167 research outputs found
Gait Ignition Failure in JNPL3 Human Tau-mutant Mice
No full textCognitive impairments and motor dysfunction are commonly observed behavioral phenotypes in genetic animal models of neurodegenerative diseases. JNPL3 transgenic mice expressing human P301L-mutant tau display motor disturbances with age- and gene dose-dependent development of neurofibrillary tangles, suggesting that tau pathology causes neurodegeneration associated with motor behavioral abnormalities. Although gait ignition failure (GIF), a syndrome marked by difficulty in initiating locomotion, has been described in patients with certain forms of tauopathies, transgenic mouse models mirroring human GIF syndrome have yet to be reported. Using the open field and balance beam tests, here we discovered that JNPL3 homozygous mice exhibit a marked delay of movement initiation. The elevated plus maze excluded the possibility that hesitation to start in JNPL3 mice was caused by enhanced levels of anxiety. Considering the normal gait ignition in rTg4510 mice expressing the same mutant tau in the forebrain, GIF in JNPL3 mice seems to arise from abnormal tau deposition in the hindbrain areas involved in locomotor initiation. Accordingly, immunohistochemistry revealed highly phosphorylated paired helical filament tau in JNPL3 brainstem areas associated with gait initiation. Together, these findings demonstrate a novel behavioral phenotype of impaired gait initiation in JNPL3 mice and underscore the value of this mouse line as a tool to study the neural mechanisms and potential treatments for human GIF syndrome. Copyright © Experimental Neurobiology 2019.1
니페디핀의 광 화학적 분해반응 메카니즘에 관한 연구
No full text학위논문(석사) - 한국과학기술원 : 화학과, 1988.2, [ iii, 59 p. ]Irradiation of nifedipine in methylene chloride at 366 nm yielded 2,6-dimethyl-3,5-dimethyl-3,5-dicarbomethoxy-4-(2``nitrosophenyl)-pyridine with the quantum efficiency of 0.37, while irradiation at 254 nm initially gave nitroso compound which in turn is photooxidized to 2,6-dimethyl-3,5-dicarbomethoxy-4-(2``-nitrophenyl)-pyridine with quantum efficiency of 0.014 on further irradiation in the presence of oxygen. The intramolecular hydrogen abstraction of nifedipine appeared to proceed from the triplet excited state. The quantum yield of photo-degradation of nifedipine at 366 nm decreased as the concentration of amine increased. The quantum yields at 254 nm irradiation of nitroso compound(II) sharply increase with the decrease in polarity of the solvents. It is probably due to the strong charge transfer character in the creation state of nitroso compound(II).한국과학기술원 : 화학과
Translocator protein (TSPO) ligands for the diagnosis or treatment of neurodegenerative diseases: a patent review (2010 – 2015; part 2)
No full textIntroduction: The 18-kDa translocator protein (TSPO) has been highlighted as a potential drug target in diverse neurodegenerative diseases because the up-regulation of TSPO in the CNS is related to neuroinflammation. Diverse TSPO ligands are currently in clinical trials or are under development at the preclinical stage for the treatment and/or diagnosis of neurodegenerative processes. These TSPO ligands may shed light on novel therapeutics for neurodegenerative diseases in the near future. Areas covered: This review describes TSPO ligands that have been patented from 2010 to 2015. Numerous indole-derived TSPO ligands will be analyzed on the basis of their TSPO affinities. Furthermore, cholesterol-like compounds and miscellaneous TSPO ligands will be summarized along with their pharmaceutical uses. Expert opinion: Diverse TSPO ligands have demonstrated their biological efficacies in experimental models of neurodegenerative diseases, and some of them are now in clinical trials. The indole-derived TSPO ligands can be highlighted as efficient diagnostic agents because they have high selectivity and affinity for TSPO. Moreover, one potent cholesterol-like TSPO ligand has been described as a neuroprotective compound. Therefore, additional preclinical and clinical studies for highly potent TSPO ligands are recommended for the successful pharmacological application of TSPO ligands.</p
P1‐077: Discovery of Novel TSPO Ligands as Modulators of Mitochondrial Function: A Potential Treatment for Alzheimer’s Disease
No full textGlutamate Permeability of Chicken Best1
No full textBestrophin-1 (Best1) is a calcium (Ca(2+))-activated chloride (Cl(-)) channel which has a phylogenetically conserved channel structure with an aperture and neck in the ion-conducting pathway. Mammalian mouse Best1 (mBest1) has been known to have a permeability for large organic anions including gluconate, glutamate, and D-serine, in addition to several small monovalent anions, such as Cl(-), bromine (Br(-)), iodine (I(-)), and thiocyanate (SCN(-)). However, it is still unclear whether non-mammalian Best1 has a glutamate permeability through the ion-conducting pathway. Here, we report that chicken Best1 (cBest1) is permeable to glutamate in a Ca(2+)-dependent manner. The molecular docking and molecular dynamics simulation showed a glutamate binding at the aperture and neck of cBest1 and a glutamate permeation through the ion-conducting pore, respectively. Moreover, through electrophysiological recordings, we calculated the permeability ratio of glutamate to Cl(-) (P(Glutamate)/P(Cl)) as 0.28 based on the reversal potential shift by ion substitution from Cl(-) to glutamate in the internal solution. Finally, we directly detected the Ca(2+)-dependent glutamate release through cBest1 using the ultrasensitive two-cell sniffer patch technique. Our results propose that Best1 homologs from non-mammalian (cBest1) to mammalian (mBest1) have a conserved permeability for glutamate
Virtual screening and synthesis of novel antitubercular agents through interaction-based pharmacophore and molecular docking studies
No full textTuberculosis continues to become a major threat and wide spreading disease though out the world. Therefore it is required to identify the new drugs for the treatment of tuberculosis with better activity profile than the prevalent compounds. In present study we have screened and modified the antitubercular compounds from commercial chemical database using the interaction-based pharmacophore and molecular docking studies. In the first step different pharmacophores of cocrystal structures of enyol acyl carrier reductase (also known as InhA) proteins (2B36 and 3FNG) were generated and employed for screening of ChemDiv database. Four different pharmacophore hypothesis retrieved 3456 hits from approximately 0.67 million compounds. In the second filter, these hit molecules were subjected to the molecular docking studies in 2NSD and 3FNG crystal structures. On the basis of high fit values, GScore, structural diversity and visual inspection, one hundred compounds were selected, purchased and subjected to experimental validation for antitubercular activity against H37Rv Mycobacterium tuberculosis (MTB) strain. Three compounds showed the minimal inhibitory concentration (MIC) value at 16 μg/mL and one compound VH04 showed the value at 1 μg/mL. Then a more active amidoethylamine compound was developed by chemical modifications of the virtual hit VH04 against the MTB strain. We believe that this newly identified scaffold could be useful for the optimization of lead from hit compounds of new antitubercular agents.restrictio
Classification of dopamine antagonists using functional feature hypothesis and topological descriptors
No full textThe designing of selective dopamine antagonists for their own subreceptors can be useful in individual therapy of various neuropsychiatric disorders. Three-dimensional pharmacophore hypothesis and two-dimensional topological descriptors were used to investigate and compare different classes of dopamine antagonists. The structurally diverse D(3) and D(4) antagonists above preclinical trials were selected to map common structural features of highly selective and efficacious antagonists. The generated pharmacophore hypotheses were successfully employed as discriminative probe for database screening. To filter out the false positive from screening hits, the classification models by two-dimensional topological descriptors were built. Molconn-Z and BCUT topological descriptors were employed to develop a classification model for 1328 dopamine antagonists from MDDR database. The soft independent modeling of class analogy and artificial neural network, two supervised classification techniques, successfully classified D(1), D(3), and D(4) antagonists at the average of 80% rates into their own active classes. The mean classification rates for D(2) antagonists were obtained to 60% due to insufficient selective D(2) antagonists. In this paper, we report the validity of our models generated using functional feature hypotheses and topological descriptors. The combining both of classification using functional feature hypotheses and topological descriptors would be a useful tool to predict selective antagonists.ope
Identification of novel antitubercular compounds through hybrid virtual screening approach.
No full textGrowing resistance of prevalent antitubercular (antiTB) agents in clinical isolates of Mycobacterium tuberculosis (MTB) provoked an urgent need to discover novel antiTB agents. Enoyl acyl carrier protein (ACP) reductase (InhA) from Mtb is a well known and thoroughly studied as antitubucular therapy target. Here we have reported the discovery of potent antiTB agents through ligand and structure based approaches using computational tools. Initially compounds with more than 0.500 Tanimoto similarity coefficient index using functional class fingerprints (FCFP_4) to the reference chemotype were mined from the chemdiv database. Further, the molecular docking was performed to select the compounds on the basis of their binding energies, binding modes, and tendencies to form reasonable interactions with InhA (PDB ID=2NSD) protein. Eighty compounds were evaluated for antitubercular activity against H37RV M. tuberculosis strain, out of which one compound showed MIC of 5.70 microM and another showed MIC of 13.85 microM. We believe that these two new scaffolds might be the good starting point from hit to lead optimization for new antitubercular agents.ope
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