RESUMEN
Clarithromycin (active against Gram positive infections) and 1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole derivatives (effective for Gram negative microbes) are the ligands of bacterial RNA. The antimicrobial activities of these benzoxaboroles linked with clarithromycin at 9 or 4â³ position were compared. Two synthetic pathways for these conjugates were elaborated. First pathway explored the substitution of the C-9 carbonyl group of macrolactone's cycle via oxime linker, the second direction used the modification of the 4â³-O-group of cladinose via the formation of carbamates of benzoxaboroles. 4â³-O-(3-S-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborole)-methyl-carbamoyl-clarithromycin showed twofold decrease in MICs for S. epidermidis and S. pneumoniae than clarithromycin. 4â³-O-Modified clarithromycin demonstrated an efficacy against Gram positive strains only. Compounds with C-9 substitution were more active than 4â³-O-substituted antibiotics for susceptible strains E. coli tolC and did not exceed the activity of initial antibiotics.
Asunto(s)
Antibacterianos/farmacología , Compuestos de Boro/farmacología , Claritromicina/farmacología , Compuestos Heterocíclicos/farmacología , Antibacterianos/química , Compuestos de Boro/química , Espectroscopía de Resonancia Magnética con Carbono-13 , Claritromicina/química , Compuestos Heterocíclicos/química , Modelos Moleculares , Espectrometría de Masa por Ionización de ElectrosprayRESUMEN
To examine the cytotoxic activity of congeners of 3-amino-isoquinoline, we performed the phenotypic screening using panel of 60 cell lines and found that (N-(6,7-dimethoxy-1-methyl-isoquinolin-3-yl)-4-{[(1-ethyl-4-methyl-1H-pyrazol-3-yl)methyl]amino}benzamide (4d)) exhibited the significant effect against different tumor cell lines while showing the high activity toward human colorectal cancer HCT-116 cells (IC50 = 18 µm) and human breast cancer T-47D cells (GI50 = 1.9 µm). Virtual screening indicated that these compounds target protein kinases and phosphodiesterases (PDE). However, wet screening among panel of protein kinases did not show any significant activity. By contrast, 50 µm of 4c and 4d inhibited the growth of HKe3-mtKRAS spheroids in the 3D floating (3DF) culture suggesting that 4c and 4d target PDE4B which is selectively upregulated by mtKRAS in 3DF culture.
Asunto(s)
Isoquinolinas/química , Isoquinolinas/farmacología , Inhibidores de Fosfodiesterasa 4/farmacología , Línea Celular Tumoral , Cromatografía Liquida , Simulación por Computador , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Técnicas In Vitro , Isoquinolinas/síntesis química , Espectrometría de Masas , Espectroscopía de Protones por Resonancia MagnéticaRESUMEN
Ten protein kinase C (PKC) isozymes play divergent roles in signal transduction. Because of sequence similarities, it is particularly difficult to generate isozyme-selective small molecule inhibitors. In order to identify such a selective binder, we derived a pharmacophore model from the peptide EAVSLKPT, a fragment of PKCε that inhibits the interaction of PKCε and receptor for activated C-kinase 2 (RACK2). A database of 330 000 molecules was screened in silico, leading to the discovery of a series of thienoquinolines that disrupt the interaction of PKCε with RACK2 in vitro. The most active molecule, N-(3-acetylphenyl)-9-amino-2,3-dihydro-1,4-dioxino[2,3-g]thieno[2,3-b]quinoline-8-carboxamide (8), inhibited this interaction with a measured IC50 of 5.9 µM and the phosphorylation of downstream target Elk-1 in HeLa cells with an IC50 of 11.2 µM. Compound 8 interfered with MARCKS phosphorylation and TPA-induced translocation of PKCε (but not that of PKCδ) from the cytosol to the membrane. The compound reduced the migration of HeLa cells into a gap, reduced invasion through a reconstituted basement membrane matrix, and inhibited angiogenesis in a chicken egg assay.
Asunto(s)
Proteína Quinasa C-epsilon/antagonistas & inhibidores , Quinolinas/farmacología , Receptores de Superficie Celular/antagonistas & inhibidores , Animales , Proliferación Celular/efectos de los fármacos , Embrión de Pollo , Descubrimiento de Drogas , Células HeLa , Humanos , Modelos Moleculares , Fosforilación , Unión Proteica , Proteína Quinasa C-epsilon/química , Inhibidores de Proteínas Quinasas/farmacología , Transporte de Proteínas/efectos de los fármacos , Receptores de Cinasa C Activada , Receptores de Superficie Celular/química , Relación Estructura-Actividad , Proteína Elk-1 con Dominio ets/metabolismoRESUMEN
It was found by virtual screening that 3-amino-1H-pyrazolo[3,4-b]quinolines could have wide protein kinase inhibitory activity. Amides of titled amines and thioureas were synthesized regioselectively. 3-Amino-7-methoxy-1H-pyrazolo[3,4-b]quinoline demonstrated in vitro significant inhibitory activity on bacterial serine/threonine protein kinases (inhibition of resistance to kanamycin in Streptomyces lividans regulated by protein kinases). The studies of Structure Activity Relationship (SAR) showed that the substitution of the NH2 group and 1-NH of pyrazole ring or aromatic ring at the position 6 decreased or removed inhibitory activity.
Asunto(s)
Antibacterianos/farmacología , Mycobacterium smegmatis/efectos de los fármacos , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Pirazoles/farmacología , Quinolinas/farmacología , Streptomyces lividans/enzimología , Acilación , Antibacterianos/síntesis química , Antibacterianos/química , Relación Dosis-Respuesta a Droga , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Proteínas Serina-Treonina Quinasas/metabolismo , Pirazoles/síntesis química , Pirazoles/química , Quinolinas/síntesis química , Quinolinas/química , Estereoisomerismo , Streptomyces lividans/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
The acute effects of ethanol on dopamine (DA) release and clearance in the caudate-putamen were evaluated in wild-type and dopamine transporter (DAT) knockout (DAT-KO) mice, using microdialysis and voltammetry. Dialysate DA levels were elevated, approximately 80% above baseline levels, after administration of 2 g/kg ethanol in both wild-type and DAT-KO mice. In brain slices containing the caudate-putamen, a low (20 mM) concentration of ethanol produced no change in electrically stimulated DA release in either wild-type or DAT-KO mice. A high concentration (200 mM) of ethanol caused a similar decrease in DA release in slices from both types of mice. DA clearance was unaltered across the genotypes at low and high concentrations of ethanol. The fact that ethanol had similar effects in wild-type and DAT-KO mice, measured by in vivo microdialysis or brain slice voltammetry, supports the idea that acute ethanol does not interact with the DAT to produce its effects on the DA system.
Asunto(s)
Depresores del Sistema Nervioso Central/farmacología , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/fisiología , Dopamina/metabolismo , Etanol/farmacología , Neostriado/metabolismo , Animales , Núcleo Caudado/efectos de los fármacos , Núcleo Caudado/metabolismo , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/genética , Electrofisiología , Espacio Extracelular/efectos de los fármacos , Espacio Extracelular/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Microdiálisis , Neostriado/efectos de los fármacos , Putamen/efectos de los fármacos , Putamen/metabolismo , Transmisión Sináptica/efectos de los fármacosRESUMEN
The aim of this research was to study the effect of 12-minute clinical death on innate and acquired behavior, biogenic amine concentration, and the composition and quantity of neural populations in specific brain regions of white rats. The study shows that in animals during the postresuscitation period with formal restoration of neurological status, there are changes in emotional reactivity, orientation-exploration reactions, impairment of learning and memory, decrease in exercise tolerance and pain sensitivity. These processes are accompanied by alterations in serotonin and norepinephrine levels in the frontal cerebral cortex, dopamine and serotonin levels in the striatum, certain biochemical indices in blood plasma and neural loss in the CA1 sector of the hippocampus and lateral portions of the cerebellum.
Asunto(s)
Conducta Animal/fisiología , Paro Cardíaco/complicaciones , Hipoxia-Isquemia Encefálica/psicología , Resucitación/efectos adversos , Animales , Nivel de Alerta/fisiología , Reacción de Prevención/fisiología , Encéfalo/patología , Encéfalo/fisiopatología , Emociones/fisiología , Conducta Exploratoria/fisiología , Paro Cardíaco/fisiopatología , Paro Cardíaco/psicología , Hipoxia-Isquemia Encefálica/fisiopatología , Aprendizaje por Laberinto/fisiología , Actividad Motora/fisiología , Examen Neurológico , Neurotransmisores/análisis , Orientación/fisiología , Umbral del Dolor/fisiología , Esfuerzo Físico/fisiología , Ratas , Valores de ReferenciaRESUMEN
The aim of this research was to study the effect of 12-minute clinical death on innate and acquired behavior, biogenic amine concentration, and the composition and quantity of neural populations in specific brain regions of white rats. The study shows that in animals during the postresuscitation period with formal restoration of neurological status, there are changes in emotional reactivity, orientation-exploration reactions, impairment of learning and memory, decrease in exercise tolerance and pain sensitivity. These processes are accompanied by alterations in serotonin and norepinephrine levels in the frontal cerebral cortex, dopamine and serotonin levels in the striatum, certain biochemical indices in blood plasma and neural loss in the CA1 sector of the hippocampus and lateral portions of the cerebellum (AU)
El propósito de este estudio fue examinar el efecto de una muerte clínica de 12 minutos de duración sobre el comportamiento innato y adquirido, la concentración amino biogénica, y la composición y cantidad de las poblaciones neuronales en regiones específicas en ratas blancas. El estudio muestra que durante el período con restauración formal del estatus neurológico, hay cambios en los animales en la reactividad emocional, las reacciones de orientación-exploración, trastornos de aprendizaje y memoria, reducción de la tolerancia al ejercicio y la sensibilidad al dolor. Estos procesos se acompañan de alteraciones en los niveles de serotonina y no repinefrina en la corteza cerebral frontal, en los niveles de dopamina y serotonina en el cuerpo estriado, ciertos índices bioquímicos en el plasma sanguíneo y pérdida neuronal en el sector CA1 del hipocampo y en porciones laterales del cerebelo (AU)
Asunto(s)
Masculino , Ratas , Animales , Trastornos Psicomotores/etiología , Reanimación Cardiopulmonar/efectos adversos , Monoaminas Biogénicas/análisis , Corteza Cerebral/química , Factores de Tiempo , Cromatografía Líquida de Alta Presión , Células PiramidalesRESUMEN
In this study, fast-scan cyclic voltammetry in brain slices was used to evaluate the effects of acute ethanol on dopamine terminal release and uptake in the nucleus accumbens of C57BL/6 mice. We found that pharmacologically relevant concentrations of ethanol (20 and 100 mM) did not alter electrically evoked dopamine release, while the highest concentration (200 mM) significantly decreased release (approximately 45%). No significant changes were observed in the rate of dopamine uptake after ethanol (20, 100 or 200 mM). In addition, it was established that a moderate dose (2 g/kg, i.p.) of ethanol did not alter the rate of dopamine synthesis, measured as L-dihydroxyphenylalanine (L-DOPA) accumulation. However, a high dose (5 g/kg, i.p.) of ethanol significantly increased the levels of L-DOPA to 60% above the control value. These data are consistent with earlier findings obtained in brain slices from rats; dopamine release, but not clearance, is affected by acute ethanol.
Asunto(s)
Ganglios Basales/efectos de los fármacos , Dopamina/metabolismo , Etanol/farmacología , Neuronas/efectos de los fármacos , Núcleo Accumbens/efectos de los fármacos , Transmisión Sináptica/efectos de los fármacos , Animales , Ganglios Basales/metabolismo , Relación Dosis-Respuesta a Droga , Etanol/administración & dosificación , Cinética , Levodopa/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Modelos Animales , Neuronas/metabolismo , Núcleo Accumbens/metabolismo , Terminales Presinápticos/efectos de los fármacos , Terminales Presinápticos/metabolismoRESUMEN
The synthesis of potent 4-aryl methoxypiperidinol inhibitors of the dopamine transporter is described. Symmetrical para substituents of the benzene rings are important for high potency in binding to the dopamine transporter. 4-[Bis(4-fluorophenyl) methoxy]-1-methylpiperidine has an IC50 of 22.1+/-5.73 nM and increases locomotor activity in mice.
Asunto(s)
Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/antagonistas & inhibidores , Piperidinas/síntesis química , Piperidinas/farmacología , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Concentración 50 Inhibidora , Estructura Molecular , Piperidinas/química , Relación Estructura-ActividadRESUMEN
Diphenylpyraline hydrochloride (DPP) is used clinically as an antihistamine drug, but its neurobiological effects are not completely understood. Voltammetry and microdialysis were used to investigate potential actions of DPP on the dopamine system. Voltammetric monitoring of dopamine signals in mouse nucleus accumbens slices showed that DPP (10 microM) markedly inhibited dopamine uptake. There was a 20-fold increase in apparent Km for dopamine uptake, while Vmax was unchanged. Microdialysis experiments demonstrated that DPP (5 mg/kg, i.p.) elevated extracellular dopamine levels (approximately 200%) in mouse nucleus accumbens. DPP (5 and 10 mg/kg) also induced locomotor activation. All of the effects of DPP were comparable with those of cocaine. Taken together, these results indicate that DPP acts as a competitive dopamine transporter inhibitor similar to cocaine.