RESUMEN
We have designed and synthesized a series of novel molecules having a residue of a classical NSAID and an antioxidant moiety, both attached through amide bonds to a known nootropic structure, an L-proline, trans-4-hydroxy-L-proline or DL-pipecolinic acid residue. The compounds were found to retain anti-inflammatory and antioxidant activities, to acquire hypocholesterolemic action, and to possess a greatly reduced gastrointestinal toxicity. The novel molecules could find useful applications, among others, in slowing the progression or delaying the onset of neurodegenerative diseases.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Antioxidantes/farmacología , Artritis/tratamiento farmacológico , Inflamación/tratamiento farmacológico , Ácidos Pipecólicos/farmacología , Prolina/farmacología , Animales , Antiinflamatorios no Esteroideos/síntesis química , Antiinflamatorios no Esteroideos/química , Anticolesterolemiantes/síntesis química , Anticolesterolemiantes/química , Anticolesterolemiantes/farmacología , Antioxidantes/síntesis química , Antioxidantes/química , Colesterol/sangre , Modelos Animales de Enfermedad , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Femenino , Ácidos Pipecólicos/síntesis química , Ácidos Pipecólicos/química , Prolina/análogos & derivados , Prolina/síntesis química , Ratas , Ratas Endogámicas F344 , Relación Estructura-Actividad , Triglicéridos/sangreRESUMEN
QSAR studies of a series of blockers of the SK(Ca) channel in guinea-pig hepatocytes suggests that the polarizability of the blocker is an important factor controlling the binding to the channel. It is suggested that, upon binding, an ion-pair is formed, a process that is promoted by the reorganization of the water molecules. The polarizability is not adequate to describe the potency of the most potent blockers with a good stereochemical fit to the channel, presumably due to more specific interactions taking place.
Asunto(s)
Apamina/farmacología , Hepatocitos/fisiología , Canales de Potasio Calcio-Activados/antagonistas & inhibidores , Canales de Potasio Calcio-Activados/química , Animales , Apamina/análogos & derivados , Apamina/química , Cobayas , Hepatocitos/efectos de los fármacos , Cinética , Conformación MolecularRESUMEN
The synthesis, pharmacological evaluation, and molecular modeling studies of unsymmetrical bis-alkylene bis-quinolinium cyclophanes and xylylene-alkylene bis-quinolinium cyclophanes is described. Two important structural features of the pharmacophore for SK(Ca) channel blockade have been identified. These are (i) an optimum distance of ca. 5.8A between the centroids of the pyridinium rings of the two quinolinium groups and (ii) a preference for conformations having the quinolinium groups in a synperiplanar orientation.
Asunto(s)
Apamina/farmacología , Canales de Calcio/efectos de los fármacos , Modelos Químicos , Neuronas/efectos de los fármacos , Quinolinas/farmacología , Sistema Nervioso Simpático/efectos de los fármacos , Estructura Molecular , Neuronas/metabolismo , Quinolinas/química , Sistema Nervioso Simpático/citologíaRESUMEN
The synthesis and pharmacological evaluation of a series of amide derivatives of NSAIDs with L-cysteine ethyl ester is described. The novel derivatives are potent antiinflammatory, antioxidant and hypocholesterolemic-hypolipidemic agents, while they demonstrate considerably reduced gastrointestinal toxicity. This molecular modification may offer a general route to safer antiinflammatory agents, potentially suitable for chronic use in conditions such as neurodegenerative disorders.
Asunto(s)
Amidas/farmacología , Antiinflamatorios no Esteroideos/farmacología , Antioxidantes/farmacología , Cisteína/análogos & derivados , Cisteína/química , Enfermedades Gastrointestinales/inducido químicamente , Amidas/efectos adversos , Amidas/síntesis química , Animales , Antiinflamatorios no Esteroideos/efectos adversos , Antiinflamatorios no Esteroideos/síntesis química , Antioxidantes/efectos adversos , Antioxidantes/síntesis química , Colesterol/sangre , Colesterol/metabolismo , Evaluación de Medicamentos , Lipoproteínas LDL/sangre , Lipoproteínas LDL/metabolismo , Ratones , Ratas , Triglicéridos/sangre , Triglicéridos/metabolismoRESUMEN
We show that doped Mott insulators such as the copper-oxide superconductors are asymptotically slaved in that the quasiparticle weight Z near half-filling depends critically on the existence of the high-energy scale set by the upper Hubbard band. In particular, near half-filling, the following dichotomy arises: Z not equal to 0 when the high-energy scale is integrated out but Z=0 in the thermodynamic limit when it is retained. Slavery to the high-energy scale arises from quantum interference between electronic excitations across the Mott gap. Broad spectral features seen in photoemission in the normal state of the cuprates are argued to arise from high-energy slavery.
RESUMEN
[structure: see text] Three novel halogenated rearranged sesquiterpenes (1-3) have been isolated along with brasilenol (4) and epibrasilenol (5) from the organic extract of the red alga Laurencia obtusa, collected at Symi island in the Aegean Sea, Greece. The new metabolites possess the unusual skeleton of brasilane and contain the unprecedented 1,6-epoxy moiety. The structures of the new natural products, as well as their relative stereochemistry, were established by means of spectral data analyses, including two-dimensional NMR experiments along with molecular calculations.