarizotan) and 5-HT2A antagonists (eg, quetiapine). Lastly, we examine a growing number of neuroprotective agents that seek to halt or even reverse disease progression. These include anti-apoptotic kinase inhibitors (eg, CEP-1347), modulators of mitochondrial function (eg, creatine), growth factors (eg, leteprinim), neuroimmunophilins (eg, V-10367), estrogens (eg, MITO-4509), c-synuclein oligomerization inhibitors (eg, PAN-408) and sonic hedgehog ligands.
...
PMID:Drugs in development for Parkinson's disease. 1529 67

<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>