RESUMEN

The neuropeptide Y2 receptor (Y2 R) is involved in various pathophysiological processes such as epilepsy, mood disorders, angiogenesis, and tumor growth. Therefore, the Y2 R is an interesting target for drug development. A detailed understanding of the binding pocket could facilitate the development of highly selective antagonists to study the role of Y2 R in vitro and in vivo. In this study, several residues crucial to the interaction of BIIE0246 and SF-11 derivatives with Y2 R were investigated by signal transduction assays. Using the experimental results as constraints, the antagonists were docked into a comparative structural model of the Y2 R. Despite differences in size and structure, all three antagonists display a similar binding site, including a deep hydrophobic cavity formed by transmembrane helices (TM) 4, 5, and 6, as well as a hydrophobic patch at the top of TM2 and 7. Additionally, we suggest that the antagonists block Q3.32 , a position that has been shown to be crucial for binding of the amidated C terminus of NPY and thus for receptor activation.

Asunto(s)

Arginina/análogos & derivados , Benzazepinas/química , Benzazepinas/farmacología , Interacciones Hidrofóbicas e Hidrofílicas , Receptores de Neuropéptido Y/antagonistas & inhibidores , Receptores de Neuropéptido Y/química , Animales , Arginina/química , Arginina/farmacología , Sitios de Unión , Células COS , Células Cultivadas , Chlorocebus aethiops , Relación Dosis-Respuesta a Droga , Células HEK293 , Humanos , Simulación del Acoplamiento Molecular , Estructura Molecular , Relación Estructura-Actividad