Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A 3D pharmacophore model predicting anticonvulsant activity was obtained for a series of 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline derivatives recently disclosed as a new class of noncompetitive AMPA receptor antagonists. The training set included 17 compounds with varying potency against audiogenic seizures in DBA/2 mice. The best statistical hypothesis, generated with the HypoGen module of Catalyst 4.9, consisted of five features: two hydrogen bond acceptors, two hydrophobic features, and one hydrophobic aromatic region, providing a model with a correlation coefficient of 0.919. The obtained model was an efficient tool in the design of some new anticonvulsant agents containing the tetrahydroisoquinoline scaffold. Moreover, in order to explain the different degree of efficacy of the newly designed N-substituted derivatives, excluded volumes were also considered.
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PMID:3D pharmacophore models for 1,2,3,4-tetrahydroisoquinoline derivatives acting as anticonvulsant agents. 1678 40

C-Jun N-terminal kinase (JNK) is a therapeutic target for inhibitors which may provide clinical benefit in the pathogenesis of rheumatoid arthritis (RA) as well as in various apoptosis-related disorders. The benzothiazol-2-yl acetonitrile derivatives, recently reported by Pascale et al. (J. Med. Chem. 2005, 48, 4596-4607), are the first generation JNK inhibitors of this class. To understand inhibitory mechanisms and elucidate pharmacophoric properties of these derivatives molecular docking and 3D-QSAR studies were performed on a set of 44 compounds. Ligand Fit module of Cerius2 (4.9) was employed to locate the binding orientations of all the compounds within the JNK-3 ATP binding site. A good correlation (r2=0.810) between the calculated binding free energies (-PMF score) and the experimental inhibitory activities suggests that the identified binding conformations of these potential inhibitors are reliable. Based on the binding conformations, robust and highly predictive 3D-QSAR models were developed with conventional r2 0.886 and 0.802, full cross-validation r2 0.980 and 0.788, and predictive r2 0.965 and 0.968 for MFA and MSA, respectively. The interaction mode was demonstrated taking into consideration inhibitor conformation, hydrogen bonding, and electrostatic interaction. The 3D-QSAR model built in this study will provide clear guidelines for a novel inhibitor design based on the benzothiazole derivatives against JNK-3 for the treatment of inflammatory disorders.
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PMID:Exploration of a binding mode of benzothiazol-2-yl acetonitrile pyrimidine core based derivatives as potent c-Jun N-terminal kinase-3 inhibitors and 3D-QSAR analyses. 1685 8

X-Ray absorption spectra of supported Pt catalysts with various Pt cluster sizes were collected between 77 and 673 K, in inert and hydrogen atmospheres. When analyzing these spectra with the standard EXAFS equation, a Pt-Pt bond contraction and a large increase in the inner potential correction were observed with increasing temperature. These errors are up to 0.08 A and 10 eV for clusters of 1 nm diameter. They were corrected by including the third and fourth cumulants as fit parameters. Fit guidelines were developed to analyze EXAFS data of supported metal catalysts collected at elevated temperatures, allowing for asymmetry and broadening or sharpening of the pair distribution function. These comprise fixing fit parameters, using different k-weightings and identifying trends in a series of experiments. By fitting the EXAFS spectra using these guidelines, it was determined that in small Pt clusters the Pt-Pt bond is 0.10 A shorter than in bulk Pt. These contracted bonds relax to distances near that of bulk Pt upon hydrogen chemisorption.
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PMID:Analysis of in situ EXAFS data of supported metal catalysts using the third and fourth cumulant. 1690 17

The forensic luminol test is used to screen large areas for the presence of blood. The heme-induced reduction of hydrogen peroxide is coupled to the oxidation of luminol resulting in luminescence. However, photographic documentation of the relatively weak and short-lived luminescence is difficult and luminol is now often replaced by other chemicals. In this study, we investigated reports from the Rostock police department that the addition of "Fit", a dishwashing detergent from former Eastern Germany, could both intensify and prolong the luminescence of luminol on blood stains. Even though this effect was reported only for the original composition of Fit but not the currently sold version, we found that both the old and the new version of Fit increase the brightness of the luminescence while decreasing its duration. This may be due to detergents in the dishwashing liquid, which permeabilize the plasma membrane of the erythrocytes, exposing the Fe3+ inside the cell and speeding up the entire reaction. We did not find any evidence of special ingredients in the old version of Fit that would cause both the increased brightness and prolonged duration of luminescence as reported by the Rostock PD.
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PMID:[Effect of "Fit" dishwashing detergent from former Eastern Germany (GDR) on luminol luminescence]. 1691 Feb 97

Extracellular proton concentrations in the brain may be an important signal for neuron function. Proton concentrations change both acutely when synaptic vesicles release their acidic contents into the synaptic cleft and chronically during ischemia and seizures. However, the brain receptors that detect protons and their physiologic importance remain uncertain. Using organotypic hippocampal slices and biolistic transfection, we found the acid-sensing ion channel 1a (ASIC1a), localized in dendritic spines where it functioned as a proton receptor. ASIC1a also affected the density of spines, the postsynaptic site of most excitatory synapses. Decreasing ASIC1a reduced the number of spines, whereas overexpressing ASIC1a had the opposite effect. Ca(2+)-mediated Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) signaling was probably responsible, because acid evoked an ASIC1a-dependent elevation of spine intracellular Ca(2+) concentration, and reducing or increasing ASIC1a levels caused parallel changes in CaMKII phosphorylation in vivo. Moreover, inhibiting CaMKII prevented ASIC1a from increasing spine density. These data indicate that ASIC1a functions as a postsynaptic proton receptor that influences intracellular Ca(2+) concentration and CaMKII phosphorylation and thereby the density of dendritic spines. The results provide insight into how protons influence brain function and how they may contribute to pathophysiology.
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PMID:Acid-sensing ion channel 1a is a postsynaptic proton receptor that affects the density of dendritic spines. 1706 Jun 8

Proton magnetic resonance spectroscopy ((1)H MRS) is beneficial in the lateralization of the epileptogenic zone in temporal lobe epilepsy; however, its role in extratemporal and, especially, MRI-negative epilepsy has not been established. This study seeks to verify how (1)H MRS could help in localizing the epileptogenic zone in patients with MRI-negative extratemporal epilepsy. Seven patients (8-23 years) with MRI-negative refractory focal epilepsy were studied using (1)H MRS on a 1.5T MR system. Chemical shift imaging sequence in the transversal plane was directed towards the suspected epileptogenic zone localized by seizure semiology, scalp video/EEG, ictal SPECT and (18)FDG-PET. Spectra were evaluated using the program CULICH, and the coefficient of asymmetry was used for quantitative lateralization. MRS detected lateralization in all patients and was able to localize pathology in five. The most frequent findings were decreased ratios of N-acetylaspartate to choline compounds characterized by increasing choline concentration. The localization of the (1)H MRS abnormality correlated well with ictal SPECT and subdural mapping. In all cases, histopathological analysis revealed MRI-undetected focal cortical dysplasias. (1)H MRS could be more sensitive for the detection of discrete malformations of cortical development than conventional MRI. It is valuable in the presurgical evaluation of patients without MRI-apparent lesions.
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PMID:(1)H MR spectroscopic imaging in patients with MRI-negative extratemporal epilepsy: correlation with ictal onset zone and histopathology. 1734 Jan 2

Sandhoff disease (gangliosidosis type 0) is a lysosomal storage disorder with a deficiency of hexosaminidases A and B. After an initially normal development the clinical course of affected children is severe and rapidly progressive leading to spastic tetraparesis, epileptic seizures and early death. In a 10-month-old girl with enzymatically established diagnosis of Sandhoff disease MRI of the brain showed signal changes in the periventricular white matter, pyramidal tract, basal ganglia, and cerebellar hemispheres. Proton MR spectroscopy (MRS) at the age of 13 months revealed a reduction of total N-acetylaspartate (neuroaxonal marker) as well as strongly elevated inositol (glial marker) in white matter, gray matter, and basal ganglia. A new resonance at 2.07 ppm was detected in all regions and ascribed to N-acetylhexosamine with highest concentrations in white matter and thalamus. While conventional MRS findings are in line with neuroaxaonal damage and pronounced astrocytosis, the observation of N-acetylhexosamine appears as a specific marker of Sandhoff disease indicating accumulation of hexosamine-containing oligosaccharides. This interpretation is supported by a recent in vitro MRS study of a Sandhoff mouse model. In conclusion, proton MRS of cerebral metabolites offers specific insights into the pathopysiologic processes of children with Sandhoff disease and may prove to represent another disease specific MRS pattern of the brain.
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PMID:Proton MRS of a child with Sandhoff disease reveals elevated brain hexosamine. 1762 39

A 32-year-old man who had experienced fever and a pulsating headache of the right occipital region for a month and a transient left hemianopia and numbness in the left arm two weeks prior to presentation was admitted to our hospital because of a seizure. Fluid-attenuated inversion recovery and diffusion-weighted magnetic resonance imaging (MRI) showed high-intensity signals, without reduction of apparent diffusion coefficient value, in the right temporo-occipital cortices. Proton MR spectroscopy (1H-MRS) indicated a decrease in N-acetylaspartate, and single-photon emission CT (SPECT) showed hyperperfusion in the right temporo-occipital territory. An examination of the cerebrospinal fluid showed an elevation of mononuclear cells and the presence of anti-glutamate epsilon2 receptor antibodies. All abnormalities shown by these imaging techniques were normalized in the clinical course. This report suggests that MRI, 1H-MRS and SPECT studies were useful in understanding the pathogenesis of encephalitis associated with glutamate receptor antibodies.
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PMID:[Subacute encephalitis associated with anti-glutamate receptor antibodies: serial studies of MRI, 1H-MRS and SPECT]. 1840 40

Glycogen Synthase Kinase 3beta is one of the important targets in the treatment of type II diabetes and Alzheimer's disease. Currently this target is in pursuit for type II diabetes and a few GSK-3beta inhibitors have been now advanced to Phases I and II of clinical trials. The best validated HypoGen model consists of four pharmacophore features; 1) two hydrogen bond acceptors, 2) one hydrogen bond donor and 3) one hydrophobic. This pharmacophore model correlates well with the docking model, one hydrogen bond acceptor is necessary for the H-bond interaction with VAL135, and second hydrogen bond acceptor is important for the H-bond interactions with ARG141 and the hydrophobic feature may be required for the weak H-bond interactions with ASP133. The comparative model was developed from analogue and structure-based models like Catalyst, Glide SP & XP, Gold Fitness & ChemScore and Ligand Fit using multiple linear regression analysis. A virtual library of 10,000 molecules was generated employing fragment and knowledge-based approach and the comparative model was used to predict the activities of these molecules. The H-bond with ARG141 appears to be unique to GSK-3beta and explains the high GSK-3beta selectivity observed for 1H-Quinazolin-4-ones and Benzo[e][1,3]oxazin-4-ones. This understanding of protein-ligand interactions and molecular recognition increases the rapid development of potent and selective inhibitors, and also helps to eliminate the increase in number of false positives and negatives.
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PMID:Fragment and knowledge-based design of selective GSK-3beta inhibitors using virtual screening models. 1892 33

Advances in the understanding of mechanisms underlying the pathophysiology of epilepsy have led to the identification of sodium hydrogen exchanger (NHE) as one of the possible targets for future antiepileptic drugs (AEDs). There are indicators from several experimental studies that NHE inhibitors could be of significant value as potential anticonvulsants. Various in-vitro reports (brain slices) have suggested anticonvulsant potential of these agents. Recently we provided the in-vivo data on anticonvulsant efficacy of amiloride (an NHE inhibitor) in different animal models of seizure and epilepsy. In addition to blocking NHE, these agents are known to affect other traditional targets like voltage-gated Na(+) channels, Ca(2+) channels, glutamate concentration, etc. Thus NHE inhibitors may represent a novel class of AEDs and surely deserve more scientific attention. In this review, we focus on the role of NHE in epilepsy and provide the experimental evidence available so far on the effect of NHE inhibitors in various animal models.
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PMID:Seizures and sodium hydrogen exchangers: potential of sodium hydrogen exchanger inhibitors as novel anticonvulsants. 1899 62


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