RESUMO
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.
Assuntos
Receptores Nicotínicos/metabolismo , Tropanos/química , Técnicas de Química Sintética , Toxinas de Cianobactérias , Relação Dose-Resposta a Droga , Ligantes , Conformação Molecular , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Benzoxazinas/química , Piperazinas/química , Inibidores Seletivos de Recaptação de Serotonina/química , Antagonistas do Receptor 5-HT1 de Serotonina , Antagonistas da Serotonina/química , Animais , Benzoxazinas/metabolismo , Benzoxazinas/farmacologia , Células CHO , Cricetinae , Cricetulus , Canal de Potássio ERG1 , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Canais de Potássio Éter-A-Go-Go/metabolismo , Humanos , Piperazinas/metabolismo , Piperazinas/farmacologia , Ratos , Receptores 5-HT1 de Serotonina/metabolismo , Antagonistas da Serotonina/metabolismo , Antagonistas da Serotonina/farmacologia , Inibidores Seletivos de Recaptação de Serotonina/metabolismo , Inibidores Seletivos de Recaptação de Serotonina/farmacologiaRESUMO
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.
Assuntos
Pirazinas/farmacologia , Pirróis/farmacologia , Receptores de Glutamato Metabotrópico/antagonistas & inibidores , Proteínas da Membrana Plasmática de Transporte de Dopamina/antagonistas & inibidores , Fluorescência , Humanos , Estrutura Molecular , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/antagonistas & inibidores , Pirazinas/síntese química , Pirróis/síntese química , Receptor de Glutamato Metabotrópico 5 , Relação Estrutura-AtividadeRESUMO
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.