title: Tricyclic isoxazolines: identification of R226161 as a potential new antidepressant that combines potent serotonin reuptake inhibition and alpha2-adrenoceptor antagonism.
abstract: 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.
authors.affiliation: Johnson & Johnson Pharmaceutical Research & Development, Research & Early Development-EU, CNS-Psychiatry, Division of Janssen-Cilag, Medicinal Chemistry Department, Jarama 75, 45007 Toledo, Spain. iandres@prdes.jnj.com
authors.forename: J Ignacio
authors.initials: JI
authors.lastname: Andrés
authors.forename: Jesús
authors.initials: J
authors.lastname: Alcázar
authors.forename: José M
authors.initials: JM
authors.lastname: Alonso
authors.forename: Rosa M
authors.initials: RM
authors.lastname: Alvarez
authors.forename: Margot H
authors.initials: MH
authors.lastname: Bakker
authors.forename: Ilse
authors.initials: I
authors.lastname: Biesmans
authors.forename: José M
authors.initials: JM
authors.lastname: Cid
authors.forename: Ana I
authors.initials: AI
authors.lastname: De Lucas
authors.forename: Wilhelmus
authors.initials: W
authors.lastname: Drinkenburg
authors.forename: Javier
authors.initials: J
authors.lastname: Fernández
authors.forename: Luis M
authors.initials: LM
authors.lastname: Font
authors.forename: Laura
authors.initials: L
authors.lastname: Iturrino
authors.forename: Xavier
authors.initials: X
authors.lastname: Langlois
authors.forename: Ilse
authors.initials: I
authors.lastname: Lenaerts
authors.forename: Sonia
authors.initials: S
authors.lastname: Martínez
authors.forename: Anton A
authors.initials: AA
authors.lastname: Megens
authors.forename: Joaquín
authors.initials: J
authors.lastname: Pastor
authors.forename: Shirley
authors.initials: S
authors.lastname: Pullan
authors.forename: Thomas
authors.initials: T
authors.lastname: Steckler
mesh_terms: D058669:Adrenergic alpha-2 Receptor Antagonists; D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D007555:Isoxazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D008297:Male; D010080:Oxazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011719:Pyrazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D017367:Selective Serotonin Reuptake Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D058669:Adrenergic alpha-2 Receptor Antagonists; D000929:Antidepressive Agents, Tricyclic; D007555:Isoxazoles; D010080:Oxazoles; D011719:Pyrazines; D017367:Selective Serotonin Reuptake Inhibitors; C521387:R226161