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 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.
Andrés
J Ignacio
JI
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
Alcázar
Jesús
J
Alonso
José M
JM
Alvarez
Rosa M
RM
Bakker
Margot H
MH
Biesmans
Ilse
I
Cid
José M
JM
De Lucas
Ana I
AI
Drinkenburg
Wilhelmus
W
Fernández
Javier
J
Font
Luis M
LM
Iturrino
Laura
L
Langlois
Xavier
X
Lenaerts
Ilse
I
Martínez
Sonia
S
Megens
Anton A
AA
Pastor
Joaquín
J
Pullan
Shirley
S
Steckler
Thomas
T
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*
D058669:Adrenergic alpha-2 Receptor Antagonists; D000929:Antidepressive Agents, Tricyclic; D007555:Isoxazoles; D010080:Oxazoles; D011719:Pyrazines; D017367:Selective Serotonin Reuptake Inhibitors; C521387:R226161