RESUMEN
The introduction of the isoxazole ring as bioisosteric replacement of the acetyl group of anatoxin-a led to a new series of derivatives binding to nicotinic acetylcholine receptors. Bulkier substitutions than methyl at the 3 position of isoxazole were shown to be detrimental for the activity. The binding potency of the most interesting compounds with α1, α7 and α3ß4 receptor subtypes, was, anyway, only at micromolar level. Moreover, differently from known derivatives with pyridine, isoxazole condensed to azabicyclo ring led to no activity.
Asunto(s)
Receptores Nicotínicos/metabolismo , Tropanos/química , Técnicas de Química Sintética , Toxinas de Cianobacterias , Relación Dosis-Respuesta a Droga , Ligandos , Conformación Molecular , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
8-[2-(4-Aryl-1-piperazinyl)ethyl]-2H-1,4-benzoxazin-3(4H)-ones have been identified as highly potent 5-HT(1A/B/D) receptor antagonists with and without additional SerT activity and a high degree of selectivity over hERG potassium channels. Modulation of the different target activities gave compounds with a range of profiles suitable for further in vivo characterization.
Asunto(s)
Benzoxazinas/química , Piperazinas/química , Inhibidores Selectivos de la Recaptación de Serotonina/química , Antagonistas del Receptor de Serotonina 5-HT1 , Antagonistas de la Serotonina/química , Animales , Benzoxazinas/metabolismo , Benzoxazinas/farmacología , Células CHO , Cricetinae , Cricetulus , Canal de Potasio ERG1 , Canales de Potasio Éter-A-Go-Go/antagonistas & inhibidores , Canales de Potasio Éter-A-Go-Go/metabolismo , Humanos , Piperazinas/metabolismo , Piperazinas/farmacología , Ratas , Receptores de Serotonina 5-HT1/metabolismo , Antagonistas de la Serotonina/metabolismo , Antagonistas de la Serotonina/farmacología , Inhibidores Selectivos de la Recaptación de Serotonina/metabolismo , Inhibidores Selectivos de la Recaptación de Serotonina/farmacologíaRESUMEN
The synthesis and the structure activity of a new series of pyrrolo[1,2-a]pyrazine is reported. These molecules are potent and selective non-competitive mGluR5 antagonists and may shed new light on the pattern of substitution tolerated by this receptor.
Asunto(s)
Pirazinas/farmacología , Pirroles/farmacología , Receptores de Glutamato Metabotrópico/antagonistas & inhibidores , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/antagonistas & inhibidores , Fluorescencia , Humanos , Estructura Molecular , Proteínas de Transporte de Noradrenalina a través de la Membrana Plasmática/antagonistas & inhibidores , Pirazinas/síntesis química , Pirroles/síntesis química , Receptor del Glutamato Metabotropico 5 , Relación Estructura-ActividadRESUMEN
The SAR of a new series of tetrahydrocarbazole derivatives is described: the appropriate decoration of this template led to the identification of a new class of NPY-1 antagonists showing good in vitro potency and a promising in vivo pharmacokinetic profile in rat.