Tricyclic isoxazolines: Identification of R226161 as a potential new antidepressant that combines potent serotonin reuptake inhibition and α2-adrenoceptor antagonism

In previous articles we have described the discovery of a new series of tricyclic isoxazolines combining central serotonin (5-HT) reuptake inhibition with α2-adrenoceptor antagonistic activity. We report now on the synthesis, the in vitro binding potency and the primary in vivo activity of six enantiomers within this series, one of which was selected for further pharmacological evaluation and assigned as R226161. Some additional in vivo studies in rats are described with this compound, which proved to be centrally and orally active as a combined 5-HT reuptake inhibitor and α2-adrenoceptor antagonist.

We report on the synthesis, in vitro binding and in vivo activity of R226161, identified within our series of tricyclic isoxazolines as a potential antidepressant combining 5-HT reuptake inhibition and α2 antagonism.Figure optionsDownload as PowerPoint slide