RESUMEN
High-performance liquid chromatography method coupled with tandem mass spectrometry was developed for the quantitative determination of I3,II8-biapigenin. The procedure includes solid-phase extraction and separation on an XTerra MS C18. The assay was linear over a wide range; precision and accuracy were acceptable. Biapigenin was present in mouse and rat plasma after a standardized Hypericum perforatum extract. It was not detected in brain (<5ngg(-1)), suggesting poor brain-to-blood permeability. Biapigenin concentrations were measurable in mice after intraperitoneal biapigenin (10mgkg(-1)) but these amounted to about 2% of the equivalent systemic exposure, after correction for the contribution from residual blood.
Asunto(s)
Apigenina/análisis , Biflavonoides/análisis , Hypericum/química , Animales , Apigenina/farmacocinética , Biflavonoides/farmacocinética , Química Encefálica/efectos de los fármacos , Cromatografía Líquida de Alta Presión , Interpretación Estadística de Datos , Espectroscopía de Resonancia Magnética , Masculino , Ratones , Extractos Vegetales/análisis , Ratas , Estándares de Referencia , Soluciones , Espectrometría de Masa por Ionización de Electrospray , Espectrofotometría Infrarroja , Espectrometría de Masas en TándemRESUMEN
Amentoflavone crosses the blood-brain barrier in vitro but did not inhibit benzodiazepine binding in vivo suggesting poor brain permeability. This prompted us to examine its brain distribution in mice. After Hypericum perforatum and Gingko biloba extracts its brain concentrations were below the limit of quantification. Levels were consistently detected only after intraperitoneal amentoflavone (10 mg/kg), with mean brain-to-plasma ratio of about 0.02. These concentrations were possibly related to the compound's contribution from residual blood, but in any case are too low to support any interaction with central mechanisms so far tested.
Asunto(s)
Biflavonoides/farmacocinética , Ginkgo biloba/química , Hypericum/química , Extractos Vegetales/farmacocinética , Administración Oral , Animales , Biflavonoides/administración & dosificación , Biflavonoides/aislamiento & purificación , Transporte Biológico , Barrera Hematoencefálica/metabolismo , Encéfalo/metabolismo , Inyecciones Intraperitoneales , Masculino , Ratones , Extractos Vegetales/aislamiento & purificación , Distribución TisularRESUMEN
Previous structure-activity relationship studies in the search for a potent, noncompetitive alpha-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) receptor antagonist led to 2,3-dimethyl-6-phenyl-12H-[1,3]dioxolo[4,5-h]imidazo[1,2-c][2,3]benzodiazepine (ZK 187638). However, the first synthesis had some drawbacks regarding reagents, processes, and overall yield, which furthermore decreased when the synthesis was scaled up. Therefore, we now report a new synthetic route for this compound which requires fewer steps and is suited for large-scale production. This compound significantly relieved the symptoms of neuromuscular deficit in mnd mice, a model of neuronal ceroid lipofuscinosis with motor neuron dysfunction. After oral administration, the concentrations of the compound in the brain and spinal cord were about threefold higher than those in the plasma. In summary, this novel AMPA antagonist is accessible through an optimized synthetic route, has good neurobehavioral activity, oral bioavailability, and favorable brain penetration. This opens new possibilities for the treatment of devastating neurological diseases that are mediated by the AMPA receptor.