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)

Subcutaneous administration of fluphenazine elicits catelepsy that can be attenuated by the glutamate antagonists MK801 and phencyclidine (PCP). 3-[-(+)-2-carboxy piperazine-4-yl]-propyl-1-phosphanate (CPP) was found to be ineffective in this model. Intrastriatal injections of sulpiride or fluphenazine were also found to induce catalepsy which could be attenuated by MK801 and PCP. These results illustrate that nondopaminergic compounds might possibly be of value in the treatment of Parkinson's disease. Furthermore it was demonstrated that this paradigm can be utilized to investigate neurotransmitter interactions within the striatum. This was clearly emphasized by the observation that bilateral administration of MK801 into the striatum increased basal locomotor activity.
 ...
PMID:Neuroleptic-induced catalepsy as a model of Parkinson's disease. II. Effect of glutamate antagonists. 197 10

The present study shows that high doses of the non-competitive NMDA antagonist phencyclidine (PCP) as well as of the competitive NMDA antagonist SDZ EAA494 (D-CPPene) increase locomotion in monoamine-depleted mice. The pattern of movement produced following treatment with these agents is very similar to that previously observed following MK-801 administration to monamine-depleted mice. When subthreshold doses of MK-801, PCP and SDZ EAA494 were combined with the alpha-adrenergic agonist clonidine, a dramatic stimulation of locomotion was observed in monoamine-depleted mice; the gross appearance of the animals was similar with the three drug combinations. These results support our previous conclusion that suppression of glutamatergic neurotransmission promotes the locomotor stimulatory potential of other (e.g. adrenergic) transmitter systems. The present findings may be of relevance for future treatment strategies in (L-DOPA-resistant) Parkinson's disease.
 ...
PMID:The non-competitive NMDA antagonists MK-801 and PCP, as well as the competitive NMDA antagonist SDZ EAA494 (D-CPPene), interact synergistically with clonidine to promote locomotion in monoamine-depleted mice. 214 54

Memantine is an uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist with therapeutic potential in dementia, spasticity and Parkinson's disease. The Ki-value of memantine at the phencyclidine (PCP) binding site of the NMDA receptor is 0.5 microM in human frontal cortex. We investigated whether concentrations of memantine in cerebrospinal fluid (CSF) and serum samples under therapeutic conditions are in the range of its Ki-value at the PCP binding site. The serum levels ranged from 0.025 to 0.529 microM with daily doses between 5 and 30 mg. CSF levels were highly correlated to serum levels and were below serum levels in each patient with a mean CSF/serum ratio of 0.52. Serum and CSF levels were correlated to the daily dose, but not to the duration of treatment. At the concentrations reported here, memantine is expected to specifically interact with the PCP binding site of the NMDA receptor.
 ...
PMID:Cerebrospinal fluid and serum concentrations of the N-methyl-D-aspartate (NMDA) receptor antagonist memantine in man. 747 69

Amantadine (1-amino-adamantane) is clinically used for the management of Parkinson's disease and drug-induced extrapyramidal symptoms. It has previously been shown that amantadine is a low-affinity uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist with rapid blocking and unblocking channel kinetics (Ki-value at the PCP binding site = 10 microM). The aim of the present studies was to estimate concentrations of amantadine in the central nervous system under therapeutic conditions. In homogenates of postmortem human brain tissue the amantadine concentration appeared to be homogeneously distributed over a wide range of brain areas. Amantadine concentration increased with duration of treatment and decreased wit drug-free time. When the duration of treatment was > or = 10 days and drug-free time < or = 3 days, mean amantadine concentrations in postmortem brain tissue ranged from 48.2 to 386 microM. In contrast to brain tissue, amantadine concentration in cerebrospinal fluid (CSF) and serum was in the low micromolar range ( < 17 microM). CSF and serum total values were highly correlated to each other and were always lower in CSF. The mean CSF/serum ratio for total amantadine was 0.76. To further estimate the extracellular concentration, amantadine was determined in microdialysates in the rat striatum. At behaviorally active doses, amantadine concentration in striatal microdialysates ranged between 6 and 21 microM. These results indicate that extracellular concentrations of amantadine (CSF and serum values in patients, striatal microdialysates in the rat) are in the range of its Ki-value at the PCP binding site. Amantadine concentrations in brain tissue are much higher, probably due to intralysosomal accumulation.
 ...
PMID:Therapeutic brain concentration of the NMDA receptor antagonist amantadine. 853 38

Glutamate receptor antagonists with selective action at the N-methyl-D-aspartate (NMDA) receptor are promising agents for the neuroprotective and symptomatic pharmacotherapy of various neuropsychiatric disorders. Although NMDA receptor antagonists of the phencyclidine (PCP) type are precluded from clinical use because of their psychotomimetic properties, amantadine and memantine have been administered to human patients with idiopathic Parkinson's disease and spasticity for many years without serious adverse effects. The mechanisms underlying these differences in psychotogenicity of different NMDA receptor antagonist are currently being discussed. Different affinity to the PCP binding site of the NMDA receptor, region-specific pharmacology, as well as different binding profiles to neurotransmitter receptors other than the NMDA type glutamate receptor, most likely play a role in determining whether an NMDA receptor antagonist drug will be tolerated clinically or not.
 ...
PMID:[New therapeutic possibilities with low-affinity NMDA receptor antagonists]. 867 93

The development of neuroprotective agents for the prevention of neuronal loss in acute conditions such as stroke and epilepsy or chronic neurodegenerative disorders including Parkinson's disease, Alzheimer's disease, Huntington's chorea, and motor neuron disease is currently focusing on drugs that inhibit excitatory amino acid neurotransmission or exhibit antioxidant properties. Unfortunately, potent antagonists at the N-methyl-D-aspartate (NMDA) type glutamate receptor, which is thought to mediate excitotoxic neuronal injury, e.g., MK-801 or phencyclidine (PCP), share a high probability of inducing psychotomimetic side effects. Further, these drugs have been associated with acute neurotoxicity in vitro and in vivo, precluding their clinical use. In contrast, low affinity NMDA receptor antagonists like amantadine and its dimethyl derivative, memantine, have been administered clinically for the management of Parkinson's disease, dementia, neuroleptic drug-induced side effects, and spasticity. These agents have only rarely induced significant psychotomimetic side effects. Recent pharmacologic advances have helped to elucidate how high drug affinity for the PCP binding site of the NMDA receptor may enhance psychotogenicity. Low affinity and associated fast voltage-dependent channel unblocking kinetics are likely to be responsible for the better tolerance of amantadine and memantine compared with MK-801 and PCP. Further factors apparently modulating psychotogenicity of glutamate receptor antagonists include differential actions on neuronal populations in various brain regions and interactions with neurotransmitter receptors other than the NMDA type glutamate receptor.
 ...
PMID:Psychotogenicity and N-methyl-D-aspartate receptor antagonism: implications for neuroprotective pharmacotherapy. 901 83

Four major components of the mechanism of action have been identified for the antiparkinsonian drug budipine up to now. 1) The primary action of budipine is an indirect dopaminergic effect as shown by facilitation of dopamine (DA) release, inhibition of monoamine oxidase type B (MAO-B) and of DA (re) up-take and stimulation of aromatic L-amino acid decarboxylase (AADC), which in sum might be responsible for enhancing the endogenous dopaminergic activity. 2) Radioligand and functional studies at the N-methyl-D-aspartate (NMDA) type glutamate receptor characterize budipine as a low-affinity, uncompetitive antagonist with fast kinetics and moderate voltage-dependency at the phencyclidine (PCP) binding site, comparable to that observed with amantadine, thereby counteracting an increased excitatory glutamatergic activity. 3) The antimuscarinic action of budipine, verified by functional and binding studies at native muscarinic M1-M3 and human recombinant m1-m5 receptor subtypes in vitro, is up to 125-fold weaker than that of biperiden and corresponds to its approximately 100-fold lower potency to cause experimentally-induced peripheral antimuscarinic effects and explains only part of its high potency, which equals biperiden, to suppress cholinergically evoked tremor. 4) An additional inhibition of striatal gamma-aminobutyric acid (GABA) release by budipine may be beneficial to suppress an increased striatal GABAergic output activity. The contribution of other observed effects to the therapeutic action of budipine, i.e. weak stimulation of noradrenaline and serotonin release, binding to brain sigma1 receptors and blockade of histamine H1 receptors, is not yet clear. By means of these multiple mechanisms, budipine might correct the imbalance of striatal output pathways by restoring DA levels in the striatum, and positively influence the secondary changes in other transmitter systems (glutamate, acetylcholine, GABA) observed in Parkinson's disease.
 ...
PMID:Multiple mechanisms of action: the pharmacological profile of budipine. 1037 Sep 4

Excitatory amino acids (EAA), such as glutamate, are thought to be involved in various disorders (e.g., ischemic brain damage, epilepsy, Parkinson's disease), and EAA antagonists have been suggested as potential treatments for these disorders. Phencyclidine (PCP), with produces psychotomimetic effects in humans, has antagonist properties at the N-methyl-D-aspartate (NMDA) subtype of glutamate receptors that have been suggested to underlie some of its actions. This suggestion, and concern about possible psychotomimetic activity, has stimulated research aimed at examining to what extent the behavioral profile of other NMDA antagonists resembles that of PCP. Drug discrimination (DD) is prominent among the procedures used to carry out such comparisons. The results of clinical studies with NMDA antagonists provide feedback about the predictive validity of the DD procedures used to characterize their preclinical behavioral profile. Further, DD is used also to examine the ability of compounds to attenuate the discriminative stimulus (DS) effects of PCP-type drugs, and results of such studies have been suggested to provide evidence of antipsychotic potential. Finally, although many instances of intermediate responding in DD can be explained by low efficacy at the receptors that mediate the DS effects of the training drug, certain outcomes produced by PCP-type drugs do not offer valid measures of efficacy, and require more detailed behavioral analyzes.
 ...
PMID:N-methyl-D-aspartate antagonists and drug discrimination. 1051 3

The N-methyl-D-aspartate (NMDA) ion channel plays a role in neuroprotection, neurodegeneration, long-term potentiation, memory, and cognition. It is implicated in the pathophysiology of several neurological and neuropsychiatric disorders including Parkinson's Disease, Huntington's Chorea, schizophrenia, alcoholism and stroke. The development of effective radiotracers for the study of NMDA receptors is critical for our understanding of their function, and their modulation by endogenous substances or therapeutic drugs. Since the NMDA/PCP receptor lies within the channel, it is a unique target and is theoretically accessible only when the channel is in the active and "open" state, but not when it is in the inactive or "closed" state. The physical location of the NMDA/PCP receptor not only makes it an important imaging target but also complicates the development of suitable PET and SPECT radiotracers for this site. An intimate understanding of the biochemical, pharmacological, physiological and behavioral processes associated with the NMDA ion channel is essential to develop improved imaging agents. This review outlines progress made towards the development of radiolabeled agents for PCP sites of the NMDA ion channel. In addition, the animal and pharmacological models used for in vitro and in vivo assessment of NMDA receptor targeted agents are discussed.
 ...
PMID:Imaging the PCP site of the NMDA ion channel. 1469 91

In order to investigate the functional interaction between the native dopamine receptors and their coupled guanine nucleotide-binding regulatory (G) proteins, dopamine-stimulated [(35)S]guanosine 5'-O-(gamma-thiotriphosphate) ([(35)S]GTPgammaS) binding was pharmacologically characterized in rat striatal membranes. Following optimizing the experimental conditions as to the concentrations of GDP, MgCl(2) and NaCl in the assay medium, the agonist and antagonist properties for a series of dopamine receptor ligands were determined mainly under the standard assay condition. The pharmacological profile of this response clearly indicated the involvement of dopamine D(2)-like receptors, but not of dopamine D(1)-like receptors. Among the types of dopamine D(2)-like receptors, dopamine D(2) receptors most likely appeared to be involved in dopamine-stimulated [(35)S]GTPgammaS binding in rat striatal membranes, because the affinities of agonists and antagonists determined in the present study were significantly correlated with those reported in the previous literature only for dopamine D(2) receptors, but not for dopamine D(3) or D(4) types. Though the concentration-dependent inhibition curves of dopamine-stimulated [(35)S]GTPgammaS binding by spiperone and S(-)-raclopride were apparently biphasic, the origin of the low-affinity minor components was not fully determined. The antiparkinsonian drugs with the properties of dopamine receptor agonism were shown to behave as stimulants with varied affinities and relative efficacies in the current assay system. On the other hand, neither phencyclidine (PCP) nor ketamine stimulated the specific [(35)S]GTPgammaS binding, in contrast with the previous report demonstrating that these two N-methyl-D-aspartic acid (NMDA) receptor antagonists behaved as agonists at human dopamine D(2) receptors expressed in Chinese hamster ovary (CHO) cells. These results provide important information about the functional activation of G proteins coupled with dopamine D(2) receptors as well as agonist actions of various compounds at native dopamine D(2) receptors, which are potentially involved in pathophysiology and pharmacotherapy of neuropsychiatric diseases such as Parkinson's disease, schizophrenia and depression.
 ...
PMID:Dopamine D2 receptor-mediated G protein activation assessed by agonist-stimulated [35S]guanosine 5'-O-(gamma-thiotriphosphate) binding in rat striatal membranes. 1682 59


1 2 Next >>