Tricyclic isoxazolines: identification of R226161 as a potential new antidepressant that combines potent serotonin reuptake inhibition and alpha2-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 alpha(2)-adrenoceptor antagonistic activity. We report now on the synthesis, the in vitro binding potency and the primary in vivo activity of six...

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Published in:Bioorganic & medicinal chemistry 2007-06, Vol.15 (11), p.3649-3660
Main Authors: Andrés, J Ignacio, Alcázar, Jesús, Alonso, José M, Alvarez, Rosa M, Bakker, Margot H, Biesmans, Ilse, Cid, José M, De Lucas, Ana I, Drinkenburg, Wilhelmus, Fernández, Javier, Font, Luis M, Iturrino, Laura, Langlois, Xavier, Lenaerts, Ilse, Martínez, Sonia, Megens, Anton A, Pastor, Joaquín, Pullan, Shirley, Steckler, Thomas
Format: Article
Language:English
Subjects:
Adrenergic alpha-2 Receptor Antagonists
Animals
Antidepressive Agents, Tricyclic - chemical synthesis
Antidepressive Agents, Tricyclic - chemistry
Antidepressive Agents, Tricyclic - pharmacology
Humans
Isoxazoles - chemical synthesis
Isoxazoles - chemistry
Isoxazoles - pharmacology
Male
Oxazoles - chemical synthesis
Oxazoles - chemistry
Oxazoles - pharmacology
Pyrazines - chemical synthesis
Pyrazines - chemistry
Pyrazines - pharmacology
Rats
Rats, Wistar
Serotonin Uptake Inhibitors - chemical synthesis
Serotonin Uptake Inhibitors - chemistry
Serotonin Uptake Inhibitors - pharmacology
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Summary: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.
ISSN:0968-0896