Search results for "SOX"
showing 10 items of 240 documents
Pharmacological activity of C10-substituted analogs of the high-affinity kainate receptor agonist dysiherbaine
2009
Kainate receptor antagonists have potential as therapeutic agents in a number of neuropathologies. Synthetic modification of the convulsant marine toxin neodysiherbaine A (NDH) previously yielded molecules with a diverse set of pharmacological actions on kainate receptors. Here we characterize three new synthetic analogs of NDH that contain substituents at the C10 position in the pyran ring of the marine toxin. The analogs exhibited high-affinity binding to the GluK1 (GluR5) subunit and lower affinity binding to GluK2 (GluR6) and GluK3 (GluR7) subunits in radioligand displacement assays with recombinant kainate and AMPA receptors. As well, the natural toxin NDH exhibited approximately 100-f…
Design, synthesis, and biological evaluation of nonsteroidal cycloalkane[d]isoxazole-containing androgen receptor modulators.
2012
We report here the design, preparation, and systematic evaluation of a novel cycloalkane[d]isoxazole pharmacophoric fragment-containing androgen receptor (AR) modulators. Cycloalkane[d]isoxazoles form new core structures that interact with the hydrophobic region of the AR ligand-binding domain. To systematize and rationalize the structure-activity relationship of the new fragment, we used molecular modeling to design a molecular library containing over 40 cycloalkane[d]isoxazole derivatives. The most potent compound, 4-(3a,4,5,6,7,7a-hexahydrobenzo[d]isoxazol-3-yl)-2-(trifluoromethyl)benzonitrile (6a), exhibits antiandrogenic activity significantly greater than that of the most widely used …
From Five- to Six-Membered Rings: 3,4-Diarylquinolinone as Lead for Novel p38MAP Kinase Inhibitors
2007
In this study we describe the design, synthesis, and biological evaluation of 3-(4-fluorophenyl)-4-pyridin-4-ylquinoline-2(1H)-one (5) as a new inhibitor of MAPK with a p38alphaMAPK IC50 of 1.8 muM. By keeping the common vicinal pyridine/4-F-phenyl pharmacophore, such as in prototypical imidazole 20 or isoxazole 13 but in 5 connected to the six-membered quinoline core, we were particularly interested in comparing biological activity, details of molecular geometry, and different binding modes of these compounds. Compounds 20 and 13 were active both in the p38alpha- and JNK3-assay, whereas 5 was selective for p38alpha, with no JNK3 inhibition. By comparing the X-ray structures of the compound…
Synthesis of GABAA receptor agonists and evaluation of their alpha-subunit selectivity and orientation in the GABA binding site.
2008
Drugs used to treat various disorders target GABA A receptors. To develop alpha subunit selective compounds, we synthesized 5-(4-piperidyl)-3-isoxazolol (4-PIOL) derivatives. The 3-isoxazolol moiety was substituted by 1,3,5-oxadiazol-2-one, 1,3,5-oxadiazol-2-thione, and substituted 1,2,4-triazol-3-ol heterocycles with modifications to the basic piperidine substituent as well as substituents without basic nitrogen. Compounds were screened by [(3)H]muscimol binding and in patch-clamp experiments with heterologously expressed GABA A alpha ibeta 3gamma 2 receptors (i = 1-6). The effects of 5-aminomethyl-3 H-[1,3,4]oxadiazol-2-one 5d were comparable to GABA for all alpha subunit isoforms. 5-pipe…
A Molecular Electron Density Theory Study of the Chemoselectivity, Regioselectivity, and Diastereofacial Selectivity in the Synthesis of an Anticance…
2019
The [3 + 2] cycloaddition (32CA) reaction of an &alpha
Synthesis of 4(5)-phenacyl-imidazoles from isoxazole side-chain rearrangements
2010
A novel base-induced rearrangement of isoxazoles into imidazole derivatives is reported. In the isoxazole series, this represents the first example of a three-atom side-chain rearrangement involving a CNC sequence. The reactions are carried out under nitrogen and produced 2-aryl-4(5)-phenacyl-5(4)-phenyl-imidazoles in high yields. In the presence of oxygen, a cascade rearrangement-oxidation reaction sequence was observed and imidazole derivatives bearing an oxidized side-chain were isolated.
Experimental and DFT Studies on Competitive Heterocyclic Rearrangements. 3. A Cascade Isoxazole−1,2,4-Oxadiazole−Oxazole Rearrangement
2008
The thermal rearrangements of 3-acylamino-5-methylisoxazoles 1 have been investigated under basic and neutral conditions and interpreted with the support of computational data. The density functional theory (DFT) study on the competitive routes available for the base-catalyzed thermal rearrangement of isoxazoles 1 showed that the Boulton-Katritzky (BK) rearrangement, producing the less stable 3-acetonyl-1,2,4-oxadiazoles 5, is a much more favored process than either the migration-nucleophilic attack-cyclization (MNAC) or the ring contraction-ring expansion (RCRE). In turn, an increase in reaction temperature will promote the MNAC of oxadiazoles 5, producing the more stable 2-acylaminooxazol…
Study of thermal spin crossover in [Fe(II)(isoxazole)(6)](BF4)(2) with Mossbauer spectroscopy
2007
Fe-57 Mossbauer spectroscopy of the mononuclear [Fe( II)( isoxazole)(6)]( BF4)(2) compound has been studied to reveal the thermal spin crossover of Fe( II) between low- spin ( S = 0) and high- spin ( S = 2) states. A temperature-dependent spin transition curve has been constructed with the least- square fitted data obtained from the Mossbauer spectra measured at various temperatures in the 240 - 60 K range during the cooling and heating cycle. The compound exhibits a temperature- dependent two- step spin transition phenomenon with T-SCO ( step 1) = 92 and TSCO ( step 2) = 191 K. The compound has three highspin Fe( II) sites at the highest temperature of study; among them, two have slightly …
Reduced presynaptic efficiency of excitatory synaptic transmission impairs LTP in the visual cortex of BDNF-heterozygous mice
2006
The neurotrophin brain-derived neurotrophic factor (BDNF) plays an important role in neuronal survival, axonal and dendritic growth and synapse formation. BDNF has also been reported to mediate visual cortex plasticity. Here we studied the cellular mechanisms of BDNF-mediated changes in synaptic plasticity, excitatory synaptic transmission and long-term potentiation (LTP) in the visual cortex of heterozygous BDNF-knockout mice (BDNF(+/-)). Patch-clamp recordings in slices showed an approximately 50% reduction in the frequency of miniature excitatory postsynaptic currents (mEPSCs) compared to wild-type animals, in the absence of changes in mEPSC amplitudes. A presynaptic impairment of excita…
Dendritic Ih selectively blocks temporal summation of unsynchronized distal inputs in CA1 pyramidal neurons.
2004
The active dendritic conductances shape the input-output properties of many principal neurons in different brain regions, and the various ways in which they regulate neuronal excitability need to be investigated to better understand their functional consequences. Using a realistic model of a hippocampal CA1 pyramidal neuron, we show a major role for the hyperpolarization-activated current, I-h, in regulating the spike probability of a neuron when independent synaptic inputs are activated with different degrees of synchronization and at different distances from the soma. The results allowed us to make the experimentally testable prediction that the I-h in these neurons is needed to reduce ne…