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)

RDC8 (correction of RCD8), a recently cloned new putative member of the G protein-coupled receptor family protein, is exclusively present in the medium-sized neurons of the striatum. This restricted localisation mimics the major striatal dopamine D1 receptor localisation and is of major importance for the understanding of basal ganglia physiology and degenerative diseases pathogeny such as Huntington's and Parkinson's disease. RDC7, another putative G protein-coupled receptor chemically closely related to RDC8 (correction of RCD8), is mainly distributed in pyramidal neurons of the cerebral cortex, the hippocampus and the claustrum, and in the amygdala, and may represent the minor extra-striatal variant of the D1 receptor.
 ...
PMID:[A cloned protein belonging to the G protein-coupled receptor family has an essentially striatal distribution copying that of the major component of the D1 receptor]. 216 9

RDC8, a recently cloned new putative member of the G protein-coupled receptor family, is exclusively present in the medium-sized neurons of the dorsal and ventral striatum in the rat and dog brains. The existence of a striatum-restricted putative G protein-coupled receptor is of major importance for the understanding of basal ganglia physiology and degenerative diseases pathogeny such as Huntington's and Parkinson's disease. This striatal restricted localization mimics the major striatal dopamine D1 receptor localization. RDC7, another putative G protein-coupled receptor presenting a close sequence similarity with RDC8, is mainly distributed in the cerebral cortex, the amygdala, the hippocampus and the claustrum. This localization is also compatible with that expected from a subtype of dopamine D1 receptors.
 ...
PMID:A cloned G protein-coupled protein with a distribution restricted to striatal medium-sized neurons. Possible relationship with D1 dopamine receptor. 216 85

A series of pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine derivatives (10a-o,q,r), bearing alkyl and aralkyl chains on positions 7 and 8, were synthesized in the attempt to obtain potent and selective antagonists for the A(2A) adenosine receptor subtype. The compounds were tested in binding and functional assays to evaluate their potency for the A(2A) compared with the A1 adenosine receptor subtype. In binding studies in rat brain membranes, most of the compounds showed affinity for A(2A) receptors in the low nanomolar range with a different degree of A(2A) versus A1 selectivity. Comparison of N(7) (10a-d,h-o)- and N(8) (10e-g)-substituted pyrazolo derivatives indicates that N(7) substitution decreases the A1 affinity with the concomitant increase of A(2A) selectivity. Specifically, the introduction of a 3-phenylpropyl group at pyrazolo nitrogen in position 7 (101) increased significantly the A(2A) selectivity, being 210-fold, while the A(2A) receptor affinity remained high (Ki=2.4 nM). With regards to the affinity for A(2A) receptors, also the compound 10n, bearing in the 7-position a beta-morpholin-4-ylethyl group, deserves attention (Ki=5.6 nM) even though the A2A selectivity (84-fold) was not as high as that of 101. Conversely, the compound 10m (N(7)-4-phenylbutyl derivative) showed a remarkable selectivity (A1/a(2A) ratio = 129) associated with lower A(2A) affinity (Ki = 21 nM). In functional studies, most of the compounds examined reversed 5'-(N-ethylcarbamoyl) adenosine-induced inhibition of rabbit platelet aggregation inhibition which is a biological response mediated by the A2A receptor subtype. The compounds are potent and selective A2A antagonists which can be useful to elucidate the pathophysiological role of this adenosine receptor subtype. These compounds deserve to be further developed to assess their potential for treatment of neurodegenerative disorders such as Parkinson's disease.
 ...
PMID:Pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine derivatives: potent and selective A(2A) adenosine antagonists. 867 54

In rats with unilateral 6-hydroxydopamine lesions of the dopaminergic nigrostriatal pathway, administration of the A2a adenosine antagonist SCH 58261 alone did not induce any motor asymmetry but strongly potentiated the contralateral turning behaviour induced by the dopamine D1 agonist SKF 38393. SCH 58261 also increased the number of Fos-like positive nuclei induced by SKF 38393 in the 6-hydroxydopamine-lesioned striatum. Intense potentiation of D1-dependent turning behaviour and c-Fos expression was also observed after administration of the A2a/A1 antagonist CGS 15943. Administration of the A1 adenosine receptor antagonist DPCPX induced a small potentiation of D1-mediated contralateral turning while c-Fos expression induced by SKF 38393 was not modified. The results suggest that endogenous adenosine acting on A2a receptors can exert an inhibitory influence on the functional expression of D1-mediated responses in dopamine-denervated rats, and propose new possible therapeutic approaches in the treatment of Parkinson's disease.
 ...
PMID:Blockade of A2a adenosine receptors positively modulates turning behaviour and c-Fos expression induced by D1 agonists in dopamine-denervated rats. 875 87

The effect of adenosine A1 and A2 receptor agonists and antagonists was investigated on haloperidol-induced catalepsy in rats. Pretreatment (i.p.) with the non-selective adenosine receptor antagonist, theophylline, or the selective adenosine A2 receptor antagonist, 3,7-dimethyl-1-propargylxanthine (DMPX), significantly reversed haloperidol-induced catalepsy, whereas the selective adenosine A1 receptor antagonists, 8-phenyltheophylline and 8-cyclopentyl-1,3-dipropylxanthine produced no effect. Similar administration of the adenosine A2 receptor agonists, 5'-(N-cyclopropyl)-carboxamidoadenosine and 5'-N-ethylcarboxamidoadenosine (NECA), and the mixed agonists with predominantly A1 site of action, N6-(2-phenylisopropyl) adenosine or 2-chloroadenosine, potentiated haloperidol-induced catalepsy. Higher doses of the adenosine agonists produced catalepsy when given alone. However, N6-cyclopentyladenosine, a highly selective adenosine A1 receptor agonist, was ineffective in these respects. The per se cataleptic effect of adenosine agonists was blocked by DMPX and the centrally acting anticholinergic agent, scopolamine. Scopolamine also attenuated the potentiation of haloperidol-induced catalepsy by adenosine agonists. Further, i.c.v. administration of NECA and DMPX produced a similar effect as that produced after their systemic administration. These findings demonstrate the differential influence of adenosine A1 and A2 receptors on haloperidol-induced catalepsy and support the hypothesis that the functional interaction between adenosine and dopamine mechanisms might occur through adenosine A2 receptors at the level of cholinergic neurons. The results suggest that adenosine A2, but not A1, receptor antagonists may be of potential use in the treatment of Parkinson's disease.
 ...
PMID:Adenosine A2 receptors modulate haloperidol-induced catalepsy in rats. 921 95

Allosteric modulation of G protein-coupled receptors is a relatively novel and unexplored pharmacological concept that may lead to more selective and more 'natural' drugs for these receptors. In particular, allosteric enhancers may serve as tools to intensify selectively a weakened hormone or neurotransmitter signal caused by a localized deficit, such as in Alzheimer's or Parkinson's disease. In this paper, attention is paid to the adenosine A1 receptor, for which novel allosteric enhancers were synthesized and characterized that proved superior to the prototypic allosteric enhancer PD 81,723.
 ...
PMID:Allosteric modulation of G protein-coupled receptors. 1134 69

Abnormalities in dopaminergic control of basal ganglia function play a key role in Parkinson's disease. Adenosine appears to modulate the dopaminergic control in striatum, where an inhibitory interaction between adenosine and dopamine receptors has been demonstrated. However the interaction has not been established in substantia nigra pars reticulata (SNr) where density of both receptors is high. Here we have explored the interaction between A1/D1 receptors in SNr. In SNr slices, SKF 38393, a selective D1 receptor agonist, produced a stimulation of depolarization-induced Ca(2+)-dependent [(3)H]GABA release that was inhibited by adenosine. The adenosine inhibition was abolished by 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), a selective adenosine A1 receptor antagonist. DPCPX per se enhanced GABA release, indicating inhibition of the release by endogenous adenosine. When D1 receptors were blocked with SCH 23390 or the slices were depleted of dopamine, the effect of DPCPX was suppressed, showing that activation of dopamine receptors was necessary for the adenosine inhibition. In normal slices, 2-chloro-n(6)-cyclopentyladenosine (CCPA), a selective A1 agonist, inhibited GABA release, but the inhibition was prevented by the blockade of D1 receptors with SCH 23390. Superperfusion with 8-bromo-cAMP produced a stimulation of GABA release that was not blocked by CCPA: this finding indicates that the blockade of D1 effects caused by activation of A1 receptors is specific. To see if these actions on GABA release were correlated with changes in motor behavior we studied the effect of unilateral intranigral injections of modifiers of adenosine A1 and dopamine D1 receptors in rats challenged with systemic methamphetamine. Both the A1 agonist CCPA and the D1 antagonist SCH 23390 produced ipsilateral turning whereas the A1 antagonist DPCPX caused contralateral turning. These motor effects are consistent with the findings on GABA release. The results indicate the presence of an inhibitory A1/D1 receptor interaction in SNr. The inhibition exerted by A1 adenosine receptors on GABAergic striatonigral transmission would be due exclusively to blockade of the facilitation resulting from activation of D1 dopamine receptors. The data permit to better understand the action of adenosine antagonists in the treatment of Parkinson's disease.
 ...
PMID:Adenosine A1 receptors control dopamine D1-dependent [(3)H]GABA release in slices of substantia nigra pars reticulata and motor behavior in the rat. 1243 13

It is well established that in the CNS, endogenous adenosine plays a pivotal role in neurodegeneration. A low, nanomolar concentration of adenosine is normally present in the extracellular fluid, but it increases dramatically during enhanced nerve activity, hypoxia or ischemia. In these pathological conditions, adenosinergic transmission-potentiating agents, which elevate adenosine level by either inhibiting its degradation (adenosine deaminase and kinase inhibitors) or preventing its transport, offer protection against ischemic or excitotoxic neuronal damage. The directly acting adenosine A1 receptor agonists are known to mediate neuroprotection, mostly by the blockade of Ca2+ influx, which results in the inhibition of glutamate release and reduction of its excitatory effects at a postsynaptic level. More recent data have shown that antagonists of adenosine A2A receptors markedly reduce cerebral ischemic damage in animal models of focal and global ischemia. Moreover, these compounds attenuate the neuronal loss induced by excitatory amino acids (EAA). A neuroprotective effect of adenosine A2A receptor antagonists was also shown in animal models of Parkinson's disease (MPTP, 6-OHDA, methamphetamine). Hence, it might be suggested that adenosine A2A receptor antagonists may represent a novel strategy in the therapeutic approach to pathologies characterized by acute or chronic neurodegenerative events, since they not only reverse motor impairment but can act as neuroprotective compunds by promoting cell survival.
 ...
PMID:Neuroprotective role of adenosine in the CNS. 1252 85

The [1,2,4]triazolo[1,5-a]triazine derivative 3, more commonly known in the field of adenosine research as ZM-241385, has previously been demonstrated to be a potent and selective adenosine A2a receptor antagonist, although with limited oral bioavailability. This [1,2,4]triazolo[1,5-a]triazine core structure has now been improved by incorporating various piperazine derivatives. With some preliminary optimization, the A2a binding affinity of some of the best piperazine derivatives is almost as good as that of compound 3. The selectivity level over the adenosine A1 receptor subtype for some of the more active analogues is also fairly high, > 400-fold in some cases. Many compounds within this piperazine series of [1,2,4]triazolo[1,5-a]triazine have now been shown to have good oral bioavailability in the rat, with some as high as 89% (compound 35). More significantly, some piperazines derivatives of [1,2,4]triazolo[1,5-a]triazine also possessed good oral efficacy in rodent models of Parkinson's disease. For instance, compound 34 was orally active in the rat catalepsy model at 3 mg/kg. In the 6-hydroxydopamine-lesioned rat model, this compound was also quite effective, with a minimum effective dose of 3 mg/kg po.
 ...
PMID:Piperazine derivatives of [1,2,4]triazolo[1,5-a][1,3,5]triazine as potent and selective adenosine A2a receptor antagonists. 1529 1

1. This study examined whether Paeoniflorin (PF), the major active components of Chinese herb Paeoniae alba Radix, has neuroprotective effect in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease (PD). 2. Subcutaneous administration of PF (2.5 and 5 mg kg(-1)) for 11 days could protect tyrosine hydroxylase (TH)-positive substantia nigra neurons and striatal nerve fibers from death and bradykinesia induced by four-dose injection of MPTP (20 mg kg(-1)) on day 8. 3. When given at 1 h after the last dose of MPTP, and then administered once a day for the following 3 days, PF (2.5 and 5 mg kg(-1)) also significantly attenuated the dopaminergic neurodegeneration in a dose-dependent manner. Post-treatment with PF (5 mg kg(-1)) significantly attenuated MPTP-induced proinflammatory gene upregulation and microglial and astrocytic activation. 4. Pretreatment with 0.3 mg kg(-1) 8-cyclopentyl-1,3-dipropylxanthine, an adenosine A1 receptor (A1AR) antagonist, 15 min before each dose of PF, reversed the neuroprotective and antineuroinflammatory effects of PF. 5. In conclusion, this study demonstrated that PF could reduce the MPTP-induced toxicity by inhibition of neuroinflammation by activation of the A1AR, and suggested that PF might be a valuable neuroprotective agent for the treatment of PD.
 ...
PMID:Paeoniflorin attenuates neuroinflammation and dopaminergic neurodegeneration in the MPTP model of Parkinson's disease by activation of adenosine A1 receptor. 1658 33


1 2 Next >>