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Bioorg Med Chem. 2007 Jun 1;15(11):3649-60. Epub 2007 Mar 21.

Tricyclic isoxazolines: identification of R226161 as a potential new antidepressant that combines potent serotonin reuptake inhibition and alpha2-adrenoceptor antagonism.

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Johnson & Johnson Pharmaceutical Research & Development, Research & Early Development-EU, CNS-Psychiatry, Division of Janssen-Cilag, Medicinal Chemistry Department, Jarama 75, 45007 Toledo, Spain.


In previous articles we have described the discovery of a new series of tricyclic isoxazolines combining central serotonin (5-HT) reuptake inhibition with alpha(2)-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 alpha(2)-adrenoceptor antagonist.

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